"Non-modulators" are essential hypertensive patients who fail to modulate an adrenal response, renovascular response, or both, to angiotensin II (Ang II). The aim of the present study was to characterize "non-modulators" among Japanese patients with normal-renin essential hypertension and to determine whether non-modulation is related to sodium sensitivity of blood pressure. The increase in plasma aldosterone concentration (PAC response) and the decrease in renal plasma flow (RPF response) in response to Ang II infusion (3ng/kg/min) were assessed in 15 Japanese patients with essential hypertension who received a high sodium diet (250mEq/d) followed by a low sodium diet (10mEq/d). The subjects were divided into two groups (6 modulators and 9 non-modulators) based on their ability to modulate the PAC response during sodium restriction. There was no significant difference between modulators and non-modulators in electrolyte balance or in plasma Ang II levels on either diet. Changes in the PAC response during sodium restriction were significantly correlated with the change in mean blood pressure during sodium restriction (r=-0.67, p<0.01), while changes in the RPF response were not. RPF responses in both groups decreased during sodium restriction, although an effect on the RPF response in non-modulators was unexpected. These results suggest that non-modulators do exist among Japanese patients, but that this defect does not involve both the adrenal gland and the kidney. Apparently, only non-modulation of the adrenal response is involved in the mechanism of sodium sensitivity. (Hypertens Res 1996; 19: 141-145)

View full abstract

To assess the protective effect of an α₁-blocker on the development of cardiac hypertrophy, the selective α₁-receptor antagonist bunazosin (2mg/kg/d, by oral gavage and in drinking water) was given to male Dahl salt-sensitive rats fed a 4% NaCl diet for 7 weeks. Control animals received water only by the same method. Treatment with bunazosin was started when the animals were 7 weeks of age. Blood pressure, pulse rates, and body weight were measured every week during the experiment. Urine was collected for 24h on the final day of the experiment. All animals were killed by decapitation, blood was collected, and the heart was removed. In both the treated and control groups, time-dependent increases in blood pressure and body weight were observed, and there were no significant differences between the groups in blood pressure or body weight during the experiment. Pulse rate remained unchanged in both groups throughout the experiment. The left ventricular weight/body weight ratio and the left ventricular tissue DNA content were significantly lower in the rats receiving bunazosin than in the control rats. Plasma renin activity, plasma aldosterone, and plasma atrial natriuretic peptide did not differ significantly between the two groups. No significant differences in glomerular filtration rate, urine volume, sodium excretion, urinary metanephrine excretion, and urinary normetanephrine excretion were noted between the two groups. The results indicate that a sub-antihypertensive dose of bunazosin can inhibit the development of cardiac hypertrophy without suppression of the pressure load, suggesting an important role of α₁-adrenergic receptors in the pathogenesis of cardiac hypertrophy following the development of hypertension. (Hypertens Res 1996; 19: 147-150)

View full abstract

The cardiovascular consequences of mixed angiotensin converting enzyme and neutral endopeptidase (ACE/NEP) inhibition with alatriopril/alatrioprilat were compared with the consequences of endopeptidase (NEP) inhibition alone with (S)-thiorphan/ecadotril by determining the acute effects of the compounds on hemodynamic, hormonal, and renal parameters in hypertensive transgenic rats harboring an additional mouse renin gene (TGR(rRen2)27). Infusion of alatrioprilat and (S)-thiorphan in anesthetized TGR decreased blood pressure in a dose-dependent manner, but heart rate remained unchanged. The renal excretion of water, sodium, and cGMP also increased dose-dependently, with nearly the same maximal effects after infusion of (S)-thiorphan and alatrioprilat. At the end of infusion, plasma ANP and cGMP were elevated both after (S)-thiorphan and after alatrioprilat, whereas plasma renin activity increased only after alatrioprilat. The ACE inhibition effect was studied in ganglionblocked rats receiving a continous infusion of angiotensin I. Alatrioprilat decreased the mean blood pressure dose-dependently, but about 30 times higher concentrations were needed to produce the same effects as the ACE inhibitor captopril. At a dose of 30mg/kg p.o., ecadotril, the orally active prodrug of (S)-thiorphan, decreased the systolic blood pressure in conscious TGR by 22mmHg for 6h, whereas alatriopril (100 mg/kg p.o.) also reduced the systolic pressure in these rats with a maximal reduction of 22mmHg. In addition, ecadotril and alatriopril significantly increased the urinary excretion of sodium. In contrast, ACE inhibition with captopril decreased the excretion of sodium dose-dependently in conscious TGR. In conclusion, combined ACE/NEP inhibition produced a comparable lowering of blood pressure and improvement in renal function as those with NEP inhibition in TGR. Dual ACE/NEP inhibition may therefore be useful in cardiovascular conditions such as hypertension or heart failure. (Hypertens Res 1996; 19: 151-159)

