Doses Of Nifedipine Research Articles

Treatment of hypertensive venous leg ulcers with nifedipine

The effect of nifedipine in the treatment of hypertensive venous leg ulcers was studied on 30 outpatients in a double-blind placebo-controlled trail over a period of 2 months. The dose of nifedipine or the matching placebo was 10 mg 3 times daily. Most of the subjective symptoms such as pain, paraesthesia and cramps at night considerably improved during the treatment with nifedipine and were slightly affected in the placebo group. The ulcer surface area decreased after 2 months treatment with nifedipine by 26.9% (p 0.05). An improvement of the photopletysmographic record of the lower legs in the nifedipine group was observed, demonstrated by an increase of the index recovery time (by 36.1%, p < 0.05), while there were no significant changes in the placebo group. The results show favorable effect of nifedipine in the treatment of hypertensive venous leg ulcers which might be due to a great extent to improvement of the subcutaneous circulation of the lower legs. Nifedipine may be an important adjunct to the conservative management of the complications caused by chronic venous insufficiency and hypertension.

Nifedipine in Ischemic Heart Disease

Until the 1980s, Prinzmetal’s variant angina was difficult to treat—nitrates and β-blockers usually did not control symptoms or signs of ischemia. In 1980, Antman et al1 reported the first clinical experience in the United States of the use of nifedipine in patients with Prinzmetal’s angina. They used nifedipine capsules to treat 127 patients with Prinzmetal’s angina, which reduced the weekly occurrences of angina from 16 to 2, reduced nitroglycerin requirements, completely controlled angina in 63% of patients, and reduced the frequency of angina by at least 50% in 87% of cases. Since that time, a number of trials with different calcium channel blockers, including nifedipine, diltiazem, verapamil, amlodipine, and others, have consistently shown that these agents are efficacious in reducing the morbidity of Prinzmetal’s variant angina.2 Additional studies showed that calcium channel blockers, including nifedipine, were effective in patients with chronic stable angina pectoris3 ; they not only reduced symptoms but also reduced objective evidence of ischemia on exercise treadmill tests,4 5 reduced ST-segment changes on ambulatory ECG monitoring,6 increased coronary artery blood flow,7 8 9 and improved ventricular dysfunction associated with ischemia.10 Numerous studies showed that the calcium channel blockers were effective as antihypertensive agents and lacked many of the side effects of diuretics and β-blockers.11 Of course, all drugs have limits, and not all cardiovascular drugs are appropriate for all cardiovascular situations. Calcium channel blockers are no exception. In 1984, Muller et al11 showed for the first time that nifedipine capsules did not reduce the size of myocardial infarction (MI) and did not prevent patients with threatened MIs from infarcting. Patients who received nifedipine capsules in the setting of myocardial infarction had a higher 2-week mortality (7.5%) versus placebo (2.3%) but 6-month mortality was similar between nifedipine-treated (10.8%) and …

Nifedipine. Dose-related increase in mortality in patients with coronary heart disease.

The purpose of this study was to assess the effect of the dose of nifedipine, a dihydropyridine calcium antagonist, on the increased risk of mortality seen in the randomized secondary-prevention trials and to review the mechanisms by which this adverse effect might occur. We restricted the dose-response meta-analysis to the 16 randomized secondary-prevention trials of nifedipine for which mortality data were available. Recent trials of any calcium antagonist and formulation were also reviewed for information about the possible mechanisms of action that might increase mortality. Overall, the use of nifedipine was associated with a significant adverse effect on total mortality (risk ratio, 1.16, with a 95% CI of 1.01 to 1.33). This summary estimate fails to draw attention to an important dose-response relationship. For daily doses of 30 to 50, 60, and 80 mg, the risk ratios for total mortality were 1.06 (95% CI, 0.89 to 1.27), 1.18 (95% CI, 0.93 to 1.50), and 2.83 (95% CI, 1.35 to 5.93), respectively. In a formal test of dose response, the high doses of nifedipine were significantly associated with increased mortality (P = .01). While the mechanism of this adverse effect is not known, there are several plausible explanations, including the established proischemic effect, negative inotropic effects, marked hypotension, recently reported prohemorrhagic effects attributed to antiplatelet and vasodilatory actions of calcium antagonists, and possibly proarrhythmic effects. In patients with coronary disease, the use of short-acting nifedipine in moderate to high doses causes an increase in total mortality. Other calcium antagonists may have similar adverse effects, in particular those of the dihydropyridine type. Long-term safety data are lacking for most calcium antagonists.

