Dopamine (DA) availability for precursor function and peripheral biological action is dependent on synthesis and inactivation enzymes, most of them have been cloned and located. An aromatic acid decarboxylase (AADC) defect has been reported in male homozygotic twins. The syndrome of complete dopamine-β-hydroxylase deficiency with orthostatic hypotension and very high DA contributes to our understanding of the role of DA as a catecholamine with a peripheral biological action of its own. X-linked isolated monoamine oxidase A gene deficiency represents a marked disturbance of monoamine metabolism. The genes of the two major extraneuronal DA-metabolizing enzymes - catechol-O-methyl-transferase and phenolsulfotransferase (PST) - have also been defined. Of particular interest is a bidirectional shuttle system between the PST and sulfatase which have been cloned and located. DA, highly sulfoconjugated via PST, yields DA sulfate which is reconvertible by sulfatase to free DA. A defect of sulfatase catalyzing this process results in a predominance of DA as biologically inactive DA sulfate and so attenuates the DA action. Enzymatic defects of DA synthesis and metabolism are thus genetic modulators of DA action. (Hypertens Res 1995; 18 Suppl. I: S1-S10)

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We sought to determine the molecular identify of the dopamine-1 (D₁) receptor expressed in the porcine renal epithelial cell line LLC-PK₁. We first isolated a partial cDNA by the reverse transcription- polymerase chain reaction procedure and then used the partial cDNA to isolate positive overlapping clones from a porcine genomic DNA library. Sequence analysis of the gene revealed that the longest open-reading frame encoded a 446 amino acid protein that was 95% identical to the human D_1A receptor. Expression studies in mammalian cells were also consistent with the clones encoding a D₁ receptor. Northern blot hybridizations with LLC-PK₁ poly (A⁺) RNA were strongly positive. The porcine D_1A gene has two exons and a short intron in the 5′ untranslated region. The 5′ flanking region lacks a TATA and CAAT box but is high in GC content (68%) and contains multiple Sp1 binding sites. The 5′ flanking region also contains numerous other cis-acting elements for transcription factors. These results indicate that the D_1A receptor is the major D₁ receptor expressed in LLC-PK₁ cells and further suggest that LLC-PK₁ cells may be a useful model to study the regulation of renal D_1A receptor gene transcription. (Hypertens Res 1995; 18 Suppl. I: S11-S17)

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Dopamine receptors are responsible for diverse effects within and outside the central nervous system. The five dopamine receptors that have been cloned (D_1A, D_1B also known as D₅, D₂, D₃, and D₄) belong to two major families; the D₁ like and D₂ like dopamine receptors. The D₁ like receptors are linked to the stimulation while D₂ like receptors are linked to the inhibition of adenylyl cyclase. The physiologic role of the dopamine receptors has been difficult to decipher because several of the subtypes co-exist in the same tissue. However, studies of receptors artificially expressed using transfected cDNA have revealed some of the biochemical mechanisms unique to each dopamine receptor subtype. (Hypertens Res 1995; 18 Suppl. I: S19-S22)

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Combined radioligand binding and light microscope autoradiography techniques were used for investigating the pharmacological profile and the microanatomical localisation of dopamine receptor subtypes in the cardiovascular system and in the kidney. In superior mesenteric and renal arteries the predominant dopamine D₁-like receptor belongs to the D₅ (or D_1b) subtype. This site is located within smooth muscle of the tunica media. The same receptor subtype predominates in the kidney, where it has a vascular and tubular localisation. The dopamine D₂-like receptor subtype expressed by systemic arteries belongs to the D₂ receptor subtype. It has a prejunctional and endothelial localisation. In the kidney the predominating dopamine D₂-like receptor belongs to the dopamine D₃ subtype. Atria but not ventricles express dopamine D₂-like receptors belonging to the D₄ receptor subtype. The above results suggest that in spite of the emerging complexity of the dopamine receptor profile demonstrated by molecular biology techniques, radioligand binding and autoradiographic techniques, if performed with appropriate radioligands and/or in the presence of compounds active on specific receptor subtypes, may represent a useful tool for better understanding the biological significance of peripheral dopamine receptors. (Hypertens Res 1995; 18 Suppl. I: S23-S27)

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The modulation of dopamine DA₁ receptors of cultured rat renal arterial smooth muscle cells by phorbol ester, glucocorticoid and sodium chloride was studied. The extent of [³H]Sch-23390 binding to phorbol ester-treated cell was increased without any change in the dissociation constant (K_d). At a concentration of 10nmol/l, the synthetic glucocorticoid dexamethasone increased maximum receptor binding (B_max) but had no effect on the K_d. 100mmol/l sodium chloride did not change B_max, but increased the K_d for DA₁ receptor. The production of cAMP in response to DA₁ receptor stimulation was enhanced without any change of the adenylate cyclase activity. The glucocorticoid effect on DA₁ of arterial smooth muscle cells became apparent after hours of incubation in the presence of the steroid and was significantly inhibited by cycloheximide (10μg/ml) and by the glucocorticoid receptor antagonist RU- 38486, indicating that the effect required protein synthesis through glucocorticoid receptors. Treatment of cells with 1μmol/l dexamethasone for 24h increased basal and DA₁-stimulated adenylate cyclase activity. Basal adenylate cyclase was decreased by sodium chloride in a dose-dependent manner. These results suggest differential control of DA₁ receptors on vascular smooth muscle cells by protein kinase C, glucocorticoid or sodium chloride. (Hypertens Res 1995; 18 Suppl. I: S29-S33)

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Mechanical responses to dopamine of isolated human and monkey veins were isometrically measured and compared to those of the arteries. Human gastroepiploic and monkey mesenteric veins responded to dopamine with contractions, whereas the arteries in the same region responded with relaxations. Treatment with phentolamine converted the venous contraction to a relaxation, which was not influenced by propranolol but was abolished by droperidol. The relaxation was endothelium-independent and converted to a contraction by SCH23390 but unaltered by domperidone. Dopamine increased the cyclic AMP content in the human veins. Monkey vena cava and portal vein did not respond to dopamine with relaxation even under α-adrenoceptor blockade. It is concluded that primate veins and arteries from the gastric and mesenteric regions respond quite differently to dopamine; the α-adrenoceptor-mediated contraction predominates over the relaxation mediated via D₁-receptor in the veins, and vice versa in the arteries. In monkey large veins, dopamine receptor does not appear to play a functional role. The veno- constrictor action of dopamine, together with actions on myocardium and rresistance vessels, would contribute to increasing of the cardiac output. (Hypertens Res 1995; 18 Suppl. I: S35-S37)

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Dopamine is an endogenous catecholamine which exerts its actions by occupancy of specific receptors. Dopamine receptors are classified into two main groups: the two cloned D₁-like receptors (D_1A and D_1B in rats; D_1B is also known as D₅ in humans) are linked to stimulation of adenylyl cyclase, while the three cloned D₂-like receptors (D₂ or D_2A, D₃ or D_2B, D₄ or D_2C) are linked to inhibition of adenylyl cyclase. All these dopamine receptors originally cloned from the brain are expressed in tissues outside the central nervous system including the kidney. Dopamine regulates many cellular activities, including transmembrane ion transport. Activation of D₁-like receptor decreases sodium transport by cAMP dependent and cAMP independent mechanisms. Dopamine, via D₁-like receptors, may inhibit Na⁺/H⁺ exchange activity in renal brush border membranes by a cAMP independent/G_sα-linked mechanism. Another cAMP independent pathway of sodium transport inhibition is mediated by phospholipase C, which has several isoforms (PLCβ, PLCγ, and PLCδ with several members in each). Catecholamines stimulate expression and activity of phospholipase C isoforms in a concentration, time, and receptor-dependent as well as regional and subcellular compartmental-specific manner. In renal cortical membranes, intrarenal administration of norepinephrine for 3-4h increases PLCβ expression and activity but has no effect on PLCγ activity. In contrast, intrarenal administration of a D₁ agonist for 3-4h increases PLCβ₁ but decreases PLCγ expression and activity. In membranes from LTK^- cells transfected with the rat D_1A receptor cDNA, D₁ receptor stimulation initially increases and then in 4h decreases PLCγ expression and activity, similar to the results found in renal cortical membranes. The initial increase of PLCγ expression and activity due to D₁ receptors is mediated by protein kinase A. (Hypertens Res 1995; 18 Suppl. I: S39-S42)