View full abstract

The β-carbolines have a high affinity for the benzodiazepine receptor, where they demonstrate actions opposite to those of the benzodiazepines and elicit anxiogenic effects. We tested the acute cardiovascular effects of β-carbolines in conscious unrestrained rats. Intravenous infusion of ethyl-β-carboline-3-carboxylate (BCCE) or methyl-β-carboline-3-carboxylate (BCCM) caused dose-related decreases in heart rate. Pretreatment with RO 15-1788 (10.0mg/kg, i.v.), a benzodiazepine receptor antagonist, or atropine (1.0mg/kg, i.v.) prevented the bradycardia elicited by BCCE (3.0mg/kg, i.v.). In contrast, tetrahydro-β-carboline (THBC; 3.0mg/kg, i.v.) increased both heart rate and blood pressure significantly as compared with controls. However, larger doses of THBC failed to elicit further increases in heart rate or blood pressure. These experiments indicate that in conscious unrestrained rats, β-carbolines given acutely do not routinely elicit the cardiovascular changes normally associated with stress or anxiety. We next extended our observations to rats given the β-carboline noreleagnine, 2mg/kg, or vehicle twice daily intraperitoneally for 4 weeks. The rats were fed either a high salt (8%) or a low salt (0.9%) diet. At 4 weeks, rats given noreleagnine and high salt had higher tail cuff pressures (146±4 vs. 134±4mmHg) than those given noreleagnine and low salt. However, with direct arterial measurement, these differences disappeared. These data suggest that β-carbolines do not provide a useful model for investigating the effects of chronic stress on cardiovascular function in rats. (Hypertens Res 1996; 19: 161-170)

View full abstract

The present study was designed to clarify whether modulation of norepinephrine (NE) release by vascular angiotensin (Ang) II is involved in the increased peripheral sympathetic activity of spontaneously hypertensive rats (SHR). In the perfusion system of isolated mesenteric vascular beds, periarterial nerve stimulation (PNS)-evoked NE overflow was significantly greater in SHR than Wistar-Kyoto rats (WKY). Administration of Ang II increased PNS-induced NE overflow, which could be reversed by pretreatment with the AT₁ receptor antagonist CV-11974 in both types of rats; the facilitation by Ang II was more potent in SHR. Moreover, CV-11974 by itself could attenuate PNS-evoked NE overflow, the extent of which was also significantly greater in SHR, suggesting an augmented sympatho-facilitatory effect of enodogenous Ang II in SHR. Consistently, sympatho-facilitation by Ang I, which could be abolished by the angiotensin converting enzyme (ACE) inhibitor imidaprilat, was apparently greater than that of Ang II in SHR, despite no difference in WKY. These findings suggest that the increased peripheral sympathetic activity in SHR is attributed not only to the elevated sensitivity of nerve endings to Ang II but also to the increased local generation of Ang II, an effect possibly mediated by augmented vascular ACE activity. (Hypertens Res 1996; 19: 171-177)

View full abstract

Effects of isoproterenol (ISO) on the expression of cardiac angiotensinogen mRNA, angiotensin converting enzyme (ACE) activity, and mechanical functions in spontaneously hypertensive rats were investigated. In the acute phase, defined as within 24h after the subcutaneous injection of ISO 85mg/kg, cardiac Angiotensinogen mRNA was slightly induced, but ACE activity was not. In the subacute phase, defined as within 8d after ISO treatment on 2 successive d, both angiotensinogen mRNA expression and ACE activity in the heart were markedly induced. ACE activity in serum was not affected by ISO in either phase. In the subacute phase, ISO reduced body weight and blood pressure, increased ventricular weight and calcium content, and impaired cardiac mechanical function. Oral treatment with imidapril (10mg/kg/d), an ACE inhibitor, 1h before each ISO treatment and on the following 6d, improved ventricular hypertrophy, the elevation of the left ventricular end diastolic pressure, the reduction in contractility, and the prolongation of the time constant. Imidapril significantly suppressed both serum and cardiac ACE activity but did not affect cardiac angiotensinogen mRNA expression in the subacute phase. These results indicate that enhancement of cardiac angiotensinogen mRNA and ACE activity is involved in ISO-induced cardiac dysfunction. Imidapril improved ISO-induced cardiac dysfunction, possibly by suppression of the local ACE activity as well as circulating ACE activity. (Hypertens Res 1996; 19: 179-187)