A comparison between the haemodynamic effects of oral nifedipine and intravenous dihydralazine in patients with severe pre-eclampsia

To compare the effects of a single oral dose of nifedipine with those of intravenous dihydralazine on central haemodynamics in pregnant women with severe pre-eclampsia. A prospective comparative study. The High Risk Obstetric Unit, University Hospital Rotterdam Dijkzigt, Rotterdam. Twenty patients with severe pre-eclampsia between 27 and 35 weeks gestation with normal cardiac filling pressures and without fetal distress. A pulmonary artery thermodilution catheter and a radial artery line were placed. Ten patients chewed a 10-mg capsule of nifedipine and 10 patients received dihydralazine by intravenous infusion at a rate of 1-3 mg/h. Arterial pressures, heart rate, cardiac output and pulmonary capillary wedge pressure were determined before and after drug administration. Fetal condition was continuously monitored by cardiotocography. The reduction in arterial blood pressure obtained with both drugs was similar, and was associated with a similar rise in heart rate and cardiac output and a similar reduction in systemic vascular resistance. Pulmonary capillary wedge pressures decreased significantly less with nifedipine than with dihydralazine. Signs of fetal distress occurred in none of the nifedipine-treated patients, but in five of the patients treated with dihydralazine. From the haemodynamic viewpoint nifedipine seems to be a useful agent in the treatment of hypertensive emergencies in pregnancy.

Interactions of a new beta-blocker, celiprolol, with the calcium antagonists, diltiazem and nifedipine, on atrioventricular conduction

The influence of a new beta-blocker, celiprolol, on the direct dromotropic effects of the Ca antagonists, diltiazem and nifedipine, on atrioventricular (AV) conduction was estimated in the canine isolated, blood-perfused AV node preparation. Diltiazem (1-10 micrograms) and nifedipine (0.3-3 micrograms) injected i.a. into the AV node artery dose dependently prolonged the atrio-His (AH) interval (5-39 msec and 7-51 msec) in the AV mode preparation. When celiprolol (1 and 10 mg/kg) was given i.v. in the support dog, the AH interval in the AV node preparation was transiently shortened and then maintained constant as a control. These doses of i.v. celiprolol completely abolished the isoproterenol-induced decrease in the AH interval (28 msec at 0.03 microgram, i.a.) and AV nodal tachycardia. In the presence of celiprolol, the same doses of i.a. diltiazem and nifedipine increased the AH interval by the same amounts (6-43 msec and 8-53 msec) as the control. The incidence of second degree AV conduction block produced by diltiazem (2 in 5 AV node preparations at 10 micrograms) and nifedipine (2 in 6 preparations at 3 micrograms) was not changed by celiprolol. In the second experiments, diltiazem (30-300 micrograms/kg) and nifedipine (3-30 micrograms/kg), given i.v. in an open-chest in situ vagotomized dog, dose dependently increased AV conduction time (AVCT; 2-30 msec and 1-12 msec). Celiprolol 1 and 10 mg/kg i.v., which suppressed the isoproterenol-induced decrease in AVCT (32 msec at 0.3 mu/kg i.v.) and AV nodal tachycardia (4 in 6 in situ hearts), potentiated the prolongation of AVCT by the same doses of diltiazem (11-50 msec) and nifedipine (3-40 msec). The incidence of second degree AV conduction block produced by i.v., diltiazem (1 in 5 in situ hearts at 300 micrograms/kg) and nifedipine (0 in 6 in situ hearts at 30 micrograms/kg) was aggravated (4 in 5 and 3 in 6 in situ hearts) after i.v. celiprolol. These results indicate that although celiprolol does not affect the direct negative dromotropic effects of the Ca antagonists, AV block could easily be produced when celiprolol eliminates tonic adrenergic influences in vivo.

