Kyuzo Aoki

Antihypertensive effect of cardiovascular Ca2+-antagonist in hypertensive patients in the absence and presence of beta-adrenergic blockade

Abstract The effect of the administration of a cardiovascular Ca2+-antagonist (nifedipine) on arterial blood pressure, heart rate, and plasma renin activity was investigated. Blood pressure of normotensive healthy volunteers (n = 4) does not change significantly by administration of 10 mg. (from 119 78 to 120 75 mm. Hg ) and 30 mg. (from 114 69 to 105 66 mm. Hg ) of nifedipine. When nifedipine (30 mg.) is administered with propranolol (beta-blockade), a slight decrease of systolic and diastolic blood pressure was observed (from 119 73 to 104 67 mm. Hg ). Blood pressure of hypertensive patients is significantly lowered by 10 mg. of nifedipine from 172.9 to 130.3 mm. Hg (25 per cent reduction) systolic, and from 112.9 to 86.6 mm. Hg (23 per cent) diastolic (n = 7). Thirty mg. nifedipine had a slightly stronger hypotensive effect, namely 27 per cent reduction in systolic and 28 per cent in diastolic values (n = 9). Combined administration of nifedipine and propranolol, resulted in lowering initial blood pressure by 32 per cent and 30 per cent reduction in systolic and diastolic (n = 8), respectively. The heart rate of normotensive patients hardly changes with administration of 10 and 30 mg. of nifedipine and combined medication. But in hypertensive subjects it is significantly increased by nifedipine; from 66.3 to 80.3 (p Plasma renin activity of normotensive and hypertensive subjects is increased by 30 mg. of nifedipine. Combined administration of nifedipine and propranolol decreases plasma renin activity in both normotensive and hypertensive patients. The antihypertensive effect of nifedipine is enhanced and prolonged by propranolol. The observed increase in heart rate and plasma renin activity with nifedipine is inhibited by propranolol, probably by inhibiting the cardiovascular effects of the activity of the sympathetic nervous system. The results of this study indicate that oral administration of nifedipine is very effective in lowering arterial blood pressure in hypertensive patients, especially when combined with propranolol. Administration of nifedipine with beta-blockade resulted in satisfactory management of hypertension with minimal adverse drug reactions which could be possibly attributed to the preparation, especially in the management of hypertensive emergencies including hypertension associated with acute myocardial infarction and coronary insufficiency.

Effects of Bay K 8644 and nifedipine on femoral arteries of spontaneously hypertensive rats

1 Vasoconstrictor effects of Bay K 8644 (an agonist known to increase Ca2+ influx through the voltage‐dependent Ca2+ channels) on femoral arteries of 6 week old spontaneously hypertensive rats (SHR) were investigated, and data compared with findings in age‐matched normotensive Wistar‐Kyoto rats (WKY). 2 The addition of Bay K 8644 (1 × 10−10 − 3 × 10−7 M) elicited a dose‐dependent contraction in SHR femoral artery in the absence of any contractile agent. Maximum contraction induced by this agonist was the same as the maximum induced by either K+‐depolarization or α‐adrenoceptor stimulation. 3 Bay K 8644 was less effective in eliciting a contraction in the WKY femoral artery. 4 Increased sensitivity to K+ was also observed in the SHR femoral artery. In contrast, contractions in response to α‐adrenoceptor stimulation were the same in the SHR as those in the WKY. 5 The addition of nifedipine, a Ca2+ channel antagonist, to an unstimulated preparation produced a dose‐dependent relaxation in femoral arteries from SHR, but not from WKY. When the arteries were contracted with 60 mM K+, nifedipine produced similar relaxations in the SHR as those in the WKY, suggesting that the Ca2+ channels in the SHR femoral arteries are more activated than those in the WKY femoral arteries. 6 Contractile responses of SHR femoral arteries to Bay K 8644 were antagonized competitively by nifedipine. 7 Contractile responses to Ca2+ determined in K+‐depolarized strips were also antagonized competitively by nifedipine. However, Schild plot analysis clearly demonstrated a different pA2 value for nifedipine, suggesting that there may be a difference in the state of voltage‐dependent Ca2+ channels in SHR femoral artery between the stimulation with Bay K 8644 and K+‐depolarization.

