To investigate the mechanism of exercise-induced ST elevation in previous anterior myocardial infarction, exercise body surface mapping was performed on 22 patients with anterior myocardial infarction. ST elevation was compared with the findings of exercise radionuclide ventriculography and exercise thallium-201 myocardial perfusion imaging. ST-segment was quantified by the integral of ST-segment voltage. The maximal value of ST segment integral out of the 87 leads on the body surface was defined as ST max. The percent of change in ST max after exercise was closely correlated to the decrease in ejection fraction (r=-0.76). Furthermore, 9 of the 12 patients with increased ST max after exercise had exercise-induced regional wall motion abnormalities mainly i the apical and anterolateral segments, while other 10 patients without increased ST max did not (p < 0.01). There was no difference in % change of ST max a) between anterior reversible defect (+) group and the (-) group ; b) between inferior reversible defect (+) group and the (-) group ; c) between single vessel (isolated left anterior descending artery stenosis) group and the multivessel group. This fact indicated that exercise-induced ST elevation did not result from the exercise-induced myocardial ischemia of the infarctional segment or the remote non-infarctional segment. We concluded that exercise-induced ST elevation in previous anterior myocardial infarction is mainly due to the aggravation of anterior wall motion abnormalities induced by exercise.

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To clarify the relationship of pulmonary function with differing severity of atrial septal defect (ASD) and to assess the effects of pulmonary hemodynamics on these functions, we classified 101 patients with adult ASD by their pulmonary arterial mean pressure (PAm) and pulmonary blood flow (Qp), and compared details of pulmonary functions between pairs of groups. Classification was by drawing lines at the PAm of 20 mmHg and the Qp of 10 L/min. Group I was the low pressure-low flow group, Group II the low pressure-high flow group, Group III the high pressure-low flow group, and Group IV the high pressure-high flow group. Vital capacity as the percentage of predicted (%VC) was low in Group III and IV. There were no significant differences in the ratio of forced expiratory volume in one second to forced vital capacity (FEVl%), flow at 25% forced vital capacity and colsing volume as the percentage of predicted (%V25, %CV/VC) between each group. Both maximum midexpiratory flow rate and flow rate at 50% forced vital capacity as the percentage of predicted (%MMEF, %V50) in Group III with the most severe ASD, were significantly low. Pulmonary diffusing capacities for carbon monoxide as the percentage of predicted (%DLco) exceeded 100% in all groups, and tended to decrease with increases of PAm without relation to Qp. Pulmonary dysfunctions in adult ASD were mainly due to restrictive changes accompanied by obstructive change in proportion to the decrease of VC. Peripheral airway obstructions are mild in ASD and these might be caused by lower pressure of left atrium and no existence of pulmonary venous congestion in ASD, even in the most severe group.

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The cardiac content and plasma concentration of atrial natriuretic polypeptide (ANP) in hypertensive rats were measured by using radioimmunoassay for ANP. The animals used in this study were young (5-week-old) and adult (12- to 14-week-old) spontaneously hypertensive rats (SHR), strokeprone SHR (SHR-SP) and normotensive control Wistar-Kyoto rats (WKY). Most immunoreactive ANP in the cardiac extract of the hypertensive rats (both SHR and SHR-SP) was found to be predominantly γ-form as well as that of WKY. Cardiac ANP content in adult SHR and SHR-SP was significantly lower than in adult WKY (p < 0.01), although there were no differences among three groups in young rats. Similar tendencies were also observed for plasma ANP concentration. The level of plasma in adult hypertensive rats was significantly lower or tended to be lower than in adult normotensive rats. Furthermore, a high negative correlation was present between blood pressure and cardiac ANP content (r=-0.748, p <0.01) and between blood pressure and plasma ANP concentration (r=-0.608, p < 0.01) in all adult rats but there were no such relationships in young rats. The present study suggests that atrial natriuretic polypeptide may contribute to the pathogenesis or maintenance of high blood pressure in the genetic hypertensive rats.