Characterization of the gubernacular contractile response to calcitonin gene-related peptide in the mouse

Calcitonin gene-related peptide (CGRP) has no effect on quiescent skeletal muscle, but cultured neonatal mice gubernacula show rhythmic contractions in response to CGRP. This study investigated whether these contractions (1) require calcium ions, (2) are activated via acetylcholine receptors, or (3) require dihydropyridine receptors. Gubernacula (n = 20 for each experiment) from male mice aged 7 days old were preincubated for 30 minutes in aerated culture medium (Krebs-Henseleit solution) with (1) up to 1.8 mmol/L of calcium with or without CGRP (714 nmol/L), (2) up to 5.0 μmol/L of curare with CGRP and calcium (1.8 mmol/L), or (3) up to 1 μmol/L of nifedipine with CGRP and calcium. Then they were placed on agar-coated grids over the same compound solutions, and observed for 2 days by video camera to see contractions. Of gubernacula cultured with calcium (1.8 mmol/L) and CGRP, 90% showed contractions, which decreased to 20% without CGRP ( P < .001) and 15% without calcium ( P < .001). Only 5% of gubernacula cultured without both CGRP and calcium showed contractions. Also these contractions in response to CGRP depended on calcium concentrations in a dose-dependent manner. Curare did not suppress contractions. With increasing dose of nifedipine, the percentage of gubernacula contracting decreased from 95% to 0%. These results suggest that developing mouse gubernacular contractions in response to CGRP require influx of calcium ions to the sarcoplasm via dihydropyridine receptors in a similar manner to contractions of immature cardiac or smooth muscles, and these contractions are not activated via acetylcholine receptors.

Factors influencing nifedipine-induced gingival overgrowth in rats.

Factors such as age, the dose of nifedipine administered in the diet, serum drug level, duration of drug administration, and sex which may influence nifedipine-induced gingival overgrowth were examined in a rat model using 20-, 50-, and 90-days-old male and female rats. Oral administration of nifedipine (50 to 250 mg/kg diet) increased the serum level of the drug in a dose-dependent manner in both males and females. However, a higher serum level was required in females than males to attain the same degree of gingival overgrowth. The minimum dietary concentrations of the drug required to elicit gingival overgrowth in males and females were 150 and 100 mg/kg, respectively, which gave respective minimum serum levels of 800 and 1100 ng/ml. The degree of overgrowth depended on the serum concentration of the drug after it had reached the required minimum in male and female animals. Administration of nifedipine (250 mg/kg diet) for 20 days was enough to induce maximal overgrowth, but this induction occurred only in rats that started to receive the drug when they were 20 days old, not in those that started at 50 and 90 days of age for the same administration period of 55 days, and the overgrowth regressed and the gingiva were normal 40 days after ceasing drug administration. These results suggest that gingival overgrowth occurred in accordance with the drug concentration in the diet, as well as that in the serum, and was more likely to occur in males and younger individuals.

958-93 Prevention of Mental Stress-induced Wall Motion Abnormalities by Nifedipine GITS and Atenolol Therapy

