Calcium Channel Blocking Agent Nifedipine Research Articles

Effects of endothelin, calcium channel blockade and EDRF inhibition on the contractility of human uteroplacental arteries

In order to examine the possibility that endothelin might be important in the regulation of placental blood flow, human uteroplacental vessels were superfused in vitro to study the contractile effect of endothelin as compared with a known strong contractor of placental blood vessels, serotonin (5-HT). The contractile responses were compared in the presence and absence of calcium channel blocking agents, as well as in the presence of L-NMA, an inhibitor of EDRF/nitric oxide. Endothelin (ET, 10(-10)-10(-6) M) and 5-HT (10(-8)-10(-4) M) induced contractions in the vessels. Maximal contractions in the presence of endothelin were elicited at 10(-7) M, whereas 5-HT elicited maximal contractions at 10(-5) M. At 10(-7) M, ET was more potent than 5-HT. The calcium-channel blocking agents nifedipine, diltiazem and NiCl2 relaxed the vessels by 5-15% from baseline. The contractile response to ET in the presence of nifedipine or diltiazem was reduced by 55 and 67%, respectively. The response of 5-HT in the presence of nifedipine was reduced by 58%. The contractile response to 5-HT as well as ET in the presence of both nifedipine and NiCl2 was not significantly lower than in the presence of nifedipine only. The EDRF-inhibiting agent L-NMA caused a small contractile response at concentrations of 10(-6)-10(-5) M. ET as well as 5-HT added after pretreatment with L-NMA produced a larger contractile response than ET or 5-HT alone. The results show that ET has a strong contractile effect on placental blood vessels at concentrations likely to occur during labor and delivery. The mechanism whereby ET as well as 5-HT contracts placental vessel smooth muscle appears to partly involve nifedipine- and diltiazem-sensitive calcium channels, but almost half of the response depends on mobilization of calcium through other means.

Endothelin contracts human uterine myometrium by a partly dihydropyridine‐sensitive mechanism

The effect of endothelin (ET), a recently discovered 21-amino-acid polypeptide with powerful vasoconstrictor properties, was examined on human uterine myometrial strips in vitro. ET dose-dependently (10(-11)-10(-7) M) increased the contractile force (monitored as contraction amplitude) of the myometrium with significant effects at 10(-8) and 10(-7) M. ET (10(-8) M and up) also increased the basal tone of the myometrium. The calcium channel blocking agents nifedipine (10(-7) M) and diltiazem (10(-6) M) both inhibited the spontaneous tonic contractions of the myometrium. When ET was given in the presence of nifedipine, the tonic contractions were further inhibited, whereas the ET-induced increase in basal tone remained. The same result was obtained with diltiazem (10(-6) M). The results indicate that the contractility of human myometrium may be modulated by ET, and that the effects of ET on the human myometrium are only partly mediated by dihydropyridine-sensitive calcium channels.

Differing calcium sensitivities of human cerebral and digital arteries, human metatarsal veins, and rat aorta.

1. The effects of the voltage dependent calcium channel blocking agent nifedipine, and of a calcium free bathing medium, on the responses of human blood vessels obtained postmortem to various agonists have been compared with those of the rat aorta. The human vessels studied were digital arteries, basilar arteries and metatarsal veins. 2. Responses to potassium chloride (5-80 mM), noradrenaline (10(-9)-10(-4) M), 5-hydroxytryptamine (10(-8)-10(-4) M) and U46619 (10(-11)-10(-6) M), in the presence and absence of nifedipine (1, 10, and 100 nM) or in a calcium-free bathing medium, were assessed using an area-under-curve analysis. 3. In general, the order of sensitivity of the vessels to inhibition of agonist induced contractures by nifedipine was basilar arteries greater than metatarsal veins = digital arteries = rat aorta. 4. For all the vessels, the order of sensitivity for antagonism of responses to the agonists by nifedipine was potassium chloride greater than 5-hydroxytryptamine = noradrenaline greater than U46619. 5. A calcium free bath inhibited responses of digital arteries to potassium chloride more than noradrenaline, 5-hydroxytryptamine or U46619, and responses of rat aorta to a greater extent than responses of the digital arteries. 6. In the rat aorta, a calcium-free bath inhibited responses to all agonists (except KCl) to a greater degree than did nifedipine. 7. We conclude that inhibition of extracellular calcium entry through voltage dependent calcium channels affects contractile responses of different blood vessels to different extents, and, within the same blood vessel, responses to different contractile agonists to different extents.