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A sensitive assay method to evaluate the inhibitor of Na⁺, K⁺-ATPase in human urine was developed by measuring the inorganic phosphate liberated from ATP in vitro using Na⁺, K⁺-ATPase from porcine cerebral cortex. Ouabain inhibited the Na⁺ K⁺-ATPase by competing with the potassium ion (an apparent Ki= 2.6 ± 0.89 × 10^-8 M, n=8) under the condition of 100 mM NaCl, 4.5 mM MgSO₄ and 0.56 mM ATP. The apparent Km value of KCl was 0.4 mM. Factors inhibiting Na⁺, K⁺-ATPase were detected in the post-salt fraction on Sephadex G-15 chromatography following the ethanol extraction of lyophilized fresh urine of sodium loaded human subjects (300 meq Na⁺/day, for 4 days) with essential hypertension. Two active fractions around the 400 daltons following salt were eluted on Sephadex G-15 chromatography. The slower eluted factor competed kinetically with potassium ion, but the inhibitory activity was lost within two days during storage at 4°C. The faster-eluted inhibitor lost its activity within a day. These results indicate that the unstable inhibiting factors of Na⁺, K⁺-ATPase exist in human urine and one of these factors inhibits ouabain sensitive Na⁺, K⁺-ATPase by binding to the potassium binding site (or very close to it), which exists at the outer surface of the cell membrane of this enzyme.

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Thirty hypertensive patients were studied during a low-sodium diet for three days and high-sodium diet for six days. They were classified as "salt-sensitive" (SS) (n=10) or "non-salt-sensitive" (NSS) (n=20) based on the increase in mean blood pressure (BP) with changes in sodium intake from 25 mEq/day to 250 mEq/day (14.7 ± 1.3% versus 4.0 ± 0.8%, p < 0.001). With the high-sodium diet, the SS patients had a greater increase in cardiac output (p < 0.001) and the increment in mean BP with the salt loading significantly correlated to that in cardiac output (r=0.672, p < 0.01). Thus, the increase in BP during short-term salt loading may be attributed to the increase in cardiac output. The role of renal hemodynamics in the increment of BP with salt loading after sodium restriction was evaluated in six SS and 14 NSS patients. Although the glomerular filtration rate was not different in the two groups, the renal vascular resistance was greater (p < 0.05) in the SS patients than in the NSS ones. Moreover, renal vascular resistance positively correlated to the increment in mean BP with salt loading (r=0.612, p < 0.01). Thus, it is suggested that renal vasoconstriction may be an important factor influencing salt-sensitivity in essential hypertension, possibly via the impaired renal sodium excretion.

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Baroreflex control of heart rate, pressor responses to α agonist (phenylephrine) and isometric exercise before and during salt loading were compared between 13 normotensive subjects with hypertensive relatives (group A) and 9 normotensive subjects with no family history of hypertension (group B). Baroreflex slope was significantly lower in group A than in group B (9.6 ± 1.6 vs 17.6 ± 1.9 msec/mmHg ; p < 0.01), although blood pressure, heart rate and aortic distensibility were not different between two groups. Pressor responses to phenylephrine and isometric exercise were identical for both groups. During salt loading, pressor responses to phenylephrine and isometric exercise were significantly greater in group A than in group B. Baroreflex slope was not affected by salt loading in the two groups. These results suggest that baroreflex control of heart rate is impaired in normotensive young subjects with hypertensive relatives and this defect may be inherited rather than the result of elevated arterial pressure and decreased aortic distensibility. Pressor responses to agonist and isometric exercise during high-sodium diet were augmented in subjects with a family history of hypertension.

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The role of the renal nerve in influencing the hypothalamo-sympathetic nerve system to regulate the cardiovascular system was studied in normotensive Wistar and spontaneously hypertensive rats (SHR). Renal denervation attenuated pressor and sympathetic nerve responses to electrical stimulation of the hypothalamus without lowering the basal blood pressure at 48 hours after denervated operation. These findings suggest that renal denervation could inhibit the hypothalamo-sympathetic nerve system in normotensive rats. The development of hypertension in SHR was completely inhibited by renal denervation during 2 weeks of observation (from 7 to 9 weeks of age) without increasing water intake and urine volume. Pressor responses to intravenous injection of norepinephrine were not affected by renal denervation. The results show that the antihypertensive effect of renal denervation was not due to the changing of vascular reactivity. Pressor and sympathetic nerve responses to hypothalamic stimulation were strongly diminished in renal denervated rats. These results suggest that renal denervation strongly inhibited they hypothalamo-sympathetic nerve system. It is also suggested that the renal afferent nerve may facilitate the hypothlamo-sympathetic nerve system in regulating blood pressure and that this facilitation may contribute to the development of hypertension in SHR.

