Hypotensive Effect Of Verapamil Research Articles

The Effect of Long-Term Verapamil Treatment on the Secretion of Cortisol and Aldosterone in Subjects with Normal and High Blood Pressure

Based on their previous observations of the stimulating action of verapamil on the secretory reserve of cortisol after one-week oral administration to healthy volunteers, the author investigated the effect of this calcium entry blocker on the adrenocortical function (cortisol and aldosterone secretion) during therapeutic administration to patients with mild arterial hypertension and normotensive patients suffering from Raynaud's syndrome. Verapamil, 3-4 X 80 mg per day by the oral route, did not lead to significant changes of cortisol levels at rest nor after ACTH stimulation when assessed at the end of the first month of treatment in both groups. However, normotensive subjects with Raynaud's syndrome showed a decline of ACTH stimulated cortisolaemia during the 3rd month (p less than 0.05) and 4th month (p less than 0.01) and a reduction of cortisol secretory reserve (delta cortisol) during the 3rd month of treatment (p less than 0.05). In aldosterone secretion of normotensives with Raynaud's syndrome no significant changes were observed. In hypertensive subjects, the decline of ACTH stimulated cortisolaemia at the end of the 3rd and 4th month was not significant and delta cortisol did not change. The initial aldosterone levels before and after ACTH and delta aldosterone before treatment of hypertensives was lower as compared with normotensives (p less than 0.01, p less than 0.01 and p less than 0.05, respectively), and increased gradually during treatment in the 4th month significantly (p less than 0.05, p less than 0.01 and p less than 0.01, respectively). The hypotensive effect of verapamil persisted throughout the treatment.(ABSTRACT TRUNCATED AT 250 WORDS)

L-type Ca 2+ channels mediate cardiovascular symptoms of alcohol withdrawal in humans

The cardiovascular effects and plasma concentrations after intravenous verapamil injection (5 mg) were compared in seven alcohol dependents during alcohol withdrawal syndrome (AWS) to those after resolution of these symptoms. At the onset of AWS, verapamil caused a bradycardiac response, which was absent after resolution of AWS. At the same period, a hypotensive effect of verapamil was weakened. No differences in verapamil plasma concentrations were observed between different periods. These results suggest that L-type Ca 2+ channels are involved in mediating cardiovascular symptoms of AWS.

Calcium channel blockers reduce blood pressure in part by inhibiting vascular smooth muscle carbonic anhydrase I.

Calcium channel blockers are a group of drugs used for the treatment of hypertension. Carbonic anhydrase (CA) I detected in vascular smooth muscle and in other cells in the organism has a major role in the acid-base balance and in vascular processes. Our previous work has proven that verapamil inhibits CA activity by a direct mechanism of action. Starting from our results in this article we studied in vitro and in vivo the effect of calcium channel blockers (verapamil and amlodipine) on erythrocyte CA I, on vascular smooth muscles CA I, and on arterial blood pressure values in human and in animals. Our in vitro and in vivo results have proved that verapamil and amlodipine are strong CA I inhibitors both in human erythrocytes and also in vascular smooth muscles in animals. In humans, calcium channel blockers studied here progressively reduce arterial blood pressure in hypertensive subjects, in parallel with progressive lowering of erythrocyte CA I activity in the normal range in normotensive subjects. From our point of view verapamil and amlodipine possess a dual mechanism of action: the first well-known action consists of their action on calcium channels. The second mechanism, suggested by us, directly acts on the vascular smooth muscle CA I isozyme, so that its inhibition should ensure an adequate pH for calcium ions transport through the channels, having as result vasodilation. This double mechanism could explain the hypotensive effect of verapamil and amlodipine, with a mechanism that partially dependent on CA I inhibition.

Acute Haemodynamic Effects of Felodipine, Verapamil and Hydralazine in the Anaesthetized Dog

Felodipine, a potent dihydropyridine calcium antagonist with a pronounced vascular selectivity, was given intravenously (0.006-0.025 mumol kg-1) to anaesthetized, open-chest dogs with denervated hearts. The result was a dose-dependent decrease in mean arterial pressure (MAP) and total peripheral resistance (TPR), while heart rate (HR), stroke volume (SV) and left ventricular end-diastolic pressure remained relatively unchanged. Cardiac tension work (TTI) and oxygen consumption (MVO2) were reduced, probably due to the decrease in afterload. The relative reduction of the coronary vascular resistance (CVR) was greater than that of TPR. The hypotensive effect of verapamil (0.05-0.20 mumol kg-1) was small and MAP decreased mainly via a decrease in HR and SV. Higher doses of verapamil which induced vasodilatation could not be given without the development of complete atrio-ventricular dissociation. Hydralazine (11-45 mumol kg-1) decreased TPR and CVR in parallel but the decrease in MAP was partly counteracted by a powerful increase in HR, SV and cardiac inotropy which was associated with elevated catecholamine levels in plasma. When MAP and HR were maintained constant by means of aortic balloon inflation and atrial pacing, felodipine markedly increased coronary blood flow and coronary sinus oxygen saturation while SV, TTI, inotropy and MVO2 remained relatively unchanged. It is concluded that felodipine markedly dilates peripheral resistance vessels, and in particular those in the coronary vascular bed, without any cardiodepressant effects.

