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Nifedipine, a slow-channel calcium blocker, is thought to provide useful myocardial protection during prolonged total ischemia and reperfusion. An isolated, isovolumic, feline heart model was used to asses the effectiveness of nifedipine in both cardioplegic (100 microgram/10 ml) and noncardioplegic (10 microgram/10 ml) doses for providing myocardial preservation during 90 minutes of hypothermic ischemic arrest and 45 minutes of normothermic reperfusion. Use of nifedipine was compared to hypothermia (27 degrees C) alone and to hypothermia with potassium cardioplegia. Ventricular function was assessed by recovery of isovolumic left ventricular developed pressure and dP/dt. Myocardial carbon dioxide tension (PCO2) and myocardial oxygen tension (PO2) were measured by mass spectrometry. Potassium cardioplegia and the higher dose of nifedipine resulted in immediate asystole. The rates of rise of PCO were greatest in the group receiving 10 microgram nifedipine and in the control group. The rates of rise in the two cardioplegic groups were significantly lower. Recovery of ventricular function was significantly lower with low-dose nifedipine than with potassium cardioplegia. Higher dose nifedipine resulted in a return of function, which was no different than with potassium cardioplegia. Morphologic protection was better with higher dose nifedipine and potassium cardioplegia than with either low-dose cardioplegia or hypothermia alone. These results demonstrate that nifedipine in a cardioplegic dose results in preservation of myocardial structure and function that is similar to that obtained with potassium cardioplegia. In lower noncardioplegic dose, nifedipine does not appear to offer additional protection compared to hypothermia alone. Whether persistent depression of ventricular contractility will limit nifedipine's clinical usefulness as a myocardial protection agent will require further study.
Twenty-one patients, mean age 60.3 years, with stable angina pectoris earlier treated with beta-blockers, were investigated with standardized exercise tests to evaluate the action of nifedipine alone and in combination with a beta-blocker. The first exercise test was performed 3 weeks after treatment with the patient's usual beta-blocker. Following this, the patients were tested twice after a double-blind cross-over 3-week trial with nifedipine and placebo. The patients were subsequently treated for 3 weeks with nifedipine 10 mg 3 times daily or placebo and then performed an exercise test. During the 4th period of 3 weeks the patients took a combination of nifedipine, 10 mg 3 times daily, and their usual beta-blocker and then performed the final exercise test. Nifedipine alone raised the heart rate by 5 beats/min at rest and diminished the systolic blood pressure at rest by 17 mm Hg. During exercise at comparable load the heart rate did not change significantly, but the systolic blood pressure decreased with 22 mm Hg. The exercise tolerance expressed as total work increased on a average by 20%, range-14 - + 194%. Nifedipine in combination with a beta-blocker gave a further decrease in the systolic blood pressure, totally 37 mm Hg at comparable load. The exercise tolerance increased more, totally by an average of 41%. There was a significant correlation between basal values for systolic blood pressure registered during the placebo period at rest and the percentage change in total work. The atrioventricular conduction time did not change significantly compared to placebo during treatment with nifedipine or the combination nifedipine + beta-blocker. No serious side-effects were observed during the study.
Nifedipine was evaluated in the management of eight patients with intractable coronary arterial spasm. All had Prinzmetal's variant angina, normal or mildly abnormal coronary arteriograms, and a positive ergonovine maleate provocative test. Anginal attacks occurred at least three times a week in all patients during isosorbide dinitrate therapy. All patients had a decrease in frequency of ischemic attacks with nifedipine. Seven patients underwent repeat Holter monitor evaluation, which confirmed the absence of ischemic changes while they were taking nifedipine. When nifedipine dosage was decreased.or therapy discontinued in six patients, all experienced a recurrence of anginal attacks. Two patients had minor side effects, which required a decrease in the dose of nifedipine. Nifedipine was well tolerated, and no major complications occurred with its use. Nifedipine appears to be effective in the management of patients with symptomatic coronary arterial spasm and normal or mildly abnormal coronary arteriograms. Our data justify further investigation of nifedipine for treatment of such patients.