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Readily detectable levels of renin activity were demonstrated in the human brain. This activity was inhibited by specific antibody raised against human renal renin, indicating that it was not due to the nonspecific action of proteases such as cathepsin D. The pineal gland was found to be the richest source of renin followed by the pituitary, hypothalamus and hippocampus. The substantia nigra, caudate nucleus, putamen and thalamus contained moderately high concentrations of renin. The brain renins from pineal and pituitary glands shared some biochemical features with well-known kidney renin, such as molecular weight (46, 000 daltons for pineal renin ; 37, 000-45, 000 daltons for pituitary renin), optimum pH (6.0-7.0), the presence of trypsin-activatable inactive renin, and a glycoprotein nature. However, the electro-focusing pattern of renin from pituitary tissue (pI = 4.43, 5.77) differed from that of plasma and kidney enzymes heretofore reported, a discrepancy which could be interpreted as evidence for the endogeneous synthesis of renin in the brain tissue. Furthermore, a high activity of immunoreactive renin was found in human neuroblastoma tissue. The biochemical characteristics of the neuroblastomal renin were generally similar to the known properties of kidney renin in many respects, providing evidence of the presence of the renin-angiotensin system within human neuronal cells.

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To investigate the relationship of renal prostaglandin E₂ (PGE₂) synthesis to medullary interstitial osmolality, rat renal papillary collecting tubule (RPCT) cells in culture were exposed to media with different osmolaties. PGE₂ released into the media was measured by radioimmunoassay. Increasing osmolality with equiosmolar sodium chloride and urea from 300 to 900 mOsm slightly increased PGE₂ synthesis, whereas further increase above 1200 mOsm markedly inhibited PGE₂ synthesis in RPCT cells. Hyperosmolar media also inhibited calsium ionphore-stimulated PGE₂ synthesis, but did not inhibit arachidonate-stimulated PGE₂ synthesis. In contrast, decreasing osmolality from 1800 to 300 mOsm induced a prominent but transient increase in PGE₂ synthesis. This increase was abolished by TMB-8, an intracellular calcium antagonist, and trifluoperazine, a calmodulin antagonist. Osmolar increments with sodium chloride or urea alone resulted in the similar inhibition of PGE₂ synthesis by sodium chloride but not by urea. These results indicate that extracellular sodium chloride inhibits PGE₂ synthesis in RPCT cells at the step of arachidonic acid release, possibly at phospholipases, in a calcium-dependent manner.

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The effects of dietary potassium on the hemodynamics and plasma norepinephrine (NE) kinetics were studied in 10 patients with borderline hypertension. Potassium supplement (96 mEq daily for 5-7 days) induced a significant (p < 0.05) fall in blood pressure and a slight decrease in cardiac output. Both urine volume and urinary sodium excretion increased significantly (p < 0.05) for a first few days following the potassium supplement. The baseline values of the half-time of the rapid NE removal from plasma was significantly delayed in the hypertensive patients (1.05 ± 0.06 min, p < 0.05) when compared with those (0.88 ± 0.04) in normal controls. Potassium supplement induced a significant rise in both plasma NE levels and NE outflow rate (p < 0.01) in the hypertensive patients, while their half-times were significantly shortened (0.89 ± 0.07 min, p < 0.01). The pressor responsiveness to exogenously infused NE tended to diminish during the potassium supplement. These findings indicate that a high potassium intake might accelerate the slowed neuronal NE uptake in the hypertensive patients, while a potassium-induced fall in blood pressure might exert a baroreflex stimulation of NE release. As a net result, an increased NE outflow into the circulation has been confirmed. It is likely that a natriuresis-induced volume contraction might be a predominant factor responsible for the early reduction of blood pressure during the high potassium intake.