Nifedipine administered after reperfusion ablates systolic contractile dysfunction of postischemic “stunned” myocardium

Recent evidence suggests that postischemic contractile dysfunction of viable myocardium salvaged by reperfusion (“stunned myocardium”) may be a consequence of abnormal calcium flux within the previously ischemic cells. Calcium channel blocking agents have been shown to enhance contractile function of stunned postischemic tissue, but it is not certain whether these improvements in function are due to the profound hemodynamic and vasodilator effects of these agents or to a direct effect on calcium flux within the stunned myocytes. Therefore, the effects of 1) high doses of nifedipine, given intravenously at 30 min after reperfusion, and 2) minute doses of nifedipine, infused directly into the coronary circulation at 30 min after reflow, were assessed and compared in anesthetized open chest dogs subjected to 15 min of transient coronary artery occlusion.As anticipated, intravenous nifedipine significantly reduced arterial pressure and increased regional myocardial blood flow. In addition, intravenous nifedipine restored systolic contractile function of the stunned, previously ischemic tissue to essentially normal preocclusion values: segment shortening averaged 102 ± 8% versus 26 ± 11 % of baseline at 2 h after treatment in treated versus control dogs, respectively (p < 0.003). Low dose intracoronary infusion of nifedipine did not alter hemodynamic variables or myocardial blood flow, but did improve segment shortening (90 ± 9% versus 37 & 10% of preocclusion values at 1 h after treatment versus 25 min after reperfusion [that is, pretreatment], respectively; p < 0.03).These data indicate that the calcium channel blocking agent nifedipine, given 30 min after reperfusion, enhances systolic contractile function of postischemic stunned myocardium. Because these improvements in function could be obtained even in the absence of systemic hemodynamic or coronary vasodilator effects, the data suggest that nifedipine may act by favorably modulating calcium flux within the stunned myocytes.

The calcium channel blocking agent nifedipine improves contractile function of stunned myocardium by a direct cellular mechanism: Karin Przyklenk, Georges B. Ghafari, Daniel T. Eitzman and Robert A. Kloner, Harper Hospital/Wayne State University, Detroit MI and Hospital of the Good Samaritan/University of Southern California, Los Angeles CA

The calcium channel blocking agent nifedipine improves contractile function of stunned myocardium by a direct cellular mechanism: Karin Przyklenk, Georges B. Ghafari, Daniel T. Eitzman and Robert A. Kloner, Harper Hospital/Wayne State University, Detroit MI and Hospital of the Good Samaritan/University of Southern California, Los Angeles CA

Use of antihypertensive agents in patients with glucose intolerance

The selection, use, and potential adverse effects of antihypertensive agents in patients with glucose intolerance are reviewed. Thiazide diuretics frequently impair glucose tolerance, but this deterioration is usually modest and should not preclude use of these agents in most patients with glucose intolerance. The loop diuretics furosemide and ethacrynic acid have also been associated with decreased glucose tolerance. The beta-adrenergic blocking agents may inhibit insulin secretion, but few patients will experience clinically important elevations in blood glucose. Rather than producing glucose intolerance, these agents may delay recovery from hypoglycemic episodes and may mask catecholamine-induced symptoms of hypoglycemia. In certain cases, use of cardioselective beta blockers or avoidance of beta-blocker therapy may be indicated, especially in insulin-dependent diabetics. The calcium-channel blocking agents nifedipine and verapamil have been reported to produce diabetogenic effects in a few studies, but further investigations are needed to define the extent of these effects. Available evidence indicates that sympatholytic agents such as guanethidine and reserpine, alpha 2-adrenergic agonists such as methyldopa and clonidine, the alpha 1-blocking agent prazosin, and the vasodilators captopril and hydralazine produce few, if any, clinically important changes in glucose tolerance. While no antihypertensive agents are absolutely contraindicated in patients with glucose intolerance, patients with glucose intolerance who are receiving thiazide diuretics, beta blockers, and calcium-channel blocking agents should be monitored with extra care for hyperglycemia or deterioration in glucose tolerance.