Previous investigators have demonstrated that mental stress can induce myocardial ischemia in selected patients with coronary disease manifested by new wall motion abnormalities on radionuclide ventriculography. It is unknown whether such ischemia is due to coronary vasoconstriction or to increased myocardial O 2 demand. We studied the effect of nifedipine GITS and atenolol as single-agent therapy on mental stress-induced ischemia in a double-blind. placebo-controlled, three-way crossover trial in 16 patients with stable angina. Each patient received maximally tolerated doses of nifedipine (mean daily dose: 88 mg). atenolol (mean daily dose: 91 mg) or placebo during each of 3 4-week treatment phases. At the end of each phase, patients underwent a mental stress procedure (Stroop color word test, mental arithmetic, and stress interview) with skin conductance monitored to gauge physiologic arousal. Left ventricular wall motion was graded in each of 5 regions using a scale from 3 (normal) to -1 (dyskinesis), and by regional ejection fraction. The segment with the largest deterioration in wall motion during placebo therapy was determined, and the effects of nifedipine and atenolol on this segment were compared. Mental stress caused a significant increase in skin conductance levels, with peak values similar on each therapy. Therapy with either nifedipine or atenolol prevented a deterioration in wall motion score (-0.6 for placebo; 0.0 for nifedipine. 0.0 for atenolol, each p &lt; 0.01 vs. placebo). while only nifedipine prevented a significant decrease in regional ejection fraction (-13.0% on placebo; -5.6% for atenolol, p = 0.08 vs. placebo; -1.9% on nifedipine, p = 0.01 vs placebo, p = 0.4 vs. atenolol). The rate pressure product (heart rate x systolic blood pressure. RPP) at peak mental stress (i.e., peak myocardial O 2 demand)was 15.792 on placebo, and was reduced only by atenolol (12,287, p = 0.001). but not by nifedipine (15,185, p = NS). Both nifedipine GITS and atenolol are effective at preventing mental stress-induced ischemic wall motion abnormalities. although the mechanisms may be different. Nifedipine improved reg’lonal wall motion without reducing RPP. and thus may have prevented mental stress-induced coronary vasoconstriction. Atenolol improved regional wall motion and reduced RPP. and thus may have been effective by reducing myocardial O 2 demand.

Medical treatment to reduce total ischemic burden: Total ischemic burden bisoprolol study (TIBBS), a multicenter trial comparing bisoprolol and nifedipine

Objectives. We compared the effects of bisoprolol on transient myocardial ischemia with those of nifedipine in patients with chronic stable angina.Background. Both beta-adrenergic blocking agents and calcium antagonists reduce transient ischemic episodes, but comparisons of these agents have been made in only a few larger studies.Methods. The Total Ischemic Burden Bisoprolol Study (TIBBS) was a randomized double-blind controlled study with two parallel groups; 330 patients from 30 centers in seven European countries with stable angina pectoris, a positive exercise test and more than two transient ischemic episodes during 48 h of Holter monitoring (central evaluation) were included. Of these patients 161 were randomized to receive bisoprolol and 169 to receive nifedipine slow release. There were two treatment phases of 4 weeks each, with 48-h Holter monitoring after each phase. During phase 1, patients received either 10 mg of bisoprolol daily or 2 × 20 mg of nifedipine slow release. During phase 2, they received either 20 mg of bisoprolol daily or 2 × 40 mg of nifedipine slow release.Results. In phase 1 of the trial, 4 weeks of bisoprolol therapy (10 mg daily) reduced the mean [±SD] number of transient ischemic episodes from 8.1 ± 0.6 to 3.2 ± 0.4/48 h. Nifedipine (2 × 20 mg) reduced transient ischemic episodes from 8.3 ± 0.5 to 5.9 ± 0.4/48 h. Total duration of ischemia was reduced from 99.3 ± 10.1 to 31.9 ± 5.5 min/48 h with bisoprolol and from 101 ± 9.1 to 72.6 ± 8.1 min/48 h with nifedipine. Reductions were statistically significant for both drugs; the difference between bisoprolol and nifedipine was also significant (p < 0.0001). Bisoprolol reduced the heart rate at onset of episodes by 13.7 ± 1.4 beats/min from a baseline value of 99.5 ± 1.2 beats/min (p < 0.001). Heart rate was unchanged with nifedipine. Bisoprolol had significantly higher responder rates than nifedipine. Doubling of the dose in phase 2 of the trial had small additive effects. Only bisoprolol showed a marked circadian effect by reducing the morning peak of transient ischemic episodes (by 68% at peak time, 8:00 to 8:59 am).Conclusions. Both bisoprolol and nifedipine reduced the number and duration of transient ischemic episodes in patients with chronic stable angina. Bisoprolol was significantly more effective than nifedipine in both doses tested and reduced the morning peak of ischemic activity.