The effect of nifedipine on effort angina was investigated by means of exercise tests with bycicle ergometer and compared, in the same patients, with the effects of a nitroderivative and a betablocking agent. Five patients with stable effort angina entered the study, after an hemodynamic and contrasto-graphic control. According to the protocol of a latin square 5 X 5, all the patients received in a random sequence the following treatments: placebo, 1 c. orally; isosorbide dinitrate, 5 mg sublingually; propranolol, 40 mg orally; nifedipine, 10 mg sublingually; nifedipine, 10 mg orally. No significant change of any of the considered parameters was observed after the placebo. Isosorbide dinitrate and nifedipine produced significant increases of the duration of work before appearance of pain and EKG positivity, and of total work performed before anginal pain. Only the duration of work before EKG positivity was improved by propranolol. The comparisons between treatments showed no significant difference of the effects of the administered doses of isosorbide dinitrate and nifedipine. The improvements observed after propranolol were significantly lower than that observed after isosorbide dinitrate and oral nifedipine. On the basis of the observed changes of cardiac rate, maximal arterial pressure, ejection time index and triple product, the authors evaluate the possible mechanism of action of nifedipine.
The clinical response to therapy with the calcium-blocking agent nifedipine was assessed in 12 patients with variant angina pectoris who were 44 to 67 years old. Five patients had vasospasm of the left anterior descending coronary artery, and seven had spasm of a dominant right coronary artery. Before nifedipine therapy, the frequency of anginal attacks per 24 hour period ranged from 1 to 12, with ventricular tachycardia accompanying ischemic episodes in 7 of 12 patients and high grade atrioventricular block occurring in 2 patients. After therapy with nifedipine, 11 of 12 patients had initial relief of symptoms, and 7 of the 11 had long-term relief. Withdrawal of nifedipine led to recurrence of angina on six occasions in four patients. Provocative testing in the cardiac catheterization laboratory by means of the cold pressor test in one patient and ergonovine maleate in another before and after nifedipine administration showed that this agent can block both alpha adrenergic- and regonovine-induced vasospasm. Nifedipine may have a significant role in the therapy of angina caused by coronary spasm.
Smooth muscle preparations of the urethra, bladder, and ureter were obtained from patients undergoing operations for various urological disorders. The urethral preparations were contracted by noradrenaline (0.1-3 microgram . ml-1), prostaglandin F2alpha (1-10 microgram . ml-1), and potassium (127 mM), the bladder preparations by carbacholine (0.004-1 microgram . ml-1), prostaglandin F2alpha (1-10 microgram . ml-1), potassium (127 mM), and barium chloride (3 mM), and the ureter preparations by potassium (127 mM), and barium chloride (3 mM). Irrespective of the mode of activation, pretreatment with nifedipine (0.1 microgram . ml-1) for 10 min. reduced the responses. Nifedipine also relaxed preparations contracted by the contractile agents used. In 19 female patients, aged 20 to 73 years, undergoing investigation because of urgency and/or urge incontinence, simultaneous urethrocystometry at rest was performed before and after oral administration of 20 to 40 mg nifedipine. Bladder capacity and residual urine were also determined. Nifedipine did not affect the pressures within the bladder and urethra, nor did it increase the bladder capacity. However, after nifedipine intake there was a statistically significant increase in residual urine. The results suggest that nifedipine can inhibit contractile activity induced by drugs with different modes of action; the drug does not affect the tone in bladder and urethra.