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Renal proximal tubular Na, K-ATPase plays an important role in the maintenance of sodium homeostasis and it is known that dopamine (DA) exerts an inhibitory effect on the activity of this enzyme. We have found that DA-induced inhibition of Na, K-ATPase is abolished in the spontaneously hypertensive rats (SHR) in comparison with age-matched Wistar-Kyoto (WKY) rats. Dopamine inhibits Na, K-ATPase via phospholipase C coupled protein kinase C pathway. The enzyme protein kinase C subsequently causes inhibition of Na, K-ATPase. In the SHR, DA-induced activation of phospholipase C is diminished, which in turn is responsible for the abolished inhibition of Na, K-ATPase. We have now shown that DA-induced activation of protein kinase C, which results from activation of DA-1 receptors is also abolished in the SHR which would account for the failure of DA to inhibit Na, K-ATPase in the hypertensive animals. Recently, we have examined the possibility that the failure of DA to inhibit Na, K-ATPase activity may be related to abnormal expression of DA receptors. In radioligand binding studies with [³H] SCH 23390 as a DA-1 receptor ligand and [³H] spiroperidol as a DA-2 receptor ligand we showed that both [³H] SCH 23390 and [³H] spiroperidol bindings are best fit to one site model in either WKY or SHR. Both B_max and K_D of either ligand binding to proximal tubule in the SHR were not statistically different from their WKY counterparts. Therefore, these results show that failure of DA to inhibit Na, K-ATPase activity in the SHR is most likely due to a defective coupling of DA-1 receptor to its G protein on the basolateral membrane, but not due to abnormal expression of DA receptors. (Hypertens Res 1995; 18 Suppl. I: S43-S46)

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The present work examines the possibility of whether the reciprocal effects of dopamine (DA) and 5-hydroxytryptamine (5-HT) are only dependent on the antagonistic nature of the signal resulting from the activation of their specific receptors or may also result from a competitive type of inhibiton at different levels of the synthetic and metabolic pathways shared by DA and 5-HT. Studies performed in isolated proximal convoluted tubules (PCT) have shown that L-5-HTP and L-DOPA use the same transporter in order to be taken up into the cell and both L-DOPA and L-5-HTP exert a competitive type of inhibition upon their cellular uptake. The decrease in the formation of 5-HT in isolated PCT induced by L-DOPA reflects most probably a reduction in the intracellular availability of L-5-HTP. However, in experiments conducted in homogenates of PCT L-DOPA was found to be a better substrate for AAAD than L-5-HTP. Appart from sharing a common synthetic pathway, DA and 5-HT also share a common metabolic pathway; type A monoamine oxidase (MAO-A), the predominant form of MAO in rat renal tissues, converts DA into 3, 4-dihydroxyphenylacetic acid (DOPAC) and 5-HT into 5-hydroxyindolacetic acid (5-HIAA). However, in contrast to 5-HT, DA can be metabolized by MAO-B and catechol-O-methyltransferase. Inhibition of MAO-A was found to produce a 2-fold increase in the urinary excretion of 5-HT; this increase in the urinary excretion of 5-HT was accompanied by an unexpected reduction in the urinary excretion of DA. It is possible that the increased availability of 5-HT might have compromised the ability of the DA outward transfer to extrude the amine into the urine. Depending on the degree of sodium loading, the increased urinary excretion of 5-HT during MAO-A inhibition is accompanied by antinatriuresis and increased urine osmolality. This antinatriuretic effect does not appears to be due to a reduction on the availability of DA, but to result from an increased availability of 5-HT. In fact, this antinatriuretic effect can be antagonized in a concentration dependent manner by the selective 5-HT_1A receptor antagonist (+) WAY 100135, but not by ketanserin. It is possible that stimulation of Na⁺-K⁺-ATPase might be relevant for the antinatriuretic effect of endogenous renal 5-HT, in contrast to the inhibitory effects of DA on the enzyme. In fact, we have recently found that the 5-HT_1A receptor agonist 8-OH-DPAT increases Na⁺-K⁺-ATPase activity with a EC₅₀ value of 355nM; this effect can be antagonized by (+) WAY 100135 with a IC₅₀ value of 20nM. It is possible, therefore, to conclude that the nature of the antagonistic effects of DA and 5-HT in renal tissues does not only depends on the reciprocal effects related to the activation of their specific receptors, but has also to do with the availability of their amino acid precursors and the ability of the amines to leave the cellular compartment. (Hypertens Res 1995; 18 Suppl. I: S47-S51)

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The pathophysiological role of renal natriuretic depressor systems and endogenous digitalis like factor (EDLF) on blood pressure (BP) elevation was studied in reduced renal mass rats (RRM) with saline loading for a model of volume dependent hypertension. Fifty-four male Sprague-Dawley rats were operated on to remove varying proportions of their kidney mass (5/6RRM, n=13; 4/6 RRM, n=16; 3/6 RRM, n=12) or sham operated (control, n=13). They were given 1% saline to drink for 4 weeks. BP was elevated significantly at the 1st week in 5/6 RRM and continued to increase until the 4th week, but this was not seen in the other 3 groups. Urine volume (UV) and urinary sodium excretion (UNaV) increased after saline loading in all groups. Urinary kallikrein excretion was significantly lower in order of the 5/6, 4/6 and 3/6 RRM at the basal state and after saline loading. A significant negative correlation was observed between urinary kallikrein and BP. Urinary PGE₂ was increased in each RRM in order of the 5/6, 4/6 and 3/6 RRM groups. A significant positive correlation was observed between urinary PGE₂ and BP, UV or UNaV. The basal urinary DA excretion was significantly lower in 3 RRMs than in the control. After saline drinking, urinary DA increased in 3 RRMs, while differences disappeared in the control and RRMs. Urinary EDLF increased immediately after the initiation of saline loading in all groups, except the control group, and returned to the basal level 2 weeks later in 3/6 and 4/6 RRM. Only in 516 RRM, the urinary EDLF remained higher than the basal level. A significant positive correlation was found between urinary EDLF and BP or UNaV. From these observations, it was suggested that 1) in 5/6 RRM, EDLF has an important role in the pathogenesis of hypertension, 2) suppressed renal kallikrein-kinin system may have something to do with the BP elevation, and 3) renal PGE₂ and DA systems may act to compensate for sodium retention and BP elevation. (Hypertens Res 1995; 18 Suppl. I: S53-S57)

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Although aldosterone (Aldo.) secretion is regulated by various humoral factors, evidence has accumulated to support an involvement of dopaminergic system in its regulation. The pathophysiological significance of the dopaminergic system in primary aldosteronism (PA) however remains unknown. In the present study, we examined the effects of metoclopramide (MCP) on Aldo. secretion in normal subjects (n=11) and patients with essential hypertension (EH, n=8), aldosterone-producing adenoma (APA, n=10), and idiopathic hyperaldosteronism (IHA, n=6). Plasma Aldo., prolactin (PRL), renin, cortisol, serum sodium, and serum potassium levels were determined before and 30min after i.v. bolus injection of 10mg MCP at 9 a.m. Plasma Aldo. showed a significant increase after MCP in normal subjects, EH, and APA, but not in IHA. The incremental response of plasma Aldo. was largest in APA and smallest in IHA. The percentage increase in plasma Aldo. from the basal level was significantly attenuated in IHA, while no significant difference was seen among other groups. Although plasma PRL showed a significant increase in response to MCP, no difference of the change was seen among the groups. There was no significant change in plasma cortisol, renin, serum sodium, and serum potassium levels in response to MCP. In addition, the response of Aldo. to MCP was normalized in APA after unilateral adrenalectomy, while that of PRL did not change. These results indicate that the adrenal dopaminergic activity is enhanced in APA and attenuated in IHA and suggest an involvement of the dopaminergic system in the pathogenesis of IHA. The MCP challenge test could be an useful diagnostic tool for the differential diagnosis of subsets of PA. (Hypertens Res 1995; 18 Suppl. I: S59-S64)