Efficacy and Safety of Bepridil in Chronic Stable Angina Pectoris Refractory to Nifedipine.

The efficacy and safety of bepridil in chronic stable angina pectoris refractory to an extended-release preparation of nifedipine were evaluated in this open-label prospective study. Patients whose angina had not responded adequately to maximum tolerated doses of nifedipine received bepridil for 8 weeks after a 2-week baseline period at their established dose of nifedipine. Twenty-five patients entered the bepridil treatment period. Total exercise time (mean plus minus SD) was significantly increased at the end of bepridil therapy (9.3 plus minus 2.3 min) compared with the end of nifedipine baseline period (8.40 plus minus 2.3 min, p = 0.02). Time to the onset of angina increased from 6.1 plus minus 2.7 min to 8.1 plus minus 2.3 min, p < 0.01. Time to 1-mm ST depression increased from 7.0 plus minus 2.7 min to 8.4 plus minus 2.3 min, p < 0.01. Nitroglycerin consumption decreased from 3.01 plus minus 5.6 to 0.56 plus minus 1.3 tablets week(minus sign1), p < 0.05. The mean weekly angina attack rate decreased from 4.34 plus minus 5.3 to 1.33 plus minus 2.2, p < 0.01. Therapy with bepridil resulted in few adverse experiences. The mean QT(c) interval was significantly prolonged from 0.40 + 0.03 s at baseline to 0.45 + 0.045 s at the end of bepridil therapy (p < 0.001). There were no serious adverse events. The results of this study indicated that bepridil provides effective and safe treatment of stable angina pectoris in patients whose angina is not adequately controlled by nifedipine.

Liver enzyme activities after multiple administration of nifedipine in mice.

The effect of multiple nifedipine administration on hexobarbital sleeping time, liver monooxygenase and synthetase activities, lipid peroxidation and microsomal membrane fluidity were studied in male albino mice. The drug was administered orally at a dose of 25 mg/kg daily for 14 and 21 days. Nifedipine caused enzyme induction, demonstrated by shortened hexobarbital sleeping time, enhanced ethylmorphine N-demethylase, aniline 4-hydroxylase, ethoxycoumarine O-deethylase, UDP-glucuronyl transferase, glutathione S-transferase and NADPH-cytochrome c reductase activities and increased content of cytochrome P450 and cytochrome b5. This effect persisted until the 7th day after the last dose of nifedipine. There were no changes in lipid peroxidation and fluidity of the microsomal membranes after 14-day nifedipine administration. The increased cytochrome P450 content and drug metabolizing enzyme activities could be not associated with changes in these liver microsomal membrane properties.

Vasodilators: Scorpion envenoming and the heart (an Indian experience)

Our aim was to assess clinically whether there was any benefit in adding a single dose of sublingual nifedipine (a slow calcium channel blocker) to prazosin in the management of the cardiovascular manifestations of envenoming by the Indian red scorpion ( Mesobuthus tamulus). A total of 163 patients stung by this species was admitted to hospital at Mahad between January 1991 and October 1993. Cardiovascular abnormalities were hypertension (59), of whom 42 had bradycardia and 17 had tachycardia; pulmonary oedema (14), of whom eight had hypertension and six hypotension; supraventricular tachycardia (eight), of whom three had hypotension and one died. Of the remaining patients, 78 demonstrated severe excruciating local pain at the site of sting but had no systemic involvement. Nineteen patients with hypertension and tachycardia were given a single dose of sublingual nifedipine plus prazosin on admission, then prazosin alone repeated 6 hourly. Five patients with massive life-threatening pulmonary oedema recovered after being given intravenous sodium nitroprusside. Prazosin alone helped to alleviate cardiovascular manifestations in the remaining 52 victims. One patient was admitted in a deep coma, 12 hr after the sting, and died. Eight victims whose blood pressure had been controlled in hospital by nifedipine plus prazosin developed acute pulmonary oedema necessitating additional doses of prazosin for recovery. Fifty-two victims treated with prazosin alone did not develop pulmonary oedema and the drug appeared to hasten the recovery. In the presence of high blood pressure, tachycardia, a murmur and impending myocardial failure, nifedipine appeared to contribute to cardiopulmonary instability and to augment myocardial oxygen consumption. In this situation calcium channel blockers should probably be avoided.