Calcium blockade - nifedipine in the treatment of hypertrophic cardiomyopathy

Summary The acute effects of the calcium channel blocking agent nifedipine in hypertrophic cardiomyopathy are described. Improved diastolic function was suggested by the increase in the rate of filling of the left ventricle and the fall in left ventricular end-diastolic pressure. Left ventricular relaxation time was shortened. There was a downward shift in the left ventricular pressure-echo dimension relationship, suggesting increased left ventricular distensibility. Nifedipine caused a fall in systolic, systemic blood pressure and an increase in heart rate, but no change in the cardiac index. The reasons for the improvement in the diastolic function were thought to be systemic vasodilatation and change in left ventricular loading conditions, coronary vasodilatation with reduction of subendocardial left ventricular ischaemia and a direct myocardial effect and modification of myocardial calcium availability.

Development of immune complex nephritis during treatment with the calcium channel-blocking agent nifedipine

Following multiple myocardial infarctions, a patient was treated with the calcium channel-blocking agent nifedipine. Within three months he had proteinuria of up to 460 mg/24 hours. Renal biopsy showed an immune complex glomerulonephritis. The presence of microfibrils was associated with the capillary basement membrane and mesangial changes.

Plasma concentrations and hemodynamic effects of nifedipine: a study in anesthetized dogs.

The elimination kinetics of the calcium channel blocking agent nifedipine were studied in three male mongrel dogs after single intravenous bolus doses, and the drug's disposition followed first-order kinetics. After single intravenous doses, the elimination rate constant (mean +/- SE) was 0.693 +/- 0.069 h-1; the total body clearance, 0.736 +/- 0.226 L/h/kg; and the apparent volume of distribution, 1.15 +/- 0.12 L/kg. Based on these data, a model for the administration of nifedipine by an intravenous bolus-infusion regimen was developed to rapidly achieve and maintain stable plasma drug concentrations. Testing of this model in six anesthetized, open-chest dogs revealed pulmonary artery (mixed venous) drug concentrations that were consistently lower than those predicted, with stable plasma nifedipine levels achieved within 5 min and maintained over 60-min study periods. In these animals, a linear relationship was found between nifedipine concentrations in plasma and the total amount of drug administered (r = 0.92, p less than 0.001). Log-linear relationships were found between plasma nifedipine concentrations and mean arterial blood pressure (r = -0.93, p less than 0.001), cardiac output (r = 0.94, p less than 0.001), peripheral vascular resistance (r = -0.93, p less than 0.001), and pulmonary vascular resistance (r = -0.83, p less than 0.001). In addition, infusion of CaCl2 (3 mg/kg/min) resulted in increases in blood pressure despite the presence of stable plasma nifedipine concentrations. No electrocardiographic changes were seen at any plasma nifedipine level.

Nifedipine and Raynaud's Phenomenon

Letters and Corrections1 April 1981Nifedipine and Raynaud's PhenomenonANDRÉ KAHAN, M.D., SIMON WEBER, M.D., BERNARD AMOR, M.D., LIONEL SAPORTA, M.D., MAURICE HODARA, M.D., MICHEL DEGEORGES, M.D.ANDRÉ KAHAN, M.D.Search for more papers by this author, SIMON WEBER, M.D.Search for more papers by this author, BERNARD AMOR, M.D.Search for more papers by this author, LIONEL SAPORTA, M.D.Search for more papers by this author, MAURICE HODARA, M.D.Search for more papers by this author, MICHEL DEGEORGES, M.D.Search for more papers by this authorAuthor, Article, and Disclosure Informationhttps://doi.org/10.7326/0003-4819-94-4-546_1 SectionsAboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissions ShareFacebookTwitterLinkedInRedditEmail ExcerptTo the editor: We read with interest the review "Calcium Channel Blocking Agents in the Treatment of Cardiovascular Disorders: Part II: Hemodynamic Effects and Clinical Applications" by Stone and associates (1). We wish to emphasize another indication for use of nifedipine.Numerous therapeutic approaches to Raynaud's phenomenon have been used, with various results (2-5). We have evaluated the therapeutic effect of the calcium-channel blocking agent nifedipine in Raynaud's phenomenon. In each of the 16 patients included in our study (mean age, 38; 12 female, four male) digital vasospasm could be reproduced within 3 minutes by immersion of both hands in...