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Dopamine (DA) is the most abundant catecholamines in human plasma and exists mostly in the sulfoconjugated form (DA sulfate), a biologically inactive metabolite. The paucity of unconjugated DA (PDA) in plasma throws doubt on its physiological significance. However, PDA, when measured with a highly sensitive radioenzymatic method, showed quite different features from norepinephrine and epinephrine in some types of clinical hypertension, lower in essential hypertension and higher in primary aldosteronism and pheochromocytoma. There was a weak but significant correlation between the values of PDA and DA sulfate measured in the same specimens, but DA sulfate was more susceptible to impaired renal function. Upright posture, high salt diets and an intravenous injection of metoclopramide (MCP, 10 mg), a DA receptor antagonist, induced a slight but significant increase in PDA in normal and hypertensive subjects. An intravenous dexamethasone (2mg) caused a gradual increase in PDA over 150min after medication, which was completely blocked by concomitant administration of α-methyl-p-tyrosine, a tyrosine hydroxylase inhibitor. The responses of PDA to both high salt diets and MCP were blunted in salt-sensitive patients with uncomplicated essential hypertension. The results suggest that DA is not only a precursor of norepinephrine biosynthesis but also plays an inherent role as an active neurotransmitter in the peripheral sympathoadrenal system, and that PDA is a sensitive marker of peripheral dopaminergic activity, which may operate to modulate the cardiovascular and endocrine functions and participate in the pathogenesis of some types of hypertension. (Hypertens Res 1995; 18 Suppl. I: S65-S72)

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Physical exercise is one of the life-style modifications used for lowering blood pressure. Except for diminished norepinephrine spill over, the mechanism by which physical exercise exerts its effects was not known. Based on our preliminary finding that the reduction of blood pressure was inversely correlated to the baseline plasma renin activity, we have consequently revealed that mild exercise reduces plasma volume and hence the cardiac index. In order to elucidate the mechanism, we have investigated all possible parameters relevant to plasma volume regulation. Among them, urinary free dopamine and urinary active kallikrein increased in the early stages (weeks 2-4) while atrio-natriuretic factor (week 4) and endogeneous ouabain-like substance (EOLS) consequently (weeks 7-10) decreased. Serum taurine increased and plasma norepinephrine decreased in the late stages. The conclusion reached is that mild exercise seems to first activate the renal dopamine and kallikrein systems and second trigger other mechanism, such as an increase in taurine and decreases in EOLS and norepinephrine. (Hypertens Res 1995; 18 Suppl. I: S73-S77)

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Dopamine (DA) is synthesized and secreted in central as well as peripheral nervous system and in the adrenal medulla. Neuronal DA receptors, which have been characterized as D2 receptors, mediate an inhibition of adenylate cyclase and are located prejunctionally on sympathetic nerve endings and on chromaffin cells. Their pharmacological activation causes an inhibition of in vitro and in vivo norepinephrine (NE) release from sympathetic nerve terminals and an inhibition of in vitro epinephrine (E) release from the adrenal medulla. Endogenous DA, co-secreted with the other catecholamines (CA), modulates sympathetic-adrenal discharge only during high sympathetic stimulation through an autocrine mechanism, limiting excessive sympathetic adrenal discharge. Also pheochromocytoma cells synthesize and express D2 receptors. In patients with pheochromocytoma D2 antagonists cause hypertensive crises but the mechanism mediating this effect is still unknown as well as whether endogenous DA might modulate tumoral secretion. (Hypertens Res 1995; 18 Suppl. I: S79-S86)

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Although free and conjugated dopamine (DA) constitute most of the plasma and urine catecholamine pool, the diagnostic significance of DA estimation for the evaluation of illness is not clear. We evaluated the clinical utility of DA estimation by measuring free and conjugated DA in patients with various illness. Patients with adrenal insufficiency did not show decreases in DA concentrations but did demonstrate reductions in free and conjugated plasma adrenaline (Ad). Patients with established stage of essential hypertension exhibited decreased plasma concentrations of free and conjugated DA, although they were hyperadrenergic. In patients with chronic renal insufficiency and failure, the free DA concentration in the urine decreased depending on the severity of renal impairment. Conversely, plasma concentrations of conjugated DA are higher in patients with chronic renal failure than in normal subjects. The high plasma concentrations of conjugated DA decreased dramatically following hemodialysis and renal transplantation. Urinary free DA excretion increased markedly following renal transplantation. In conclusion, the estimation of the free and conjugated DA in plasma and urine is clinically useful for the diagnosis of adrenal insufficiency, essential hypertension, and renal insufficiency and failure. It also can be used to monitor the effectiveness of hemodialysis and renal transplantation. (Hypertens Res 1995; 18 Suppl. I: S87-S92)

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In mammals, the sympathetic neurotransmitter is norepinephrine (NE), and the main adrenomedullary hormone is epinephrine (EPI). The sources and physiological roles of the third endogenous catecholamine, dopamine (DA), outside the brain have been obscure. Several lines of evidence suggest that in the periphery, rather than DA serving only as the precursor for the active compounds, released from sympathetic nerves and the adrenal medulla, DA may also act as an autocrine/paracrine regulator of local organ function. Thus, in the kidneys, most of DA formation appears to be from proximal tubular uptake of plasma DOPA, and binding of locally formed DA to dopaminergic receptors decreases Na/K ATPase activity and thereby accentuates natriuresis. In the gastric mucosa, DA may modulate sodium absorption and acid secretion. Recent clinical and laboratory animal evidence has indicated that the lungs and mesenteric organs contribute substantially to total body production and metabolism of DA. Generation of DA in non-noradrenergic, non-adrenergic cells can explain why human urine contains higher concentrations of DA and its metabolites than of NE and its metabolites. The vast preponderance of plasma DA in humans is sulfoconjugated. Since patients with sympathoneural failure have normal plasma levels of DA sulfate, one may speculate that the sulfoconjugating mechanism is relatively independent of sympathetic nerves and acts to localize DA effects and inactivate DA entering the circulation. These considerations lead to the concept of a third peripheral catecholaminergic system, where DA derived from plasma DOPA acts as an autocrine/paracrine substance and is inactivated by conjugation. (Hypertens Res 1995; 18 Suppl. I: S93-S99)

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Sulfoconjugated catecholamines have been regarded simply as metabolites of free catecholamines. However, a conjugated form of the catecholamine, dopamine has recently attracted much attention because it is present at high levels in the plasma of humans and experimental animals. We carried out experimental and clinical studies to determine the physiological significance of this large amount of dopamine conjugate in the plasma. Clinical studies showed that the plasma level of dopamine sulfate decreased significantly during the acute phase of heart failure, whereas that of free dopamine increased. Moreover, the plasma level of conjugated dopamine in patients with essential hypertension was higher than that in control subjects, and being highest in patients with renal hypertension. In experimental studies, we examined the activity for deconjugating DA sulfate in homogenates of organs from dogs. The kidney and liver exhibited the highest activities, and in the heart, the activity was higher in the atrium than the ventricle. We also examined the effect of dopamine sulfate on isolated perfused rat heart. Dopamine sulfate was found to be converted to free dopamine, which was responsible for the positive isotropic action, in atrial tissue. Moreover, deconjugation of DA sulfate to the free form was accelerated by a high work lord on the heart. From these results, we conclude that the formation of dopamine sulfate plays a role in regulating the level of plasma free dopamine and that plasma dopamine sulfate may be a storage or reserve form of dopamine. Free (or active) dopamine may be formed through a deconjugation reaction when necessary. (Hypertens Res 1995; 18 Suppl. I: S101-S106)