Isometric tension was recorded in ring preparations of human peripherial arteries and veins contracted by potassium (127mM) and noradrenaline (1.8 X 10(-5)M). In the veins, nifedipine had a marked relaxing effect on contractions induced by both agents, and also reduced the contractile amplitude when added prior to stimulation. The inhibiting effect of nifedipine was more marked on the potassium than on the noradrenaline-evoked responses. This was in contrast to verapamil, which inhibited the noradrenaline-induced contractions significantly more, than those produced by potassium. After immersion of the vein preparations in calcium-free medium for 30 min., the potassium contracture decreased to 26+/2.0% (mean +/ S.E.M.) of the response in normal Krebs solution, and the noradrenaline-evoked to 7.1+/0.8%. The responses to both agents were completely restored when the calcium concentration was increased from 0 to 4 mM. Nifedipine (1.5X10(-7)M) depressed the potassium contracture in calcium-free solution to 7.3+/1.6%, and the noradrenaline response to 5.5+/1.6%; on addition of calcium, the response elicited by potassium increased to 16+/1.7%, and that by noradrenaline to 56+/8.6%. Compared with its actions on the veins, the effect of nifedipine on the arterial preparations was less pronounced. In the arteries, too, the inhibiting effect of nifedipine was significantly more pronounced on the potassium than on the noradrenaline-induced contraction. Immersion for 30 min. in calcium-free medium reduced the response to potassium to 61+/6.0% and that to noradrenaline to 68+/5.6% of the control in normal Krebs. Nifedipine (2.9X10(-7)M) further reduced the potassium contraction to 20+/4.0%; the response to noradrenaline was unaffected, being 74+/6.4% of the control.
The effect of pretreatment with verapamil (100 micrograms/kg i.v.) or nifedipine (10 micrograms/kg i.v.) on ischemic myocardial metabolism was studied in dogs anesthetized with pentobarbital. The results are summarized as follows: 1. Verapamil or nifedipine lowered both systolic and diastolic blood pressures markedly, and increased heart rate slightly. 2. Verapamil or nifedipine increased both endo- and epicardial phosphorylase activities significantly. 3. Coronary artery ligation increased the phosphorylase activity, and also increased the levels of glucose-6-phosphate, fructose-6-phosphate, and lactate, and decreased the levels of glycogen, fructose-1,6-diphosphate, and phosphocreatine in both endo- and epicardial layers, without affecting the level of the endo- and epicardial adenosine triphosphate. 4. In the presence of verapamil or nifedipine, coronary artery ligation did not increase but decreased the phosphorylase activity that had been increased by verapamil or nifedipine alone. 5. Changes in the levels of intermediates induced by coronary artery ligation were not markedly influenced by pretreatment of the dog with verapamil or nifedipine.
Acute sublingual administration of nifedipine 10--20 mg to 13 hypertensive patients caused a rapid decrease in blood pressure (BP) and a concomitant increase in heart rate (HR), plasma noradrenaline (NA) and plasma renin activity (PRA); there was no significant change in plasma adrenaline (A) or aldosterone (ALDO). Basal PRA was the major determinant of the rise in PRA, as a close correlation was present between the basal value and the increase caused by nifedipine (r = 0.92), p less than 0.001). The rise in PRA was also correlated with the plasma concentration of nifedipine after 60 min (r = 0.80, p less than 0.01), but it was not correlated with the decrease in BP, the rise in HR or the increase in NA. Nifedipine 30--60 mg daily for 6 weeks caused a reduction in mean BP from 133 to 113 mmHg (p less than 0.001). Body weight and serum potassium decreased but no consistent change was noted in NA, PRA, ALDO or 24 h-excretion of catecholamines. A significant correlation was present between the change in NA and that in PRA (r = 0.74, p less than 0.01). The alterations in the various parameters in the acute and chronic studies were not correlated. The findings indicate that different regulatory mechanisms are activated during acute and chronic administration of nifedipine. It is suggested that an initial rise in sympathetic activity gradually decreases during prolonged therapy, but it still remains a determinant of PRA.