View full abstract

To investigate blood pressure and pulse rate responses to dental surgery, 21 patients 18 to 73 years of age (mean age, 42±4 years) who visited our hospital for tooth extraction were studied. Before dental treatment, the patients underwent a mental arithmetic stress test, electrocardiography, and an anxiety evaluation with the State-Trait Anxiety Inventory. Baseline blood pressure and pulse rate were 118±4/70±3mmHg and 69±2 beats/min, respectively. Blood pressure rose by 24±3/17±2mmHg during the mental stress test, and the magnitude of the rise in systolic blood pressure was significantly correlated with age (r=0.81, p<0.001) and baseline blood pressure (r=0.56, p<0.01). After the topical injection of local anesthetic containing 1:80, 000 epinephrine, a transient increase in systolic blood pressure was observed. The maximum blood pressure and pulse rate increases during dental surgery were 24±4/13 ±2mmHg and 17±3 beats/min, respectively. Similarly, the rate pressure productincreased from 8, 196 ±486 to 11, 802±682. The magnitude of the blood pressure increase during dental surgery was not correlated with age, sex, family history of hypertension, baseline blood pressure, anxiety score, or response to mental stress. On the other hand, when the subjects were divided into two subgroups according to the blood pressure response during dental surgery, the larger response group (increase in mean blood pressure greater than 15mmHg, n=9) required a significantly larger dose of local anesthetic than did the smaller response group. The number of cases of pericoronitis of the third molar tended to be greater in the larger response group. These results indicate that an increase in blood pressure during dental surgery cannot be predicted on the basis of baseline blood pressure or the response to mental stress, but is related to the cause of tooth extraction and the volume of local anesthetics required to control the pain. (Hypertens Res 1996; 19: 189-194)

View full abstract

To evaluate mechanisms responsible for differences between patients showing a nocturnal fall in blood pressure ("dippers") and those showing no such fall in blood pressure ("nondippers"), we performed 24-hour (h) ambulatory blood pressure monitoring in 25 patients with untreated essential hypertension who were 37-49 years of age (16 men and 9 women). The diagnosis of essential hypertension was based on the patients' history, physical examination, routine laboratory tests, and intravenous pyelography. Blood pressure was measured by sphygmomanometer and by noninvasive ambulatory monitoring for 24 h. Exercise was performed on a supine bicycle ergometer. The initial workload was 50W and was increased progressively by 25W at 3-min intervals. Plasma and urinary norepinephrine levels were measured by high-performance liquid chromatography. Dippers were defined as patients with a difference of >10mmHg in the systolic BP or >5mmHg in the diastolic BP between daytime and nighttime. Eleven patients were dippers and 14 patients were nondippers. There was a positive correlation between the nocturnal fall in blood pressure and the rise in blood pressure during exercise (r=0.54, p<0.01), and the increase during exercise was greater in dippers than in nondippers. There was also a significant positive correlation between the urinary norepinephrine level and the fall in blood pressure at night (r=0.75, p<0.01). A significant increase in plasma norepinephrine during exercise was found in dippers, as compared with nondippers. These results suggest that in patients with hypertension a nocturnal fall in blood pressure is closely related to the blood-pressure response to exercise, and that the attenuation of sympathetic nervous activity might play an important role in the nocturnal decrease in blood pressure. (Hypertens Res 1996; 19: 195-200)