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Close relations exist between the peripheral dopaminergic system, and the sympathetic nervous and renin-angiotensin-aldosterone system: D1 dopamine receptor stimulation-induced vasodilation may activate the sympathetic nervous and renin-angiotensin system in vivo, presynaptic D2 dopamine receptor stimulation is known to inhibit stimulated norepinephrine release from sympathetic nerve terminals, in experimental conditions both in vitro and in vivo. Endogenous dopamine has a tonic inhibitory effect on aldosterone release. Conversely, basal sympathetic activity has been found to be required for the natriuretic effect of dopamine in proximal renal tubules. Other relations include the conversion of dopamine to other catecholamines, and co-release. This review considers the reflection of some of these relations and their clinical significance in man in physiological and pathophysiological conditions, especially congestive heart failure. An inhibitory effect of the nonselective dopamine agonist ibopamine on plasma norepinephrine levels was found in normal man during exercise but not at rest, and in patients with several degrees of congestive heart failure, both at rest and during exercise. Infusions of dopamine 1 μg/kg/min, but not 3μg/kg/min were found to lower plasma norepinephrine levels during sympathetic stimulation by exercise or by a cold pressor test in normal man. Dopamine antagonists enhance the rise in plasma norepinephrine levels during exercise, indicating that endogenous dopamine also inhibits norepinephrine release. Both phentolamine and prazosin abolish the natriuretic effects of dopamine in man, even when the renal hemodynamic effect of dopamine is unaffected. In conclusion, it is important to be aware of clinically significant interactions between the peripheral dopaminergic and sympathetic nervous system at different levels. (Hypertens Res 1995; 18 Suppl. I: S107-S111)

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The DA prodrug γ-L-glutamyl-L-dopa (gludopa) has a high degree of renal selectivity with 2-step conversion to DA in the kidney. The effects of gludopa, with and without DA-2 receptor blockade, on renal and total noradrenaline (NA) Spillover, were studied in two groups of rabbits. Eight rabbits received gludopa infusion (25 and 100μg/kg/min and 8) received an infusion of gludopa and DA-2 receptor antagonist, YM-09151 (50μg/kg i.v.). Renal and total NA spillover rates were measured by ³H-NA tracer method before and after gludopa infusion. Brain NA, DA, gludopa and L-dopa content were measured after gludopa infusion in 5 rabbits; control values for tissue catecholamine and drug levels were obtained in 5 untreated rabbits. Gludopa infusion markedly increased kidney DA content (300-fold) and DA excretion (6000-fold) but had little effect on plasma DA. It produced a dose-related fall in mean (±SEM) renal NA spillover (21.6±3.7 to 10.6±2.7, 7.2±2.7ng/min, p<0.01). Even greater falls were observed in total NA spillover after gludopa (43.1±10.2 to 19.7±3.4, 9.4±1.8ng/min, p< 0.01). DA-2 receptor antagonism had no influence on the effects of gludopa on either renal or total NA spillover. Significant amounts of gludopa were detected in the brain after drug infusion (0.28±13nmol/g brain tissue). Gludopa, a putative renal selective dopamine prodrug with effects mediated via DA-1 receptors also significantly inhibits both renal and extra-renal NA spillover. This effect is not a DA-2 effect but may be mediated centrally. (Hypertens Res 1995; 18 Suppl. I: S113-S118)

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Several studies have suggested that dopamine (DA) plays a major role in cardiovascular functions. Dopaminergic receptors have been found on sympathetic nerve terminals (DA2), kidney (DA1, DA2), vascular smooth muscle (DA1) as well as on sympathetic ganglia (DA1, DA2) and adrenal gland (DA1, DA2). Previous studies have shown that DA2 receptor stimulation by a specific DA2 agonist, quinpirole (1) elicits a peripheral depressor action (decreased blood pressure) and a central pressor component involving an increase in both sympathetic tone and vasopressin release and (2) does not affect under in vivo conditions adrenal catecholamine release. The present study investigates the effects of fenoldopam, a specific DA1 receptor agonist on both cardiovascular responses and catecholamine release from the adrenal medulla. In conscious normal dogs, fenoldopam (10, 20 and 40μg/kg i.v.) elicited a decrease in blood pressure and a marked increase in heart rate associated with a rise in plasma catecholamine levels. The increase in heart rate is only due to baroreflex mechanism since fenoldopam (conversely to DA2 receptor agonists like quinpirole) does not exert a central excitatory component (as shown by the absence of cardiovascular effects after intracisternal injection). Moreover, in sinoaortic denervated dogs (i.e. animals deprived from baroreflex pathways), the decrease in arterial blood pressure was more important than in normal dogs. Heart rate was unchanged. In these animals, DA1 stimulation induced a decrease in sympathetic tone, as shown by the significant fall in plasma noradrenaline levels. These "in vivo" data clearly demonstrate the inhibitory role of ganglionic DA1 receptors. In anesthetized dogs, fenoldopam (5μg/kg/min i.v.) failed to modify catecholamine release from the adrenal medulla whatever the stimulation frequencies (1, 3 and 5Hz) of the sectioned splanchnic nerve. Thus, using DA agonists (DA1: fenoldopam or DA2: quinpirole see above), we failed to demonstrate any potential role of adrenal dopamine receptors in the control of catecholamine release under in vivo conditions. Since in vivo studies carried out in normal subjects with domperidone, a DA2 receptor antagonist, suggest a modulatory role for adrenal DA receptor during high sympathetic stimulation induced by physical exercise, we further investigate in anesthetized dogs the effects of DA antagonists on adrenal catecholamine release. After blockade of alpha and beta adrenergic receptors, we found that haloperidol (1mg/kg i.v.) elicited an increase in noradrenaline release from the adrenal medulla. In conclusion, the use of appropriate experimental models in dogs (sinoaortic denervation, chronic implanted intracisternal cannula and in vivo catheterism of adrenal vein) allows us to demonstrate (1) that the stimulation of ganglionic DA1 receptors induced a decrease in noradrenaline release due to the inhibition of ganglionic transmission and (2) that, under in vivo conditions, the blockade of DA receptors by haloperidol allows to reveal the inhibitory role of adrenal DA receptors on the release of adrenal catecholamines. (Hypertens Res 1995; 18 Suppl. I: S119-S124)

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In the present study we tried to clarify the differences of the cardiovascular and renal responses to feeding in relation to the peripheral dopamine system. In control subjects (C), ingestion of protein (100g) induced an increase in Ccr accompanied by an increase in tubular sodium excretion (FENa+). Patients with non-insulin dependent diabetic (NIDDM), a protein-induced increase in Ccr was comparable to that in C, while FENa+ did not change following protein. Since an increase in urinary 3, 4-dihydroxyphenylacetic acid was blunted in NIDDM, an impaired natriuretic response to high protein may be results from an insufficient synthesis of renal dopamine. Plasma dopamine and its metabolites in NIDDM following protein tended to be greater than in C. Protein induced a greater decrease in blood pressure (BP) in NIDDM, but no increase in pulse rate was observed. An ordinary diet containing 10g of protein also induced a decrease in BP. A reflex tachycardia was observed in C and normotensive NIDDM but not in hypertensive one. In normotensive NIDDM, plasma dopamine and norepinephrine increased after the diet, while in hypertensive NIDDM there were no increases in catecholamines. From these results it is suggested that the relatively elevated peripheral dopaminergic activity and the blunted dopamine synthesis in the kidney may be responsible for the abnormal cardiovascular and renal responses to feeding in patients with NIDDM. (Hypertens Res 1995; 18 Suppl. I: S125-S130)