Effects of a new calcium antagonist, CD-832, on coronary and systemic hemodynamics in conscious dogs.

The effects of a new calcium antagonist, CD-832, on coronary and systemic hemodynamics were compared with those of nifedipine in conscious dogs. A pair of 10-MHz piezoelectric crystals and an electromagnetic flow probe were placed on the left circumflex coronary artery (LCX) under sterile conditions to measure epicardial coronary artery diameter (CoD) and coronary blood flow (CBF), respectively. CD-832 (30, 100, and 300 micrograms/kg) and nifedipine (3, 10, and 30 micrograms/kg) produced dose-related increases in large epicardial CoD and in CBF. At doses of CD-832 (100 micrograms/kg) and nifedipine (30 micrograms/kg), producing the same increases in CoD and CBF, the duration of increases in CoD and in CBF was markedly longer after CD-832 than after nifedipine. CD-832 and nifedipine produced dose-related decreases in aortic blood pressure (AoP) and reflex increases in heart rate (HR). However, nifedipine produced significantly (p < 0.01) greater tachycardia than CD-832 in equieffective hypotensive doses. These results demonstrate that CD-832 produces sustained dilation of both large epicardial coronary arteries and small resistance vessels and that the degree of tachycardia after CD-832 is significantly less than that after nifedipine.

Comparative effects of the flavonoids luteolin, apiin and rhoifolin on experimental pulmonary hypertension in the dog

AbstractThe acute effects were compared of selected flavonoids on the pulmonary vascular circuit in two experimental models of pulmonary hypertension, produced by hypoxia and by prostaglandin F2α (PGF2α) in anaesthetized dogs. In all dogs, haemodynamic variables (pulmonary artery pressure, pulmonary artery wedge and aortic pressure, pulmonary vascular resistance, cardiac output) were recorded in the control state, during hypoxia or PGF2α‐induced pulmonary vasoconstriction, and after equimolar doses (5 mM/kg/i.v.) of luteolin, apiin and rhoifolin. The effects observed after flavonoid administration were compared with those of equimolar doses of nifedipine. The results obtained have shown that luteolin and apiin caused a decrease of hypoxic pulmonary vascular resistance to normoxic values and of the pulmonary arterial pressure while cardiac output remained unchanged. Rhoifolin produced no change in hypoxic pulmonary vasoconstriction, but decreased cardiac output and aortic pressure. The response of the pulmonary hypertension induced by PGF2α to flavonoids and nifedipine was nearly identical to that of hypoxia‐induced pulmonary hypertension. The mechanism of action of these flavonoids is discussed.

Effects of felodipine versus nifedipine on exercise tolerance in stable angina pectoris

The effects of single doses of felodipine (5 and 10 mg) and nifedipine (10 and 20 mg) on chronic stable effort angina pectoris were assessed in a placebo-controlled, double-blind, crossover study of 24 patients receiving β blockers and short-acting nitroglycerin. The effects were measured by repeated bicycle ergometer tests. The total work, and time until 1 mm of ST depression increased significantly by 9 to 31% after both active drugs at both dose levels in comparison with placebo. The differences were not significant between drugs or doses. At rest, blood pressure decreased (10 to 15%) and heart rate increased (5 to 10%) significantly after both active drugs. During exercise at the highest comparable work load, systolic blood pressure decreased significantly (23 to 26%), whereas heart rate was not affected after felodipine and nifedipine compared with placebo. The 2 drugs were well tolerated, and side effects were mild. Therefore, single doses of 5 and 10 mg of felodipine, and 10 and 20 mg of nifedipine have similar antiangnal and anti-ischemic properties. However, felodipine has a longer duration of action, which may improve compliance.