Cardiovascular responses to verapamil and nifedipine in hypoventilated and hyperventilated rats

1. The influence of hypoventilation or hyperventilation on blood pressure and pulse rate responses to verapamil and nifedipine was studied in chloralose-anaesthetized rats. 2. Artificial ventilation with room air at a fixed volume of 10 ml kg-1 successfully induced combinations of hypoxaemia, hypercarbia and acidosis at a ventilator rate of 37 strokes min-1 and of hyperoxaemia, hypocarbia and alkalosis at 160 strokes min-1. 3. Hypoventilation caused significant decreases in both the blood pressure and pulse rate, whereas hyperventilation produced significant increases in these parameters. 4. In the controls, intravenous injections of graded doses of either verapamil or nifedipine caused dose-dependent decreases in mean blood pressure. The effects on pulse rate were not marked. 5. The hypotensive effects of verapamil were significantly more intense in hyperventilated rats, whereas those of nifedipine were significantly less pronounced in hypoventilated animals. The hypoventilated rats exhibited a significant dose-dependent decrease in pulse rate in response to verapamil administration. 6. It is concluded that cardiovascular responses to verapamil, nifedipine and probably other calcium antagonists are altered in the presence of blood gas abnormalities.

Sex and age differences in the effect of verapamil on rat cardiac function

The author reports that a relatively high dose of verapamil produces sex-related cardiac effects, especially on the conducting system in adult rats. A single dose of verapamil (0.5-1 mg/kg, i.v.) caused a marked AV block and a reduction in heart rate to 50-60% in adult males, but not in females. There was no sex difference in the hypotensive effect of verapamil. At 3, 5 or 7 weeks of age, verapamil (1 mg/kg, i.v.) induced a 10-20% reduction of the heart rate without AV block in both male and female rats. In 8-week-old male rats, the reduction in the heart rate became apparent, and AV block appeared following a single i.v. injection of verapamil. The adult pattern in cardiac response to verapamil was observed at 11 weeks of age and afterward. Castration in adult male and female rats resulted in an intermediate pattern of the response to verapamil in intact male and female rats. Acute treatment with testosterone (20 mg/kg, s.c.) in castrated male and female rats induced a decrease in the basal heart rate and increased the cardiac responsiveness to verapamil in castrated female rats. Estradiol-17 beta failed to alter the responsiveness of castrated rats to verapamil. These results suggest that testosterone may play a role in the sex difference of the cardiac responses to verapamil in rats.

Effect of calcium blocking agent verapamil on blood pressure, ventricular contractility, parathyroid hormone, calcium and phosphorus in plasma, catecholamines, corticosterone and plasma renin activity in spontaneously hypertensive rats.

In four-month-old spontaneously hypertensive rats (SHR) the effect of a calcium blocking agent verapamil on blood pressure, ventricular contractility indices, parathyroid hormone (PTH), plasma renin activity (PRA), plasma and adrenal corticosterone content and catecholamines in hypothalamus, myocardium and adrenal gland was evaluated. Calcium and phosphorus in plasma were also determined. Verapamil treatment resulted in a significant decrease in systolic and diastolic blood pressure and a reduction in maximum left ventricular pressure. Verapamil exerted a negative inotropic effect, evaluated by a decrease in dP/dt max and dP/dt neg. PRA was elevated, calcium tended to decrease, and no changes in PTH and phosphorus were found. The hypotensive effect of verapamil in SHR was accompanied by a decrease in plasma and adrenal corticosterone content, and a fall in catecholamine concentration in adrenal glands and myocardium.

Paradoxical Effect of Calcium on Some Cardiovascular Effects of Verapamil in the Rat

The ability of calcium infusions to reverse some cardiovascular effects of verapamil was tested in anesthetized rats and on isolated rat atria. Intravenous infusions of 1.88 mg/kg verapamil increased the cycle length (CL), lengthened the PR interval (PRi), and decreased the mean arterial pressure (Pa). After these effects were stabilized, a series of infusions of calcium chloride (338 mumol/kg each) were performed. Calcium on the one hand promoted the return of Pa to its basal value; on the other hand, it failed to reverse the effect of verapamil on AV conduction and the first infusion of calcium produced an additional increase in CL of 55 +/- 16 ms. This paradoxical effect of calcium was prevented by previous infusion of atropine (0.2 mg/kg). On isolated atria, the increase of calcium concentration in the media ([Ca2+]0) from 1.0 to 6.0 mM increased the concentration frequency by approximately 40 beats/min, both in atropinized and in nonatropinized preparations. After verapamil, however, the same increase in [Ca2+]0 decreased atrial rate in 50 +/- 15 beats/min in nonatropinized atria. The results obtained indicate that extra calcium can overcome the hypotensive effect of verapamil, whereas it paradoxically increases its negative chronotropic effect and fails to reverse its effect on AV conduction. This paradoxical effect of calcium can be prevented, both in vivo and in vitro, by atropine blockade of muscarinic receptors.

Differences between the effects of calcium antagonists in the pithed rat preparation.

The drugs classed as calcium antagonists display marked differences in vitro and it has been proposed that different subclasses of antagonists exist (Spedding M. Naunyn Schmiedebergs Arch Pharmacol 1982; 318:234-40). The effects of these drugs have now been compared in vivo using the pithed rat preparation. Whereas the hypotensive effects of verapamil (0.1-3 mumol/kg i.v.) and diltiazem (0.1-10 mumol/kg i.v.) were accompanied by prolongation of PR intervals and second-degree atrioventricular block with little bradycardia, fendiline (0.1-30 mumol/kg i.v.), cinnarizine (0.1-10 mumol/kg i.v.), and pimozide (0.1-10 mumol/kg i.v.) reduced heart rate at hypotensive doses but had less marked effects on AV conduction, thus implying different selectivities among calcium antagonists for the sinus or AV nodes. These differences were not secondary to effects on the autonomic nervous system. In contrast, nifedipine (0.01-1 mumol/kg i.v.) had no effect on the ECG in doses which markedly reduced blood pressure elevated by an infusion of angiotensin II and thus showed specificity for vascular smooth muscle. The marked differences between the effects of the calcium antagonists in vivo confirm the disparate nature of this group of drugs. The reasons for these differences are discussed.