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Both insulin-dependent diabetes mellitus (IDDM) and unilateral nephectomy (UNX) are associated with an increase in the glomerular filtration rate. Glomerular hyperfiltration has been linked to intraglomerular hypertension in both conditions, although it has only been linked to the development of nephropathy in diabetes. In this study, we examined the possibility of preventing diabetic nephropathy through early dopamine (DA) prodrugs treatment and we also investigated the participation of endogenous DA in the acute functional adaptation of the remaining kidney after UNX. In an animal model of IDDM (steptozotocin-treated Wistar rats), the early increase in the glomerular filtration rate was prevented by treatment with DA prodrugs (L-dopa or gludopa), an effect which was mimicked by fenoldopam (a D1 agonist) and suppressed by carbidopa and SCH 23390 (a D1 antagonist). An increase in endorenal DA synthesis and the subsequent stimulation of vascular D1 receptors appears to prevent early glomerular hyperfiltration in diabetic rats. However, in a long-term study lasting more than one year, streptozotocin-diabetic Wistar rats (unlike to diabetic Munich Wistar rats) failed to develop overt nephropathy characterized by albuminuria and systemic hypertension. During long-term treatment of diabetic rats with L-dopa, the renal availability of DA was diminished. The acute adaptation of the remaining kidney to UNX took the form of an early transient pressor effect with a moderate increase in the glomerular filtration rate and renal blood flow, and a marked decrease in tubular sodium reabsorption. SCH 23390 suppressed the hemodynamic and tubular responses to UNX, suggesting that endogenous DA plays a key role. (Hypertens Res 1995; 18 Suppl. I: S131-S136)

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We reported a novel intracellular mechanism of renal Na-K-ATPase regulation by dopamine (DA) in the rat cortical collecting duct (CCD), which involves stimulation of protein kinase A (PKA) and phospholipase A₂ (PLA₂). In the present experiments we determined whether this mechanism also operates in other nephron segments. In the medullary thick ascending limbs (MTAL), DA and other cAMP agonists inhibited Na-K-ATPase activity, an effect that was abolished by PKA inhibitor IP₂₀, but various protein kinase C (PKC) activators did not, analogous to our previous findings in CCD. In sharp contrast, DA inhibition on Na-K-ATPase in the proximal convoluted tubule (PCT) was reproduced by PKC agonists. These effects was blocked by PKC inhibitor staurosporine, but not by IP₂₀. Mepacrine, a PLA₂ inhibitor, reversed the pump effect of all agents, and arachidonic acid (AA) produced a dose-dependent pump inhibition, in all three nephron segments.
We conclude that the intercellular mechanisms of Na-K-ATPase regulation by dopamine differ in the proximal and distal nephron, as they involve stimulation of PKA in MTAL and CCD, and of PKC in PCT. These two pathways probably share a common mechanism in stimulating PLA₂ and AA release in both regions of the nephron. (Hypertens Res 1995; 18 Suppl. I: S137-S140)

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The present study was performed in order to examine the effects of dopamine (DA) on renin release and to clarify which subtype of DA receptor, DA₁ or DA₂ contributes to renin release. Male Wistar rats aged seven weeks were used. Glomeruli were isolated by the modified Beierwaltes' sieving method and were transferred to a sealed chamber and superfused with Krebs-Ringer solution. In the first experiment, the changes in renin release induced by DA and the effects of a non-selective DA antagonist, haloperidol and a β antagonist, propranolol on DA-induced renin release were examined. In the second experiment, the effect of a DA₂ receptors antagonist, spiperone and of a DA₁ receptor antagonist, SCH-23390 on renin release were investigated. Basal levels of renin release were 2.46± 0.36ng ATI/h/10⁴ glomeruli (mean±SEM). DA caused a dose-dependent increase in renin release. The renin release induced by DA was inhibited by haloperidol but not by propranolol. The maximum level of renin release induced by 10^-5M DA was 4.13±0.63ng ATI/h/10⁴ glomeruli. SCH-23390 at 10^-5M caused significant suppression of DA-induced renin (p<0.05). In contrast, 10^-5M spiperone failed to suppress DA-induced renin release. These results suggest that DA induced renin release from isolated glomeruli through the DA₁ receptors. (Hypertens Res 1995; 18 Suppl. I: S141-S143)

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Renal and total dopamine (DA) spillover rates at rest were measured in 25 conscious rabbits with chronically implanted renal vein catheters. Renal DA spillover rate was calculated from veno-arterial difference in plasma free DA concentrations across the kidney corrected by the fractional extraction of infused ³H-DA. Plasma free DA concentrations were 11.0±2.7pg/ml in the artery and 14.3±3.6 in the renal vein. Renal and total DA spillover rates were 0.51±0.08, 2.61±0.30ng/min, respectively, both of which were significantly (p<0.001) lower than the respective norepinephrine (NE) spillover rates (renal: 16.3±1.4, total: 39.6±1.7). The fractional extraction of ³H-DA across the kidney (55±3%) and the total DA clearance (285±31ml/min) were both significantly (p<0.05) higher than that of ³H-NE (45±3) and the total NE clearance (198±9), respectively. The ratio of renal to the total spillover rate of DA 0.23±0.05) was significantly (p<0.05) lower than that of NE (0.41±0.04). These results demonstrate that DA is released into plasma within the kidney and suggest that the measurement of renal DA spillover rate using ³H-DA radiotracer technique is useful to detect resting reenal dopaminergic nerve activity. (Hypertens Res 1995; 18 Suppl. I: S145-S146)

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Dopamine (DA) has been shown to be an endogenous catecholamine that promotes natriuresis by activating tubular DA receptors, but its role on natriuresis appears to be equivocal, and the precise mechanisms and signaling pathway of multiple DA's receptor subtypes are not yet clarified. We used low dose of DA intravenously in saline (S) volume-expanded dogs to see the alterations in natriuresis. The results showed that there is a critical dose that induces no enhacement of natriuresis of volume expansion, and that the lower and higher doses of DA produced relatively larger natriuresis. Pretreatment of metoclopramide (MCP) in this settings caused even higher and significant increases of natriuresis. In conclusion, DA seems to determine tonically the level of natriuresis in saline-expanded dogs. DA may exert a dual effect on signal transduction pathways such that one leading to antinatriuretis with high affinity and the other to natriuresis with low affinity signaling cascades for DA. MCP may block the antinatriuretic limb of the signaling pathway. (Hypertens Res 1995; 18 Suppl. I: S147-S150)

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Catecholamine contents of human, rabbit and rat pulmonary vasculature were surveyed. Human pulmonary vasculature was obtained from lobectomized specimens of lung tumors. Catecholamines were measured by high performance liquid chromatography after aluminum extraction. High dopamine (DA) content (1.4nmol/g wet weight) and high DA/noradrenaline (NA) ratio (17.9%) were observed in rabbit pulmonary arterial trunks. In rabbit pulmonary arterial brunches, DA content was 0.26nmol/g wet weight and DA/NA ratio was 4.2% . In rat, NA contents were less in intra-and extra-pulmonary arteries (1.5 and 4.0nmol/g wet weight, respectively) compared with pulmonary vasculature of rabbit or with the other vasculatures of the same animals. DA contents were 1.9 and 1.8nmol/g wet weight in intraand extra-pulmonary arteries, respectively, and DA/NA ratios were markedly high (218 and 48%, respectively). On the other hand, DA/NA ratios were around 1% in human intrapulmonary arteries and that for large-sized (more than 2mm in diameter) intrapulmonary vein was 8.5%. Species difference and regional difference among pulmonary vascular beds are evident and at least in human pulmonary artery, DA/NA ratio is not as high as rabbit and rat pulmonary arteries. (Hypertens Res 1995; 18 Suppl. I: S151-S152)

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The pharmacological profile and the anatomical localisation of dopamine receptor subtypes were investigated in the rabbit pulmonary vascular bed using combined radioligand binding and light microscope autoradiography techniques. Dopamine D₁-like receptor sites, which probably belong to the dopamine D₁ receptor subtype, were characterized in sections of lung using [³H]-SCH 23390 as a ligand. These sites were located within the tunica intima and the tunica media of large sized intrapulmonary artery branches and in the tunica media of medium sized intrapulmonary artery branches. Dopamine D₂-like receptor sites, which probably belong to the dopamine D₂ receptor subtype, were characterized using [³H]-spiroperidol as a ligand. These sites were located within the tunica adventitia of both extra- and intrapulmonary artery branches. Dopamine D₂-like receptor sites were also found in the tunica adventitia of the human pulmonary artery, but not of the rat pulmonary artery. The different anatomical localization of dopamine D₁ and D₂ receptor subtypes in the pulmonary vasculature suggests that these sites are involved in the modulation of pulmonary vascular tone by interacting with different receptors unevenly distributed throughout the pulmonary vascular bed. (Hypertens Res 1995; 18 Suppl. I: S153-S156)

