We studied the antioxidant effects of nine calcium antagonists (nisoldipine, benidipine, nilvadipine, felodipine, nicardipine; nitrendipine, nifedipine, verapamil, and diltiazem) by means of rat myocardial membrane lipid peroxidation with a nonenzymatic active oxygen-generating system (DHF/FeCl₃-ADP). The order of antioxidant potency of these agents was nilvadipine>nisoldipine>felodipine>nicardipine >verapamil>benidipine. Their IC50 values (μM) were 25.1, 28.2, 42.0, 150.0, 266.1, and 420.0, respectively. In contrast, nitrendipine, nifedipine, and diltiazem had little inhibitory effect on lipid peroxidation. These six calcium antagonists could be divided into four types on the basis of their antioxidant mechanisms. Nilvadipine, nisoldipine, and verapamil, which showed antioxidant effects both before and after the addition of active oxygen, and reduced the dihydroxyfumarate (DHF) auto-oxidation rate, were chain-breaking and preventive antioxidants. Felodipine, which showed antioxidant effects both before and after exposure to active oxygen and increased the DHF auto-oxidation rate, was only a chain-breaking antioxidant. Nicardipine, which showed an antioxidant effect only before exposure to active oxygen and reduced the DHF auto-oxidation rate, was mainly a preventive antioxidant. Benidipine, which showed an antioxidant effect only before exposure to active oxygen and had no appreciable effect on the DHF auto-oxidation rate, could interrupt the chain reaction of lipid peroxidation at the initial step alone. Although these results suggest that the antioxidant properties of some calcium antagonists may be beneficial clinically in protecting against cellular damage caused by lipid peroxidation, further studies are required to establish the antioxidant effects of these agents in vivo. (Hypertens Res 1996; 19: 223-228)

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The influence of neutral endopeptidase (NEP) inhibition with (S)-thiorphan on the hormonal, renal, and blood-pressure-lowering effects of an infusion of atrial (ANP), brain (BNP), and C-type natriuretic peptide (CNP) was evaluated in hypertensive transgenic rats (TGR) harboring an additional mouse renin gene (TGR(m(Ren2)27)). These TGR possess an activated natriuretic peptide system as compared with Sprague-Dawley rats (SDR), used in this study as control. (S)-Thiorphan significantly decreased blood pressure in anesthetized TGR but not in anesthetized SDR during the 60-min infusion period. Exogenously administered ANP decreased blood pressure in SDR with no significant effects in TGR after 60 min. In contrast, BNP infusion significantly decreased blood pressure in TGR, while changes in SDR were not significant. The blood pressure was further decreased after combined infusion of ANP and BNP with (S)-thiorphan in TGR. No effect on blood pressure was registered during infusion of CNP in either experimental group. The plasma levels of ANP, BNP, and cGMP were higher in TGR than in SDR, whereas plasma renin activity was lower. Co-administration of ANP, BNP, or CNP with the NEP inhibitor (S)-thiorphan potentiated the plasma ANP, BNP, and cGMP. Infusion of ANP alone did not affect BNP plasma levels of TGR and vice versa. In contrast, CNP infusion increased ANP plasma levels in both TGR and SDR. Renal excretion of sodium and cGMP increased after infusion of (S)-thiorphan and ANP or BNP in both TGR and SDR. The combination of ANP and (S)-thiorphan had a slightly greater effect on urinary excretion of sodium and cGMP in TGR than either compound alone, but the effects were more pronounced in SDR than in TGR. Finally, infusion of CNP alone and in combination with (S)-thiorphan influenced the excretion of sodium and cyclic GMP only slightly. These results indicate that inhibition of neutral endopeptidase by (S)-thiorphan potentiates the hemodynamic and renal effects of natriuretic peptides ANP and BNP, and to some extent those of CNP, in hypertensive TGR and normotensive SDR. In contrast to ANP and BNP, infusion of CNP had no effect on the blood pressure in anesthetized TGR or SDR. Inhibition of NEP therefore seems to be a promising way to potentiate endogenous levels of natriuretic peptides, which may be of therapeutic benefit in cardiovascular diseases such as hypertension or heart failure. (Hypertens Res 1996;19: 229-238)

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Many factors have been reported to stimulate the release of brain natriuretic peptide (BNP) as well as atrial natriuretic peptide (ANP). In hypertensive patients, however, little is known about whether these factors differ from those in normotensive subjects or if they are influenced by antihypertensive treatment. We measured the plasma concentrations of BNP and ANP in 12 hypertensive patients and examined the chronic effects of β-adrenoceptor blockade on BNP secretion during exercise with a bicycle ergometer. The exercise raised both plasma BNP and ANP with concomitant increases in systolic blood pressure, heart rate (HR) and plasma norepinephrine (NE) and epinephrine (Epi) before and after treatment. Before treatment, the changes in ANP and BNP correlated with that in HR (p<0.05). After treatment 4wk of treatment, the change in ANP correlated with those in NE and Epi as well as HR. Multivariate regression analysis indicated that only NE was a significant stimulus for ANP secretion during the treatment period. As for BNP, HR was the only significant stimulant for its secretion both before and after treatment. In essential hypertension, β-adrenergic receptor blockade affected the factors stimulating exercise-induced ANP release but not those stimulating BNP release. BNP release, therefore, seems to be stimulated by similar but distinct factors from those that stimulate ANP release. (Hypertens Res 1996; 19: 239-245)