Acute and long-term hypotensive effects and plasma concentrations of nifedipine in patients with essential hypertension.

SummaryThe acute and long-term hypotensive effects of low doses of nifedipine, and the correlation between the fall in the blood pressure (BP) and the plasma nifedipine concentration, were investigated in patients with essential hypertension. The oral administration of nifedipine 5 mg rapidly decreased BP from 163±22/101±10 to 127±12/82±9 mmHg (mean±SD; p<0.001), and increased heart rate from 72±8 to 76±6 beats/min (p<0.05), plasma renin activity rose from 1.2±0.6 to 1.4±0.8 ng/ml/h (p<0.05), and plasma nifedipine concentration was 75.6±22.0 ng/ml 30 min after administration (n=7). The nifedipine concentration was significantly correlated both with the fall in BP (r=0.410, p<0.02, n=31) and the rise in the heart rate (r=0.412, p<0.02, n=31). Treatment with nifedipine 5 mg t.d.s. alone or in combination either with propranolol 10 mg t.d.s., or thiazide 1 tablet daily, or propranolol and thiazide, controlled BP in 36 patients during the 22 week study period. During the long-term nifedipine therapy, the plasma nifedipine level was significantly correlated with the fall in systolic (r=0.577, p<0.01, n=20) and diastolic (r=0.595, p<0.01, n=20) BP. It was concluded that the plasma nifedipine concentration could be correlated with the fall in BP, and that low doses of nifedipine, either as monotherapy or in combination, were effective in the acute and long-term treatment of patients with essential hypertension.

Hypotensive effects of diltiazem to normals and essential hypertensives

SummaryThe hypotensive effect of acute and long-term, intravenous and oral administration of the calcium antagonist, diltiazem, was investigated in 8 normotensive volunteers and 55 patients with essential hypertension. Diltiazem i.v. infusion of 45 mg/h (0.5 mg/min, then 1.0 mg/min, each for 30 min rapidly decreased both blood pressure (BP) from 164±22/98±8 to 144±15/86±9 mmHg (mean±SD) and total peripheral resistance from 32.6±8.4 to 25.3±5.4 mmHg/l/min (p<0.001), and increased stroke volume from 58.2±9.5 to 64.2±8.6 ml/beat (p<0.05). It altered neither heart rate nor cardiac output in the hypertensives (n=10). Oral diltiazem 60 mg rapidly decreased BP from 155±10/103±6 to 142±12/90±8 mmHg after 3 hours (p<0.01/p<0.001) in hypertensives (n=8), but not in normotensives (n=8). Diltiazem 90 mg p.o. decreased BP from 157±15/102±9 to 129±13/83±8 mmHg (p<0.01) in hypertensives (n=15), and reduced the heart rate from 71±8 to 65±8 beats/min (p<0.01). The drug did not change plasma renin activity either in normotensives or hypertensives. The fall in diastolic BP was correlated with the plasma diltiazem concentration (r=0.910, n=6, p<0.05). Long-term treatment with diltiazem 30mg t.d.s. decreased BP from 163±12/104±8 to 145±9/88±9 mmHg (p<0.001, n=13), and 60mg t.d.s. decreased BP from 169±15/102±6 to 148±13/87±8 mmHg (p<0.001, n=8), and significantly reduced the heart rate (p<0.01) in hypertensives. Thus, the hypotensive action of diltiazem, which is due to arterial dilatation, is effective, either on intravenous or oral administration, during acute and long-term treatment of essential hypertension.

Clinical and pharmacological properties of calcium antagonists in essential hypertension in humans and spontaneously hypertensive rats.