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We examined the electrophysiological effects of dopamine on the single myocardial cells isolated from the rat and rabbit heart. Dopamine at a concentration of 1 or 10μM did not affect the L-type Ca²⁺ current (I_Ca) or the transient outward current (I_TO) in rat ventricular, rabbit atrial, ventricular, and sinoatrial node cells. It did not induce any detectable change in the action potential configuration of the rabbit ventricular cells either. We conclude that dopamine does not directly act on myocardial cells at least in terms of the electrophysiological properties. (Hypertens Res 1995; 18 Suppl. I: S157-S159)

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To elucidate whether increased plasma levels of free dopamine (F-DA) after exercise are due to deconjugation of sulfoconjugated (S-) DA in plasma, we compared the changes in plasma F- and S-DA, as well as changes in both the S- and F- forms of epinephrine (E) and norepinephrine (NE), after running a half-marathon. Free catecholamines (F-CAs) were measured by automated high-performance liquid chromatography (HPLC). Total (F+S) CAs were determined using an efficient deconjugation method as follows; 1200μl plasma was incubated with 152mU arylsulfatase (AS) for 30min at pH 7.6. The plasma levels of F-CA (pg/ml) (mean±SEM) all increased significantly (p<0.01) after the half-marathon: i.e., F-DA increased from 13.3±5.7 to 176.3±32.2; F-E from 58.0±12.3 to 764.3±136.4; F-NE from 246.6±15.2 to 3082.0±690.3. Of S-CAs, S-E (from 127.8±26.0 to 1218.2±190.8) and S-NE (from 717.1±61.6 to 5586.9±761.9) also increased, but, in contrast, among the S-CAs, only the increase in S-DA (from 5324.9±1967.3 to 7359.6±1627.9) was not statistically significant. Sulfoconjugation may play an important role in inactivating F-DA as well as F-NE and -E, that are released into plasma in response to vigorous exercise. Thus, plasma F-DA is unlikely to be derived through deconjugation of plasma S-DA. (Hypertens Res 1995; 18 Suppl. I: S161-S163)

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In order to estimate the role of the sympatho-adrenal system as a trigger in cardiovascular mortality risk after L-DOPA administration in patients with Parkinsons disease we performed the following experiments in normotensive Wistar-Kyoto-rats (WKY) and spontaneously hypertensive rats (SHR). L-DOPA was given orally in increasing doses (30, 100, 300mg/kg b.w.). Haemodynamic parameters (BP, HR) were measured by tail cuff plethysmography and catecholamine concentrations in tissues assayed by high pressure liquid chromatography. Stressful situations were induced by experimental myocardial infarction. After administration of L-DOPA a dose-dependent increase in blood pressure in both WKY and SHR was observed with a prolongation in SHR. Significantly increased concentrations of dopamine in the hearts were measured in both strains. Noradrenaline stores in the heart of WKY were more filled than in the heart of SHR. Only in SHR high adrenaline concentration in the adrenal medulla were measured after L-DOPA administration. Circulating adrenaline concentrations were significantly enhanced after myocardial infarction in WKY and could be further elevated by pretreatment with L-DOPA. From the results obtained it is concluded that L-DOPA administration in WKY and SHR leads to exaggerate synthesis and massive release of catecholamines and in consequence to an enhanced cardiovascular mortality risk due to cardiotoxicity of catecholamines. It can be extrapolated that increased cardiovascular mortality risk seen in Parkinson patients treated with L-DOPA and benzerazide is probably associated with increased synthesis and release of catecholamines during stressful situations. (Hypertens Res 1995; 18 Suppl. I: S165-S168)

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The effect of pituitary adenylate cyclase-activating polypeptide_1-38 (PACAP_1-38) on the synthesis of dopamine in cultured bovine adrenal chromaffin cells was examined. PACAP_1-38 stimulated [¹⁴C]dopamine synthesis from [¹⁴C]tyrosine, in a concentration-dependent manner, causing maximal stimulation at 10^-7M. This stimulatory action of PACAP_1-38 was not significantly inhibited by staurosporine (an inhibitor of protein kinase C) or in the cells in which protein kinase C was down-regulated by prolonged exposure to TPA (an activator of protein kinase C), whereas it was partially attenuated in Ca²⁺-free medium. PACAP_1-38 increased the formation of [³H] inositol phosphates, [Ca²⁺]i, ⁴⁵Ca²⁺ uptake and cAMP level. The peptide also stimulated the phosphorylation of tyrosine hydroxylase, the enzyme catalyzing the rate-limiting step in dopamine synthesis. Dopamine synthesis and tyrosine hydroxylase phosphorylation stimulated by the maximal effective concentration of dibutyryl cAMP or high K⁺, which activates Ca²⁺ uptake, were further enhanced by PACAP_1-38. These results indicate that PACAP_1-38 may stimulate the activities of cAMP- and calcium-dependent protein kinases in cultured bovine adrenal chromaffin cells, resulting in increase in the synthesis of dopamine probably by stimulation of phosphorylation of tyrosine hydroxylase. (Hypertens Res 1995; 18 Suppl. I: S169-S171)

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Characterization of dopamine (DA) receptor subtypes was examined on the canine exocrine pancreas using selective DA receptor agonists and antagonists in anesthetized dogs. Each drug was injected i.a. in a single bolus fashion. Graded doses of DA (0.01-3μmol) produced dose-dependent increases in the secretory rate of pancreatic juice, with a maximum effect at approximately 1μmol. SCH23390 (3-30nmol), a selective D-1 DA receptor antagonist, caused a progressive parallel shift to the right in the dose-response curve for DA-induced pancreatic secretion without changes in the maximal response. However, domperidone (3μmol), a selective D-2 DA receptor antagonist, did not antagonize the DA-induced pancreatic exocrine secretion. A Schild analysis of the data indicates that the inhibitory constant value for SCH23390 to inhibit DA-stimulated secretion was 6.9nmol. In addition, the stimulatory effects of SKF38393 (0.1-10μmol) and YM435 (0.3-30nmol), selective D-1 DA receptor agonists, and LY171555 (1-10μmol), a selective D-2 DA receptor agonist, on pancreatic secretion were demonstrated. The rank order of agonist potency was YM435>DA>SKF38393_??_LY171555. These results suggest that DA-induced pancreatic exocrine secretion is mediated by activation of D-1 DA receptors. (Hypertens Res 1995; 18 Suppl. I: S173-S174)

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The effects of Levodopa on autonomic nervous system (ANS) were investigated through the measurement of blood pressure (BP) and heart rate (HR) variability in 15 de novo parkinsonian who never received dopaminergic drugs. BP and HR were obtained using digital photoplethysmography in supine and standing positions. Measurements were achieved 90min after administration, in a double blind cross-over way, of placebo or levodopa (200mg)+benserazide (50mg). Spectral analysis was performed using fast Fourier transformation (FFT) on 512 consecutive SBP and HR values. Spectral modulus was integrated for calculation of total spectra and of low frequency (LF: 66-129mHz) or high frequency band (HF: respiratory frequency±50mHz). After placebo, orthostatism was followed by a significant increase in BP and HR whereas relative variabilities in LF and HF remained unchanged. After Levodopa, BP was significantly lower in supine position without changes in HR and LF. During orthostatism, changes observed in BP and in FFT were similar to those observed during placebo period. These data indicate that levodopa reduces supine and standing BP but does not impair orthostatic adaptation. This effect is not due to modification of BP or HR variability and appears to independant of any direct effect on ANS. (Hypertens Res 1995; 18 Suppl. I: S175-S177)