View full abstract

To determine whether angiotensin (ANG) II, a vasoconstrictor hormone, activates constitutive nitric oxide synthase (cNOS) in endothelial cells (ECs), we investigated the cellular mechanism by which ANG II induces nitric oxide (NO) formation in cultured bovine ECs. ANG II rapidly (within 1min) and dose-dependently (10^-9-10^-6M) increased nitrate/nitrite (NOx) production. This effect of ANG II was abolished by a NOS inhibitor, N^G-monomethyl-L-arginine. An ANG II type 1 (AT₁) receptor antagonist (DuP 753), but not an ANG II type 2 (AT₂)receptor antagonist (PD 123177), dose-dependently inhibited ANG II-induced NOx production. A Ca²⁺-channel blocker (barnidipine) failed to affect ANG II-induced NOx production, whereas an intracellular Ca²⁺ chelator (BAPTA) and a calmodulin inhibitor (W-7) abolished NOx production induced by ANG II. A protein kinase C (PKC) inhibitor (H-7) and down-regulation of endogenous PKC after pretreatment with phorbol ester decreased NOx production stimulated by ANG II. ANG II transiently stimulated inositol 1, 4, 5-trisphosphate (IP₃) formation, and increased cytosolic free Ca²⁺ concentrations; these effects were blocked by DuP 753. Our data demonstrate that ANG II stimulates NO release by activation of Ca²⁺/calmodulin-dependent cNOS via AT₁ receptors in bovine ECs. (Hypertens Res 1996; 19: 201-206)

View full abstract

We estimated the prevalence of hypertension and evaluated the degree of blood pressure control on the basis of ambulatory blood pressure monitoring in patients receiving antihypertensive medication. A total of 969 adults (mean age±SD, 59.3±12.1 years old, range: 20-79yr) among 1, 575 eligible persons (65.1%) recruited from a total adult population of 2, 789 people living in a rural region of northern Japan underwent measurement of initial screening blood pressure; ambulatory blood pressure was measured subsequently. A total of 285 subjects (66.5±9.2 years old) were taking antihypertensive medication (treated group), while 684 (56.3±12.0 years old) were not (untreated group). The WHO criteria were used to categorize screening blood pressure. Ambulatory blood pressure levels were classified as follows: hypertension, systolic blood pressure ≥144mmHg and/or diastolic blood pressure ≥85mmHg; and normotension, systolic blood pressure ≤133 and diastolic blood pressure ≤78mmHg. Of the 285 treated subjects, 49 (17.2%) were classified as hypertensive by screening measurements, while 36 (12.6%) were classified as such by ambulatory blood pressure monitoring. Only 12 (24.5%) of the former 49 subjects were also classified as hypertensive, while 20 (40.8%) were classified as normotensive by ambulatory blood pressure monitoring. Of the 684 untreated subjects, 34 (5.0%) were hypertensive by screening measurements and 43 (6.3%) were hypertensive by ambulatory blood pressure monitoring. Only 14 (41.2%) of the former 34 subjects were classified as hypertensive by ambulatory blood pressure monitoring. Of the 34 untreated subjects classified as hypertensive by screening measurements, ambulatory blood pressure monitoring showed 12 (35.3%) to be normotensive, suggesting that they were cases of "white coat" hypertension. The study first confirmed, based on community-derived data, that there are large discrepancies between screening (casual) blood pressure measurements and ambulatory blood pressure monitoring with respect to the recognition of hypertension and normotension. The determination of blood pressure levels by ambulatory blood pressure monitoring may result in a different prognosis of hypertension from that made on the basis of screening blood pressure measurements. The prognostic value of ambulatory blood pressure has to be further investigated. (Hypertens Res 1996; 19: 207-212)

View full abstract

We previously demonstrated that cholinergic activity in the medulla oblongata is enhanced in adult spontaneously hypertensive rats (SHR), a genetically hypertensive rat model. In this study, we examined possible alterations of medulla oblongata cholinergic mechanisms in nongenetic forms of hypertension, using deoxycorticosterone acetate (DOCA)-salt hypertensive and renal hypertensive rats. At a fully developed stage of hypertension in DOCA-salt hypertensive and renal hypertensive rats, choline acetyltransferase (CAT) activity in the rostro-ventral medulla oblongata was enhanced, whereas there was no change in the activity of CAT in other parts of the medulla oblongata. There was no alteration of the medulla CAT activity in prehypertensive SHR or at an early stage of renal hypertension. Increases in blood pressure and plasma catecholamine levels induced by physostigmine (0.5mg/kg, i.p.) were enhanced in DOCA-salt hypertensive and renal hypertensive rats. These findings suggest that cholinergic activities in the medulla oblongata are enhanced and that such activities are involved in enhancement of the sympathetic nervous system in non-genetically hypertensive rats. It seems unlikely that the altered Cholinergic activity in the rostral ventrolateral medulla of adult SHR occurs genetically. (Hypertens Res 1996; 19: 213-219)

View full abstract