The abnormal cellular contractile mechanisms causing the development of essential hypertension in humans and rats were investigated, primarily with the use of Ca2+ and Ca antagonists. Helical strips isolated from mesenteric arteries of spontaneously hypertensive rats (Aoki SHR) showed an increased Ca2+ -induced tension development in the presence of noradrenaline or a high potassium concentration. The tension development of the SHR strips was greatly inhibited by Ca antagonists. In the patients with essential hypertension, both elevated blood pressure and elevated total peripheral resistance were reduced to normal levels by Ca antagonists. The drugs increased cardiac output and stroke volume. The hypotensive effect of the drugs was due to arterial vasodilation. We concluded that there might be an abnormally high sensitivity of the cell membrane system of vascular smooth muscle to both Ca2+ and Ca antagonists in patients with essential hypertension and in SHR. Abnormalities in Ca2+ channels, Ca2+ uptake, and Ca2+ binding of the cell membrane, which cause the high sensitivity, might greatly increase the Ca2+ levels of cytosol in the muscle. The increased cytosol Ca2+ induces, in turn, either increased contraction or decreased relaxation and a decrease in the arterial lumen. Any decrease in the lumen results in peripheral resistance enhancement, which is responsible for the increase in arterial blood pressure in essential hypertension. Thus, we propose the membrane theory of essential hypertension--that membrane abnormalities lead to hypertension.

Hypertensive effects of calcium infusion in subjects with normotension and hypertension.

The hemodynamic effects of acute hypercalcemia induced by calcium infusion, 7.5 mg/kg per h for 1 h, were investigated in normotensive and hypertensive subjects, aged 43-83 years, in the absence and presence of the calcium antagonist verapamil. Calcium infusion raised blood pressure from 125 +/- 14/62 +/- 6 to 143 +/- 13/69 +/- 7 mmHg (mean +/- s.d.) and from 173 +/- 15/81 +/- 6 to 202 +/- 23/92 +/- 9 mmHg with an increase in concentration of serum calcium from 2.2 +/- 0.1 to 3.2 +/- 0.2 mmol/l and from 2.2 +/- 0.1 to 3.2 +/- 0.1 mmol/l in normotensives (n = 20) and hypertensives (n = 12), respectively. In hemodynamic studies, the calcium infusion significantly raised blood pressure and total peripheral vascular resistance and decreased heart rate with no change of cardiac output, in normotensives (n = 8) and hypertensives (n = 8). The absolute increases in both blood pressure and vascular resistance were significantly higher in hypertensives than in normotensives, but the per cent increases were not significantly different in both groups. The per cent increases in blood pressure and vascular resistance were negatively correlated with increasing age. The infusion of verapamil at the rate of 0.15 mg/kg per h inhibited the increases in both blood pressure and vascular resistance during the calcium infusion in normotensives (n = 6) and hypertensives (n = 6). In conclusion, the calcium infusion raised blood pressure because of elevated vascular resistance, and the effects of calcium on blood pressure were inhibited by the calcium antagonist.(ABSTRACT TRUNCATED AT 250 WORDS)

Diminished β-adrenoceptor-mediated relaxation of arteries from spontaneously hypertensive rats before and during development of hypertension

beta-Adrenoceptor agonists and other drugs were studied for their relaxant effects on femoral and mesenteric arterial strips from spontaneously hypertensive rats (SHR). The potency and efficacy of isoproterenol (ISO) in these arteries were decreased in SHR before and during the development of hypertension as compared with age-matched Wistar Kyoto rats (WKY). Reserpine and 6-hydroxydopamine inhibited the development of hypertension but did not alter the reduced ISO-induced relaxation of the arteries. These arteries from prehypertensive SHR (PHSHR) were less sensitive to salbutamol and cyclic AMP and cyclic GMP derivatives than arteries from age-matched WKY. The relaxation response to nitroprusside was less in the femoral but not in the mesenteric arteries from PHSHR than in arteries from age-matched WKY. The relaxation response to papaverine was not diminished in the PHSHR arteries. It was found that the SHR arteries had a reduced responsiveness to the beta-adrenoceptor agonists before the initiation of hypertension and that the diminished relaxation was not specific to the beta-agonists, although there was no generalized defect in vasorelaxation in PHSHR.