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Peripheral dopamine (DA) synthesis and release increase during hypertensive stage of spontaneously hypertensive rats (SHR). DA is generated from 3, 4-dihydroxyphenylalanine by L-amino acid decarboxylase (AADC). We have studies urinary DA and DA metabolites and the gene expression of neuron and non-neuron specific AADC mRNA in the kidney of SHR. Compared to Wister-Kyoto rats (WKY), there was an increased urinary free DA and DOPAC excretions in 8 and 12 week-old SHR. At the age of 16 weeks, the difference in free DA excretion between SHR and WKY rats disappeared, although the urinary DOPAC excretion remained significantly higher in SHR, but urinary HVA excretion did not differ from WKY rats. The expression of the neuron specific AADC mRNA in the kidney of SHR and WKY rats was not detected, but the non-neuron specific AADC mRNA in the kidney of SHR and WKY rats was detected. The gene expression of the non-neuron specific AADC mRNA tended to decrease with age in SHR. The results suggest that a decrease in renal DA production with age may be caused by diminished expression of non-neuron specific AADC mRNA in kidney. (Hypertens Res 1995; 18 Suppl. I: S179-S181)

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Baseline dihydroxyphenylalanine (DOPA) and dopamine (DA), their respective sulfates as well as oral DOPA administration-induced changes were compared in age- and blood pressure-matched hypertensive patients without and with moderate chronic renal failure (CRF) and control subjects. The only common feature of both hypertensive groups was a defective DA generation from DOPA. Hypertensive patients with moderate CRF were distinct from those without, having increased basal concentrations of plasma DOPA and DA sulfates. After oral DOPA administration, plasma and urinary DOPA sulfate rose while renal DA sulfate clearance was decreased. Possible enzymatic defects contributing to CRF-induced increases of DOPA and DA sulfates and their potential role in perpetuating renal failure via glomerular hypertension are discussed. (Hypertens Res 1995; 18 Suppl. I: S183-S185)

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The effect of chronic salt loading (10g of NaCl for a period of 7 days) on urinary dopamine release has been investigated in 3 groups of beagle dogs: normotensive dogs (group 1: n=7), and 2 groups of dogs made hypertensive by chronic sinoaortic denervation [group 2: (n=6) during the first 4 months after sinoaortic denervation i.e. a model of arterial hypertension with high levels of plasma catecholamines and group 3: (n=6) one year after denervation i.e. a model of arterial hypertension with normal sympathetic tone]. In normal dogs (group 1), salt loading induced an increase in urinary dopamine excretion during the two first days after salt loading. The rise in urinary dopamine was blunted in group 2. It was not observed in group 3. Salt loading failed to change arterial pressure and heart rate in the three groups of animals. These data show an alteration of the renal dopaminergic system in hypertensive sinoaortic denervated dogs suggesting that a dopaminergic impairment can appear during the development of arterial neurogenic hypertension. (Hypertens Res 1995; 18 Suppl. I: S187-S190)

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We investigated whether urinary excretion of free dopamine is related with the humoral factors which affect Na⁺, K⁺ ATPase activity in the kidneys. Subjects were 51 adults admitted in a hospital without renal insufficiency: they were divided into normotensive (n=36, 60±3 years old, 122±3/73±2mmHg) and hypertensive groups (n=15, 65±5 years old, 157±6/91±2mmHg). Urinary excretion of free dopamine was significantly and positively correlated with urinary excretion of C-peptide immunoreactivity of insulin (CPR) (r=0.451, p=0.014) in normotensive subjects, but not in hypertensive subjects (r= 0.155, p=0.668). Urinary excretion of endogenous digoxinlike substances (EDLS) was also significantly and positively correlated with urinary CPR (r=0.500, p=0.006) in normotensive subjects, but not in hypertensive subjects (r=0.275, p=0.363). In normotensive subjects, urinary excretion of free dopamine and EDLS may be regulated at least in part by insulin secreted endogenously. In hypertensive subjects, however, this regulatory mechanism of the diuretic factors, such as insulin, EDLS and dopamine, is thought to be deranged, which might result in decompensation of a diuretic and antidiuretic balance leading to blood pressure elevation. (Hypertens Res 1995; 18 Suppl. I: S191-S192)

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To clarify the role of renal dopaminergic activity in patients with primary aldosteronism (PA), urinary excretion of free dopamine (DA) and the conversion ratio of DA from 1-dopa in the kidney were investigated in 8 patients with PA and 10 normotensive subjects (NT). All subjects were hospitalized and received a standard diet (Na 120mEq, K 75mEq/day) and 2h renal clearance test was performed. Plasma l-dopa concentration (p-DOPA), creatinine clearance (Ccr), urinary excretion of sodium (UNaV) and DA (uDA) as well as fractional excretion of sodium (FENa) were measured. No significant difference was found in UNaV or FENa between NT and PA, or between before and after adrenalectomy (Adx) in PA. UDA was significantly higher in PA than NT, and decreased significantly after Adx. There was no difference in the product of Ccr×p-DOPA between NT and PA, or between before and after Adx in PA. The ratio of uDA/(Ccr×p-DOPA) was significantly higher in PA than NT. After Adx this ratio decreased significantly to the normal range. These results suggest that (1) renal dopaminergic activity is augmented and contributes to the escape phenomenon in PA, and (2) augmented renal DA production in PA might be caused by an increase of conversion to DA from l-dopa at the renal proximal tubules. Hypertens Res 1995; 18 Suppl. I: S193-S195)

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To investigate the peripheral dopaminergic modulation in the pathogenesis of human hypertension, we examined the responses of plasma free dopamine (DA) to dexamethasone (Dx) administration, which is suggested to activate dopaminergic activity. We administered Dx 2mg intravenously to patients with primary aldosteronism (PA), essential hypertension (EH), and normotensive controls (NT). Plasma free DA was increased significantly in all groups and the responses were more remarkable in PA than in EH and NT. Plasma epinephrine (E) showed a gradual increase while plasma norepinephrine (NE) tended to decrease in all groups. The responses of both plasma DA and E were completely blocked by 250mg of α-methyl-p-tyrosine, a tyrosine hydroxylase (TH) inhibitor, suggesting that Dx may stimulate peripheral dopaminergic activity by increasing catecholamine synthesizing enzyme (probably TH) activities. These data suggest that DA itself plays an inherent role in the sympathoadrenal regulation rather than only as a precursor of NE and that dopaminergic hyperresponses may be involved in the pathophysiology of PA. (Hypertens Res 1995; 18 Suppl. I: S197-S198)

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In order to elucidate the role of noradrenergic and dopaminergic activity in the pathogenesis of postprandial hypotension, the effect of feeding of ordinary diet on blood pressure, pulse rate, plasma catecholamine and other circulating vasoactive substances such as insulin were examined in mild essential hypertensive patients (EH) and their age-matched control subjects (N). Mean blood pressure significantly decreased in both N and EH after feeding, and the decrease tended to be greater in EH than in N. Feeding induced a marked increase in plasma norepinephrine in both N and EH. Plasma dopamine significantly increased following feeding was observed in N, while the increase in plasma dopamine following feeding was blunted in EH. The ratio of norepinephrine to dopamine following in EH was significantly greater than that in N. From these results, it is suggested that the feeding-induced stimulation of noradrenergic activity may be a result from the decrease in blood pressure, and that the blunted response of dopaminergic activity in EH may reflect the enhanced conversion of dopamine to norepinephrine probably due to the enhanced activity of dopamine β-hydroxylase in the sympathetic nerves. (Hypertens Res 1995; 18 Suppl. I: S199-S200)