CALCIUM CHANNEL ANTAGONISTS IN THE TREATMENT OF INTERSTITIAL CYSTITIS

The calcium channel antagonist nifedipine has shown efficacy in the treatment of interstitial cystitis and the urethral syndrome. The optimal daily dose of nifedipine can be determined with the use of a nifedipine titration test. To complete the repair of damaged bladder and/or urethral mucosa, nifedipine therapy should be used for a minimum of 3 months. Patients who do not respond well to nifedipine are those with the pelvic floor muscle spasm syndrome variant of interstitial cystitis.

Actions of a new Ca 2+ channel antagonist, CD832, on two types of Ca 2+ channels in smooth muscle

The purpose of this study was to determine the characteristics of blockade of L- and T-type Ca 2+ channels by a new Ca 2+ channel antagonist, 3-(2-nicotinoylamino)ethyl 5-(3-nitrooxypropyl) 2,6-dimethyl-4-(3-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylate hydrochloride (CD832), in comparison with those of nifedipine, in rat aortic smooth muscle cells in primary culture. In a whole-cell configuration under voltage-clamp, CD832 and nifedipine dose dependently blocked both L- and T-type Ca 2+ currents (L- and T-type I Ca) without shifting the axis of the current-voltage relations. The 50% inhibition concentration (IC 50) of CD832 was 310 nM for L-type and 1.1 μM for T-type I Ca. The IC 50 of nifedipine was 36 nM for L-type and 2.7 μM for T-type I Ca. CD832 blocked both types of I Ca from the first step pulses after drug application, shifted their steady-state inactivation curves to the left, and did not significantly accelerate the current decay. The effect of CD832 reached its maximum within 6 min and was hardly washed out, while that of nifedipine reached a maximum within 30 s and could be washed out within 3 min. These results suggest that (1) CD832 blocks L-type I Ca less potently than does nifedipine, (2) CD832 blocks T-type I Ca more potently than does nifedipine, (3) CD832 blocks not only the resting state but, more preferentially, the inactivated state of L- and T-type Ca 2+ channels, and (4) CD832 has a slow and long-acting activity in blocking both types of I Ca as compared with nifedipine.

Verapamil and nifedipine in combination for the treatment of hypertension.

The authors examined the efficacy and safety of the combination of verapamil and nifedipine in the control of hypertension. Retrospective analysis of blood pressures was obtained on 50 patients who had historically documented essential hypertension and were receiving verapamil and nifedipine. The patients had moderate to severe hypertension; 27 of 50 (54%) were uncontrolled on prescribed regimens of two or more separate classes of drugs. Control was defined by the ability to maintain a blood pressure of < or = 160/90 by providing doses of verapamil (max: 480 mg/day) and nifedipine (max: 180 mg/day). Twenty-nine (58%) were black and 21 (42%) were white. Ages ranged from 16 to 84 years. Mean duration of therapy was 1-2 years. Only 3 of 50 (6%) were control failures after providing verapamil and nifedipine. Three of 50 (6%) were discontinued because of side effects--reversible hepatitis (2) and rash (1). There were no serious adverse events, i.e., CHF or arrhythmias. Manageable ankle edema was seen in 14 of 50 (28%) patients. Verapamil and nifedipine, a combination of a dihydropyridine and a non-dihydropyridine calcium antagonist, was effective and safe in this group of patients with difficult-to-manage hypertension.

Suppression of follicle-stimulating hormone by the gonadal- and neurosteroid 3 alpha-hydroxy-4-pregnen-20-one involves actions at the level of the gonadotrope membrane/calcium channel.