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To clarify the peripheral origin of plasma dopamine (DA), we studied the changes in plasma levels of free and conjugated catecholamines after nephrectomy, adrenalectomy, chemical sympathectomy and renal denervation. Nephrectomy markedly increased conjugated DA levels, indicating that plasma DA is rapidly excreted through the kidney and originates outside the kidney. Adrenalectomy reduced plasma total epinephrine (E) to undetectable limits, whereas total norepinephrine (NE) and DA levels remained unchanged. In addition, the subsequent immobilization stress significantly increased both total NE and DA, but not E. Chemical sympathectomy with 6-hydroxydopamine decreased both NE and DA by 66% and 72%, respectively. E level, however, was not affected by sympathectomy. Although the following immobilization stress significantly increased all catecholamines levels, the magnitude of increase in concentrations of NE and DA were much less than that of E. These results suggest that plasma DA is mainly derived from the peripheral sympathetic nerve terminals. However, the renal nerve, one of the sympathetic nerves, did not serve as a source of plasma DA because renal denervation had no effect on plasma DA levels in spite of the marked depletion of free DA in the kidney.

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Dihydroxyphenylglycol (DOPEG) is a metabolite of noradrenaline (NA) in the sympathetic nerve endings, and dihydroxymandelic acid (DOMA) is one in the extraneuronal tissues. The measurement of plasma DOPEG and DOMA were evaluated with NA as one of the clinical indices of sympathetic nerve activity. These were measured in essential hypertension and also applied for diagnosis of pheochromocytoma. Plasma DOPEG levels were correlated with NA. Plasma NA and DOPEG were decreased after oral administration of clonidine (150 μg) and plasma DOPEG levels were slowly increased after standing. Therefore, plasma DOPEG seemed to be useful as one of the rather stable indices of the sympathetic nerve activity. Plasma NA and DOPEG levels in WHO stage I essential hypertension were higher than those in normotensive controls. Observed normal plasma noradrenaline and DOPEG levels in stage II reflect the normalized sympathetic tone in this stage. The elevation of plasma NA and DOMA levels in stage III seemed to be at least partly explained by renal function disturbance. In patients with pheochromocytoma, despite of the marked elevation of plasma NA and DOMA, plasma DOPEG showed only three-fold elevation and the ratio DOPEG/NA was reduced. The simultaneous measurement of plasma NA, DOPEG and DOMA is useful to evaluate sympathetic nerve activity in essential hypertension and to differentiate pheochromocytoma in hypertension.

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To study the cellular mechanism of vascular responsiveness by vasoactive hormones, such as catecholamines and angiotensin (A), the vascular smooth muscle cells (VSMC) of two clonal cell line (A7r5 and A 10) from rat embryo, and of adult rat aorta were established in culture. Binding studies using ¹²⁵I-labeled-hydroxyphenylethylaminoethyltetralone as an α-adrenergic ligand and ¹²⁵I-labeled-iodocyanopindolol as a β-adrenergic ligand, revealed that cultured VSMCs contain both α- and β-adrenergic receptors ; the binding was specific, rapid, reversible, and saturable. α-Adrenergic receptors appear to be a single class of high-affinity binding sites with an apparent dissociation constant (K_d) of ∼ 2× 10^-10 M and a maximal binding capacity (B_max) of ∼300, 000-400, 000 sites/cell, and exclusively of α₁-subtype that is responsible for smooth muscle contraction. On the other hand, β-adrenergic receptors show almost comparable characteristics with the apparent K_d of ∼ -0.7-1.1 10^-10 M and B_max of 50, 000-130, 000 sites/cell, and consist predominantly of ₂-subtype that mediates smooth muscle relaxation. Furthermore, -adrenergic receptors are coupled to adenylate cyclase system, of which activation by -agonists induces intracellular cyclic AMP formation. In contrast, the binding of ¹²⁵I-labeled-AII was demonstrated only in A7r5. The binding declined rapidly during incubation possibly due to faster degradation of AII by proteolytic enzyme (s). AII receptors appear to be a single class of high-affinity binding sites with the apparent K_d of 0.9 10^-10 M and B_max of 11, 000 sites/cell, of which affinity is higher than any of vascular AII receptors previously reported. Therefore, cultured VSMCs isolated from neurogenic and systemic influence should provide a valuable in vitro system to investigate the characteristics of specific receptors for vasoactive hormones, the cellular mechanisms involved in activation and regulation of the receptors and subsequent biochemical responses.

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