Isolated preparations of the thoracic aorta from spontaneously hypertensive rats (SHR) and normotensive Wistar rats (NWR) were contracted by noradrenaline (NA) 1.8 X 10(-5)M, and potassium (K+) 127 mM, after 30 min. pretreatment in a Ca++-free medium. In both SHR and NWR aortae, the contractions were markedly reduced; no significant differences were found between the two types of vessels in Ca++-free medium. On addition of Ca++, the contractions were restored to a significantly greater extent in the NWR than in the SHR aortae. In the presence of nifedipine 7.2 X 10(-9)M, the response to Ca++ was significantly more reduced in the SHR than in the NWR preparations. Relaxation of NA and K+ contracted preparations was induced by wash-out of the contractile agents, by addition of nifedipine 2.9 X 10(-8)M, and by introduction of a Ca++-free medium. After wash-out of NA, relaxation was slower in SHR than in NWR vessels. Relaxation induced by nifedipine and Ca++-free medium was more complete in SHR than in NWR preparations. After wash-out of K+, relaxation was more rapid in NWR than in SHR aortae. Nifedipine and Ca++-free medium induced relaxation was more complete in SHR than in NWR preparations. The results suggest that in the SHR aortae contraction induced by NA and K+ is more dependent on extracellular Ca++ than is the response in the NWR preparations; the SHR vessels are also more sensitive to the relaxing effects of nifedipine.
Ring preparations of human mesenteric arteries and veins were contracted by noradrenaline (1.8 x 10(-5)M) or potassium (127mM). Isometric tension was recorded. In the arterial preparations, the maximum response to noradrenaline was 97 +/- 8% (mean +/- S.E.M.) of that to potassium. In the veins, the corresponding figure was 38 +/- 4%. The calcium antagonists verapamil (2.2 x 10(-7)-2.2 x 10(-5)M) and nifedipine (2.9 x 10(-8)-2.9 x 10(-6)M) relaxed both arteries and veins contracted by noradrenaline or potassium, and reduced the responses to these agents when added 15 min. before stimulation. The time course of relaxation of potassium contracted preparations, induced by verapamil and nifedipine, was more rapid and complete than that produced by a calcium-free, high potassium solution. In contrast to verapamil, nifedipine caused a more pronounced inhibition of the potassium than of the noradrenaline evoked contractions in both arteries and veins. After exposure to a calcium-free medium for 30 min., the arterial response to noradrenaline was significantly (P less than 0.05) greater than that to potassium. However, the reverse was found in the veins. In both types of vessel, verapamil (2.2 x 10(-6)M) and nifedipine (2.9--10(-7)M) were equi-effective in reducing the noradrenaline reactivity, not only between mesenteric arteries and veins, but also between, e.g. peripheral and mesenteric vessels. The calcium antagonists nifedipine and verapamil do not have an identical mode of action. However, both agents seem to inhibit influx of extracellular calcium, and might also have an inhibitory effect on the release of intracellular calcium.
We performed in vitro experiments with a small volume chamber to determine the inhibitory effect of nifedipine on serotonin-, phenylephrine-, and potassium-induced contractions of canine basilar and femoral arteries. Nifedipine, an inhibitor of the influx of extracellular calcium into smooth muscle cells, was found to be a sensitive inhibitor of contractions of the basilar artery induced by all three agents. In contrast, nifedipine did not significantly inhibit the serotonin- and phenylephrine-induced contractions of the femoral artery but did inhibit potassium-induced contractions of the femoral artery. Calcium-induced contractions of the basilar artery were also inhibited by nifedipine. These experiments demonstrate a relatively selective effect of nifedipine on the basilar artery, and a mechanism to explain this selective effect is postulated.
A single blind randomized parallel study designed to assess the anti-anginal efficacy of pindolol and nifedipine was carried out in 42 ambulatory coronary patients with stable angina pectoris. Drug efficacy was assessed in terms of (a) pain, (b) frequency of anginal episodes, (c) nitroglycerin consumption, (d) exercise tolerance and (e) ST-segment changes. The effect of these drugs on asymptomatic resting myocardial ischemia was also assessed by means of 24-h dynamic electrocardiography (DCG). All patients were checked at weekly intervals. At the end of a 4-wk placebo period, the patients were randomly assigned either to the pindolol or nifedipine group. The treatment lasted for 45 days. During the placebo period, ischemic ECG changes and symptoms of coronary insufficiency were detected in all patients. Furthermore, 12 out of 42 patients had asymptomatic myocardial ischemia at rest. One patient from each group was dropped because of tolerance. At the end of the 45-day study, pindolol and nifedipine were equi-effective on spontaneous and effort-related angina. There were, however, some differences: increased tolerance to exercise appeared earlier with pindolol: the pindolol group showed a slightly reduced while the nifedipine group showed a slightly increased heart rate. Furthermore, nifedipine reduced or eliminated asymptomatic myocardial ischemia in 6 out of 7 patients while only 1 out of 5 improved in the pindolol group.