Malfunction of arterial sarcoplasmic reticulum leading to faster and greater contraction induced by high-potassium depolarization in young spontaneously hypertensive rats

The contribution of sarcoplasmic reticulum was studied with regard to the increase in arterial contraction induced by a high-potassium depolarization in spontaneously hypertensive rats (SHR). The 20 mmol/l potassium-induced contraction of femoral arteries was faster and greater in 6-week-old SHR than in age-matched normotensive Wistar-Kyoto (WKY) rats. Relaxation after washing the arteries with a Krebs solution was slower in SHR than in WKY rats. When the sarcoplasmic reticulum of SHR arteries had been depleted of calcium by caffeine in a calcium-free solution, the rate of high-potassium-induced contraction of the calcium-depleted SHR arteries was slowed, the same result as that with non-calcium-depleted WKY arteries. In ryanodine-treated arteries, the rate and magnitude of high-potassium-induced contraction were enhanced slightly in SHR and greatly in WKY rats, resulting in no final difference between SHR and WKY rats. Ryanodine slowed the relaxation rate in WKY rats but not in SHR. These results suggest that the diminution in ability of sarcoplasmic reticulum to sequester calcium may be responsible for the faster rate and greater magnitude of high-potassium-induced contraction with the slower relaxation in SHR arteries. We postulated that genetic malfunction of sarcoplasmic reticulum causes the increased contraction of arterial smooth muscle leading to the enhanced vasoconstriction and elevated blood pressure in SHR.

Beta1- and beta2-adrenoceptor-mediated relaxation responses in peripheral arteries from spontaneously hypertensive rats at pre-hypertensive and early hypertensive stages

Beta-adrenoceptor-mediated relaxation of isolated arteries from spontaneously hypertensive rats (SHR) was studied. The relaxation responses of the femoral arteries of pre-hypertensive SHR (PHSHR) to isoprenaline (ISO) and dibutyryl cyclic AMP were less than those of the age-matched tissues of rats of the Wistar-Kyoto strain (WKY). The responses of the mesenteric arteries of PHSHR to ISO and noradrenaline (NA) but not fenoterol (FEN) and forskolin were diminished when compared to those from the WKY tissues. The diminished relaxation response to ISO was observed in the SHR arteries with and without endothelial cells as compared to similar arteries from WKY. Relative potency ratios of ISO:FEN:NA and the Schild plot data for atenolol and butoxamine suggested that there were only beta 1-adrenoceptors and predominantly beta 2-adrenoceptors mediating relaxation in the femoral and mesenteric arteries, respectively. There was no difference in beta-adrenoceptor subtypes between the SHR and WKY arteries. The evidence in this study suggests that beta 1-adrenoceptor-mediated relaxation was diminished in the femoral and mesenteric arteries of PHSHR.

Correlation of increased serum calcium with elevated blood pressure and vascular resistance during calcium infusion in normotensive man.

The effects of intravenous calcium infusion on blood pressure (BP) and total peripheral vascular resistance (TPR) were investigated in seven normotensives at rates of 3.75, 7.5 and 15.0 mg/kg per h for 1 h. The infusions increased serum calcium levels, with significant elevations of BP and TPR, but had no effect on cardiac output, indicating that the TPR elevation induced the BP rise. The increase in serum calcium was correlated with elevations of systolic, diastolic and mean BP and TPR (r = 0.74, 0.78, 0.77 and 0.82, respectively; P less than 0.001); greater increases in serum calcium resulted in greater elevations of TPR and BP. The serum calcium increase was also associated with reductions in plasma parathyroid hormone and renin activity, and an increase in plasma aldosterone, which might have contributed to the rise in BP. Our results suggest that an increased serum calcium level led to calcium influx into arterial smooth muscle, which increases cytosolic calcium, induces muscle contraction, and thereby produces arterial vasoconstriction, leading to elevations of TPR and BP.