We have previously shown that the gonadal- and neurosteroid 3 alpha-hydroxy-4-pregnen-20-one (3 alpha HP) suppresses FSH release in cultures of anterior pituitary cells. We undertook exploration of the mechanisms of this suppression by examining the possible sites of 3 alpha HP action in isolated anterior pituitary cells of rats. The specific objective of this study was to determine if 3 alpha HP suppresses FSH by action at the level of the gonadotrope membrane and/or calcium channels. Pituitary cells from adult randomly cycling female rats were precultured for 72 h and then treated for 4 h with 10 nM GnRH and 0.1 nM 3 alpha HP with or without Ca2+ channel agonists or antagonist. In other experiments, cells were treated with BSA-conjugated 3 alpha HP, progesterone, or 3 beta HP (the stereoisomer of 3 alpha HP). Levels of FSH were determined by RIA in media and cells. GnRH-stimulated FSH release and the total FSH (released plus cellular) were significantly suppressed by 3 alpha HP. The Ca2+ ionophore A23187 induced FSH release and 3 alpha HP significantly suppressed both released and total FSH in its presence. In combination with a high dose (100 microM) of the dihydropyridine-sensitive Ca2+ channel antagonist nifedipine, 3 alpha HP suppressed FSH secretion to a greater extent than the antagonist alone. Cellular content of FSH was also decreased by nifedipine (100 microM) and was further suppressed in the presence of 3 alpha HP. The phenylalkylamine-sensitive Ca2+ channel antagonist methoxyverapamil (D600) suppressed GnRH-induced FSH release, and 3 alpha HP significantly potentiated the suppression. Released and cellular FSH were increased by the dihydropyridine-sensitive agonist BAYK 8644, whereas 0.1 nM 3 alpha HP suppressed this agonist-induced FSH to a greater extent than the maximum dose (100 microM) of nifedipine. In order to test for direct action at the level of the gonadotrope membrane, 3 alpha HP was conjugated to BSA (3 alpha HP-BSA) and administered to cultured pituitary cells. The 3 alpha HP-BSA conjugate (but not progesterone-BSA or 3 beta HP-BSA) significantly suppressed release of FSH. The results of the study suggest that 3 alpha HP may be interacting with the Ca2+ channel component of the GnRH signal transduction mechanism; in addition, 3 alpha HP may also suppress FSH release (and possibly synthesis) through direct action at the level of the gonadotrope membrane.

Modification of Exercise Performance by Sharp Reduction of Blood Pressure: A Study in Patients With Uncomplicated Hypertension

We evaluated exercise performance in 14 patients with uncomplicated essential hypertension 1 h after the administration of a single dose of placebo, nifedipine (20 mg), captopril (50 mg), and propranolol (80 mg). Drugs were administered at the same time of day following a randomized, double-blind protocol. Mean resting blood pressure (+/- SE) was 135 +/- 3 mm Hg with placebo administration, 118 +/- 4 with captopril, 110 +/- 4 with nifedipine, and 115 +/- 5 with propranolol and increased with exercise to 163 +/- 4, 146 +/- 3, 136 +/- 4, 136 +/- 4, respectively. Oxygen consumption at peak exercise and at ventilatory anaerobic threshold (VAT) was 25.2 +/- 1.1 and 18.1 +/- 1.0 ml/min/kg with placebo. Only propranolol (-2.3 ml/min/kg) decreased peak exercise oxygen consumption. Oxygen consumption at VAT was reduced by nifedipine and propranolol but unaffected by captopril. The effects on exercise capacity of blood pressure reduction in hypertensive patients are dependent on the drug utilized and are not related to the amount of blood pressure reduction. The lowered oxygen consumption at VAT observed with nifedipine and propranolol, and not with captopril, might be due to an excessive downward shift of the muscle perfusion pressure--oxygen consumption relationship which might take place during exercise.