In the present study we assessed plasma renin activity (PRA) variations induced by Ca++ antagonist antihypertensive drug Nifedipine in 8 normoreninaemic or hyporeninaemic hypertensive patients. On two successive days three venous blood samples were sampled, two in clinostatic position and the last one 120 min later in orthostatic position; on the second day 20 mg of nifedipine were administered sublingually. Nifedipine increases significantly PRA after orthostatic position compared with starting conditions (p < 0.01) and compared with the values recorded without the drug at the same times (p < 0.01). Both systolic and diastolic blood pressure decreased 15 and 120 min after nifedipine administration while heart rate increased at the same times. Acute nifedipine administration augments PRA in hypertensive subjects; explanatory hypoteses are proposed.
The effectiveness of the calcium antagonist nifedipine in preserving postischemic myocardial function and structural integrity was experimentally demonstrated in isolated rabbit hearts, in conscious dogs subjected to myocardial infarction, in open chest anesthetized dogs with normothermic regional ischemia induced for 1 to 2 hours and in dogs undergoing hypothermic global ischemia for 2 hours followed by 2 hours of reperfusion. Nifedipine had a beneficial effect on postischemic myocardial stiffness and mitochondrial calcium accumulation, which were correlated. Administration of nifedipine at the onset of myocardial infarction increased blood flow to ischemic zones of myocardial infarction and resulted in less loss of creatine kinase. It reduced by two- to three-fold the volume of the ischemia-reperfusion injury induced by left anterior descending coronary arterial occlusion and release and preserved indexes of hemodynamic function. Nifedipine was found effective in protecting myocardial performance and structure after 2 hours of global ischemia during hypothermic cardiopulmonary bypass. It is suggested that this agent may be useful as an adjunct to cold cardioplegia in man for enhanced myocardial protection during cardiac surgery.
1. Nifedipine, a calcium antagonist drug, was given sublingually (10 mg) to seven normal subjects and 19 patients with essential hypertension. In addition, 12 of the hypertensive subjects then received nifedipine (10 mg thrice daily) for 3 weeks. 2. Sublingual administration of nifedipine in hypertensive patients induced a prompt and sustained reduction of blood pressure, without a significant increase of heart rate; in normotensive subjects blood pressure did not change, and heart rate was significantly increased. After chronic treatment, blood pressure remained reduced and heart rate did not rise. 3. Plasma catecholamines and plasma renin activity increased significantly in normotensive subjects after acute administration. 4. After both acute and chronic administration, only plasma noradrenaline was significantly increased in hypertensive patients; in long-term treatment, it was increased in both the lying and standing positions. 5. Nifedipine is an active antihypertensive drug, which may induce some degree of sympathetic activation.
The effects of the calcium antagonist, nifedipine, on uterine activity induced by prostaglandins F2 alpha (PGF2 alpha) and E2 (PGE2) were studied in women undergoing therapeutic midtrimester abortion, and in patients with a missed abortion in the 16th to 27th week of pregnancy. In the five subjects receiving intra-amniotic PGF2 alpha (25 to 40 mg) for midtrimester abortion, nifedipine (30 mg orally) decreased uterine activity from a mean of 372 to 203 Montevideo Units. The effect on the intensity of the contractions was pronounced; frequently and basal tone were little affected. In patients with missed abortion, uterine contractions were induced by extra-amniotic application of PGE2 (0.5 to 1.5 mg) in a viscous gel. The activity was often more irregular than that in the women receiving intra-amniotic PGF2 alpha. However, nifedipine (30 mg orally) had a marked inhibitory effect on the uterine contractions. It is concluded that nifedipine can be used for treatment of uterine hyperactivity induced by prostaglandins. Combined treatment with beta 2-adrenoceptor stimulants might be considered.