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To elucidate the hormonal mechanisms of blood pressure (BP) reduction during hemodialysis in patients with chronic renal failure (CRF), we performed this study using 7 normotensive (NT) and 17 hypertensive (HT) patients who were strictly matched in age, body weight, body weight gain from the last HD, and duration of HD. Blood pressure, pulse rate, plasma norepinephrine (NE), and plasma dopamine levels were used as indices of sympathetic nerve activity, before, at 50% of hemodialysis (HD) and at 100% of HD (at the end of HD) on the third day after the last HD. As hemodialytic BP reduction was defined as BP decline of more than 10% in pre-HD mean BP, in normotensive patients with CRF, hemodialytic BP reduction was recognized in 0/7 (0%) at 50% of HD and 4/7 (57%) at 100% of HD, and in hypertensive patients it was recognized in 3/17 (18%) at 50% of HD and 4/17 (24%) at 100% of HD. Percentile changes in plasma NE levels increased slightly following hemodialysis in normotensive patients with hemodialytic BP reduction and in hypertensives without BP rreduction, while those in normotensives without BP reduction and in hypertensives with BP reduction did not change. However, percentage changes in plasma dopamine (DA) levels decreased significantly at the end of HD (NT; p<0.05, HT; p<0.01) following hemodialysis in both normotensive and hypertensive patients with hemodialytic BP reduction, while changes in patients without BP reduction, percentage changes in DA did not change (patients with BP reduction vs. patients without BP reduction). In conclusion, hemodialytic BP reduction may be predisposed by abnormal sympathetic nerve responsiveness. (Hypertens Res 1995; 18 Suppl. I: S201-S203)

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Although dopamine (DA) has an important role also outside the central nervous system, the physiological significance of DA in the peripheral plasma is not clearly known. In the present study, we assayed the levels of free and total (free plus conjugated) DA in the human plasma to examine the effect of posture, age and some pathophysiological conditions. Nine healthy volunteers were subjected for head up tilt study. For the examination of the effect of age and some pathophysiological conditions, venous blood samples were taken after overnight fast in 64 control subjects who have no obvious disease and patients who had essential hypertension or congestive heart failure (CHF). The plasma free adrenaline (AD), noradrenaline (NA) and DA were determined by a HPLC-diphenylethylenediamine method and total DA was determined by the same HPLC method after acid hydrolysis. After tilting neither free nor total DA changed significantly despite the increased plasma AD and NA levels. Plasma free NA, DA and total DA levels were correlated positively with age in control subjects but not in the hypertensive nor CHF patients. Patients with CHF showed higher levels of plasma free AD, NA and DA and freeDA/totalDA ratio than did in control subjects. We suspect that plasma DA increased with age partially due to change in renal catecholamine handling and cardiac function. (Hypertens Res 1995; 18 Suppl. I: S205-S207)

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Neuroblastoma (NB) is a tumor which arises from neural crest cells. In the developing neural crest cells, the induction of 3, 4-dihydroxyphenylalanine (DOPA) decarboxylase is more delayed than that of tyrosine hydroxylase and dopamine-β-hydroxylase. If NB cells are arrested in an early stage of neural crest development, the induction of DOPA decarboxylase is insufficient and the accumulation and secretion of DOPA can be caused. The biochemically immature phenotype is thought to represent the undifferentiated characteristics of the cells and might correlate with the grade of malignancy. To investigate whether the hypothesis is clinically applicable or not, we have measured plasma DOPA, dopamine and urinary catecholamine metabolites in NB patients. The levels of plasma DOPA, dopamine, urinary homovanillic acid (HVA) and vanillactic acid (VLA) were significantly higher in patients with unfavorable NBs and the higher plasma DOPA level was significantly associated with the patients' age (>1 year old), tumor stage (III, IV) and DNA diploidy. Serial determination of plasma DOPA was a good monitor of the disease course. These results are compatible with the hypothesis on DOPA decarboxylase deficiency and DOPA secretion in undifferentiated, unfavorable NBs. In conclusion, the plasma DOPA can be used to predict patients' prognosis as well as to follow up patients with NB. (Hypertens Res 1995; 18 Suppl. I: S209-S210)

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Docarpamine is a dopamine prodrug which has been selected from a large number of dopamine derivatives in order to develop an orally effective dopamine. The pharmacokinetics and metabolism after oral administration of docarpamine were studied in rats and dogs. The maximum concentration of free dopamine in plasma after oral administration of docarpamine to rats and dogs was 13 and 4-6 times, respectively, higher than those of dopamine (DA). In the first pass metabolism study in dogs, the main metabolic pathways after oral administration of docarpamine were catechol ester hydrolysis in the small intestine, and amide hydrolysis and conjugation in the liver. Conversion rates from docarpamine to DA in various rat tissue homogenates were in the order of the liver > small intestine > blood. The concentrations of DA conjugate and 3, 4-dihydroxyphenylacetic acid in plasma after oral administration of DA to dogs were higher than those of docarpamine. This result indicates that protected groups of the docarpamine molecule suppress the first pass metabolism of orally administered dopamine. In conclusion, the findings of this study suggest that docarpamine can be used as an oral dopamine prodrug. The main first pass metabolism after oral administration of docarpamine are catechol ester hydrolysis in the small intestine, and amide hydrolysis and conjugation in the liver. Free dopammine, which is a pharmacologically active form, is mainly produced in the liver. (Hypertens Res 1995; 18 Suppl. I: S211-S213)

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The present experiments were undertaken to clarify the difference of renal dopamine production from β₁-selective β-blocker with and without intrinsic sympathomimetic activity (ISA). Either β-blocker with ISA, celiprolol (100 or 300mg/kg/day; CEL-100 or CEL-300) or β-blocker without ISA, atenolol (50 mg/kg/day; ATE-50) was administered to the SHR from 19 to 26 weeks. Degrees of lowering blood pressure in CEL-300 SHR and in ATE-50 SHR were similar, but decrease in heart rate was significantly less in CEL-300 SHR than in ATE-50 SHR. Urine output, which was significantly less in control SHR than in control WKY, was significantly greater in CEL-100 SHR and CEL-300 SHR, but not in ATE-50 SHR. Urinary excretions of noradrenaline (u-NA) and dopamine (u-DA) were significantly higher in control SHR than in control WKY and a comparable u-DA/u-NA ratio was found in these two groups. U-DA and the ratio of u-DA/u-NA were significantly elevated in CEL-100 SHR and CEL-300 SHR, but not in ATE-50 SHR. There was a significant positive correlation between u-DA/u-NA ratio and urine output and a significant negative correlation between the ratio of u-DA/u-NA and change of blood pressure in control SHR, CEL-100 SHR and CEL-300 SHR. These results suggest that an enhancement of renal dopamine production by ISA (β₂ stimulation) of β₁-selective β-blocker may contribute, at least in part, to the antihypertensive effect of this drug. (Hypertens Res 1995; 18 Suppl. I: S215-S219)

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The effect of dopamine 1 and 3μg/kg/min i.v., of dopamine 1 and 3μg/kg/min i.v. combined with domperidone 30mg per os and of placebo infusion on plasma norepinephrine concentration before and during sympathetic stimulation by a cold pressor test was investigated in 10 healthy volunteers (1 female, 9 males, mean age 28, range 19-41). Dopamine 1μg/kg/min resulted in a blunting of the rise in plasma norepinephrine concentration during the cold pressor test, compared with placebo infusion. The addition of domperidone to dopamine 1μg/kg/min abolished this effect. Plasma norepinephrine levels during dopamine 3μg/kg/min infusion, both with and without domperidone, were not different from placebo, but significantly higher compared to dopamine 1μg/kg/min infusion. Dopamine 1 and 3μg/kg/min infusion, both with and without domperidone resulted in a blunted increase in blood pressure compared to placebo infusion. Dopamine 1μg/kg/min infusion resulted in a lower systolic blood pressure during the cold pressor test compared to dopamine 3μg/kg/min infusion. No significant changes in heart rate occurred during the cold pressor test comparing the different circumstances. We conclude that in healthy volunteers only dopamine 1μg/kg/min, but not dopamine 3μg/kglmin, blunts the increase in plasma norepinephrine concentration during a cold pressor test; this effect is abolished by pretreatment with domperidone. We presume that for dopamine 1μg/kg/min the inhibitory effects of presynaptic DA-2 receptor or α-2 adrenoceptor stimulation on plasma norepinephrine concentration predominate. When dopamine 3μg/kg/min is infused, the inhibitory effects might be counteracted by uptake-1 inhibition or enhanced synthesis and release of norepinephrine, either directly or indirectly. (Hypertens Res 1995; 18 Suppl. I: S221-S224)

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