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The antihypertensive effects of an angiotensin II antagonist, candesartan cilexetil (TCV-116), and other classes of antihypertensive drugs (including a calcium antagonist, manidipine; a diuretic, hydrochlorothiazide (HCTZ); an α-blocker, prazosin; and a β-blocker, atenolol) administered in combination were examined in spontaneously hypertensive rats by oral administration daily for 2wk. TCV-116 at 1mg/kg lowered the blood pressure by about 50 and 30mmHg, 5 and 24h after dosing, respectively. The blood pressure was slightly lowered by HCTZ at 10mg/kg, but it was synergistically reduced when HCTZ was given in combination with TCV-116. Manidipine at 3mg/kg lowered the blood pressure by about 50 mmHg 1h after administration. When manidipine was given in combination with TCV-116, blood pressure was reduced additively. Prazosin at 1mg/kg lowered the blood pressure by 40 to 50mmHg 1h after dosing. When prazosin was given in combination with TCV-116, the reduction was intensified more than additively, to about 100mmHg. Atenolol at 50mg/kg lowered the blood pressure by 10 to 20 mmHg 5h after dosing. Even when atenolol was administered in combination with TCV-116, the reduction in blood pressure was virtually the same as that observed when TCV-116 was given alone. TCV-116 and HCTZ had no effect on the pulse rate, whereas manidipine and prazosin both increased it, owing to reflex tachycardia, and atenolol decreased it. TCV-116 had no effect on the change in the pulse rate induced by these antihypertensive drugs and no effect on HCTZ-induced diuresis. TCV-116 and HCTZ each caused a significant increase in plasma renin concentration (PRC), and prazosin caused a slight elevation. Manidipine had no effect on the PRC, whereas atenolol reduced it. Given in combination with TCV-116, these antihypertensive drugs had the same effect on the elevated PRC induced by TCV-116 as they did on the basal PRC when administered alone. These results suggest that antihypertensive drugs that cause compensatory activation of the renin-angiotensin system have more marked antihypertensive activity when given in combination with TCV-116, but that there will is no combined effect on the pulse rate. (Hypertens Res 1996; 19: 247-254)

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To compare the influences of alcohol and salt intake on 24-h blood pressure (BP), we studied short-term effects of repeated alcohol ingestion and dietary salt intake in hypertensive patients. Thirty-two Japanese men with mild to moderate essential hypertension (54±1 years old, mean±SE) were examined. Sixteen patients were given alcohol (1ml/kg) with dinner for 7d after a 7-d control period with an isocaloric beverage. Another group consisting of 16 age- and weight-matched patients consumed a low-sodium diet (25mmol/d) for 7d, followed by a high-sodium diet (250mmol/d) for 7d. Twenty-four-hour BP was measured at the end of each period. Average 24-h BP in the alcohol period (137±4/83±2mmHg) was similar to that in the control period (138±4/84±2mmHg). However, BP in the alcohol period was significantly lower in the evening, but significantly higher in the morning than that in the control period. Heart rate increased for several hours after alcohol ingestion, resulting in a significant increase in 24-h heart rate (67±2 vs. 64±2 beats/min). Average 24-h BP was higher in the high salt period (144+4/89± 4mmHg) than in the low salt period (135±3/85±3mmHg, p<0.05). The pressor effect of high salt intake was sustained throughout the day and was associated with a decrease in 24-h heart rate (60±2 vs. 66±2 beats/min). In conclusion, short-term repeated intake of alcohol may have little effect on average 24-h BP while it causes an evening fall and a morning rise in BP, and high salt intake raises BP throughout the day. Alcohol consumption increases and salt loading decreases 24-h heart rate. (Hypertens Res 1996; 19: 255-261)

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The effects of chronic cicletanine (CICL) treatment on endothelial cell function were investigated in Dahl salt-sensitive (Dahl S) rats. Forty-four six-week-old Dahl S rats were divided into four groups: i) 10 Dahl S rats fed a low-salt (0.3% NaCl) diet and given vehicle, ii) 12 Dahl S rats fed a high-salt (4% NaCl) diet and given vehicle, iii) 11 low-dose (10mg/kg body weight/d) CICL-treated Dahl S rats fed a high- salt diet, and iv) 11 high-dose (30mg/kg body weight/d) CICL-treated Dahl S rats fed a high-salt diet. The rats were maintained on the respective salt regimen for 12wk and treated with cicletanine for the last 6wk, after which various parameters of endothelial cell function were determined. Systolic blood pressure, measured by the tail-cuff method, was reduced significantly by high-dose cicletanine (223 vs. 195mmHg, p<0.01). Scanning electron microscopy revealed that high-dose CICL attenuated endothelial injury in the aorta of Dahl S rats. Arterial lesions in the heart and glomerulosclerosis in the kidney were significantly reduced by treatment with high-dose CICL. Moreover, prostacyclin (PGI₂) and prostaglandin E₂ (PGE₂) generation in the aortic wall was significantly increased by 28% (p<0.005) and by 149% (p<0.001), respectively, by high-dose CICL. Nitric oxide (NO) generation in the aortic walls was significantly increased by high-dose CICL (0.38 vs. 15.4pmol/cm2/30min, p<0.001). This effect was accompanied by a 47% increase in cGMP synthesis in the vascular walls. In contrast, the synthesis of PGI₂, PGE₂, and NO in the kidney slices did not differ significantly among the four experimental groups. In addition, the generation of vasodilatory substances inversely correlated with the score of vascular lesions in the heart and kidney. The results suggested that the blood pressure reduction by chronic cicletanine treatment in Dahl S rats is associated with an improvement in endothelial cell function. The increased release of vasodilatory substances from endothelial cells may contribute to the blood pressure reduction and attenuation of vascular injury observed with cicletanine treatment. (Hypertens Res 1996; 19: 263-270)

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The rat angiotensin II type 2 receptor (AT2-R) gene was isolated, and cis-regulatory regions in its 5"- flanking area were analyzed. Primer extension and RNase protection analyses revealed a single transcriptional initiation site at the position 24bp downstream of the TATA box. The 5′-flanking region of AT2-R contained several cis-regulatory elements, such as AP-1, AP-2, C/EBP, NF-1, NF-IL6, NE-κB, and glucocorticoid- and cAMP-responsive elements (CRE). The treatment of PC12 cells with dibutyryl cAMP caused a marked decrease (90%) in the AT2-R mRNA level, which was blocked by the inhibitor of protein kinase A and did not require new protein synthesis. The protein level was also reduced 84% after a 24-h exposure to cAMP and the binding affinity was unchanged. The half-life of the AT2-R mRNA decreased -66% by cAMP as compared with control (18.4±0.4h). Deletion and mutation analyses of the 5′-flanking region (1.2Kb) revealed that there were one negative (-1, 199 to -739) and two positive cis-regulatory regions (-739 to -436 and -59 to +45), and that the CRE motif located at -426 repressed (-23%) the promoter activity of the rat AT2-R gene. The region between -59 and +45 containing TATA box and AP-2 site accounted for 70% of the promoter activity. These findings indicate that the promoter activity of the rat AT2-R gene is modulated by several cis-regulatory regions and that cAMP markedly downregulates the expression of the AT2-R mainly by inducing AT2-R mRNA destabilization rather than CRE-mediated inhibition of the gene transcription. Thus, humoral factors that transduce cAMP as an intracellular signal may modulate AT2-R-mediated function of Ang II by reducing AT2-R expression. (Hypertens Res 1996; 19: 271-279)

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To assess how elderly Japanese hypertensive patients are treated by specialists, we conducted a cross- sectional survey. A total of 1, 163 outpatients aged 50 years or older were studied. Hypertension was diagnosed in 939 of these patients, and 827 were receiving drug therapy. The average blood pressure during therapy was 143±16 / 81±10mmHg. In patients aged 70 years or older, systolic blood pressure during antihypertensive therapy was significantly higher (p<0.01) and diastolic blood pressure was significantly lower (p<0.01) than the corresponding values in those aged 50 to 59 years or 60 to 69 years. The calculated mean blood pressures were similar in the different age groups. The rate of monotherapy in the patients aged 70 years or older was 58.8%, which was significantly higher (p<0.01) than the rates of monotherapy in the other age groups. Calcium channel blockers were prescribed in about 80% of patients, irrespective of age or comorbidity. Of the patients receiving calcium channel blockers, 43.5% were treated with monotherapy. This rate significantly (p<0.01) increased with advancing age. Diastolic blood pressures were significantly lower (p<0.05) in patients with stroke and in those with ischemic heart disease, diabetes mellitus, or dyslipidemia, as compared with patients with no comorbidity. Among patients aged 70 years or older, the difference in systolic blood pressure between those with ischemic heart disease and those with no comorbidity was not significant. Blood pressure in elderly hypertensive patients was reduced to a level similar to that in younger patients. The target blood pressure was influenced by the presence of comorbidity. Furthermore, specialists showed a high preference for the use of calcium channel blockers in the management of hypertension. (Hypertens Res 1996; 19: 281-290)

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We present the case of a 35-year-old woman whose pregnancy was complicated by the rare condition of transient pheochromocytoma-related myocardial damage. Short-duration left ventricular dysfunction was apparently caused by acute non-transmural myocardial infarction provoked by coronary artery vasospasm rather than catecholamine-induced cardiomyopathy. Forty-eight days after onset, a 50×55× 35mm tumor was excised and histologically confirmed to be a pheochromocytoma. (Hypertens Res 1996; 19: 291-293)

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