Protective Effects Of Calcium Antagonists Research Articles

358 Protective effects of calcium antagonists on acute acetaminophen hepatotoxicity in adult male albino rats

358 Protective effects of calcium antagonists on acute acetaminophen hepatotoxicity in adult male albino rats

Mapacalcine specifically blocks hypoxia-induced calcium influx in rat hepatocytes.

Post ischaemic cell calcium invasion has been described as one of the main causes of graft failure. Protective effects of calcium antagonists have been investigated but are not convincing and their mechanisms of action remain unclear. In this work we tested the protective effect of a new calcium inhibitor described to block a calcium current insensitive to all known calcium blockers. Specific mapacalcine receptors were first characterized on rat hepatocytes membranes using the 125I-labeled mapacalcine. 45Ca fluxes were then measured on cultured hepatocytes submitted (or not) to an hypoxic period. The action of mapacalcine was investigated on the ischaemia-induced calcium influx. We demonstrate here that: (a) there are specific receptors for mapacalcine in rat hepatocytes; (b) Mapacalcine is able to specifically block ischaemia-induced calcium influx with an IC50 of 0.3 micro m and does not significantly interact with the basal calcium flux. Our work demonstrates that the mapacalcine receptor is a cellular structure directly involved in the phenomenon of postischaemic cell invasion by calcium. Specific block of ischaemia-induced Ca2+ influx by mapacalcine suggests that the development of a panel of pharmacological drugs acting on this receptor could lead to the discovery of therapeutic agents able to protect cells against one of the events responsible for organ failure after transplantation or simply after an ischaemic period. Moreover, identification of the cellular protein which binds mapacalcine may become an important step in the research of mechanisms involved in postischaemic cell invasion by calcium.

Use of calcium antagonists and worsening renal function in patients receiving angiotensin-converting-enzyme inhibitors.

The objective of this study was to assess whether calcium antagonists, which have been proven to dilate the afferent glomerular arteriole, might prevent increases in serum creatinine levels among older subjects who started treatment with angiotensin-converting enzyme (ACE) inhibitors. We explored the association between use of calcium antagonists and incident increases in serum creatinine in 780 elderly patients with baseline creatinine levels <1.2 mg/dL (106.19 micromol/L), who were enrolled in a multicenter pharmacoepidemiology study, and who started using ACE inhibitors during their hospital stay. Among these participants, 279 also started using calcium antagonists. Demographic variables, comorbid conditions, medications, and objective tests, which were associated with increasing serum creatinine levels in separate regression models, were examined as potential confounders in a summary model. Among patients receiving ACE inhibitors, serum creatinine levels increased in 22% of participants who were dispensed calcium antagonists, and in 31% of other patients (P=0.005). In the summary regression model, use of calcium antagonists was associated with a decreased risk of worsening renal function (RR 0.56, 95% CI 0.37-0.84). The adjusted risk of increasing serum creatinine was lower (RR 0.25, 95% CI 0.05-0.95) in participants receiving higher calcium antagonists dosages than in those taking lower dosages. This protective effect of calcium antagonists was not detected in patients not dispensed ACE inhibitors. ACE inhibitors are underused in older subjects, mainly because of the higher incidence of renal damage among geriatric populations. Our results indicate that among elderly patients receiving ACE inhibitors, the use of calcium antagonists is associated with a reduced risk of worsening renal function. Thus, these results warrant trials aiming at establishing whether combined treatment with calcium antagonists might allow the use of ACE inhibitors in clinical practice to be expanded to the elderly population.

Modulation of endothelial function: strategy for long-term cardiovascular protection.

Calcium antagonists primarily affect the cellular interactions of endothelial cells, smooth muscle cells, monocytes and thrombocytes, which are important in the early phases of the development of atherosclerosis. The protective effect of calcium antagonists on the vascular system appears to be low at later stages, which include increased matrix formation and central necrosis of atherosclerotic plaques. Present evidence indicates that calcium antagonists may be useful prophylactic agents at an early stage in the development of atherosclerotic vascular changes.

Renal haemodynamic and protective effects of calcium antagonists in hypertension

In recent years, the ability of the various antihypertensive drugs to provide renal protection has been the subject of increased attention. Whether calcium antagonists prevent or reduce the rate of progression of renal damage is still a matter of controversy. This paper reviews the findings of recent animal and human studies on the haemodynamic and renal protective effects of calcium antagonists. These agents preferentially vasodilate afferent arterioles, leading to an increase in renal blood flow and glomerular filtration rate. These effects are more pronounced in hypertensive patients than in normotensive subjects and persist even when renal function is impaired. In animal models of chronic renal failure, calcium antagonists can reduce glomerulosclerosis. However, the mechanisms involved in their renal protective effect appear to be different from those of angiotensin converting enzyme (ACE) inhibitors as they do not reduce intraglomerular pressure. Renal failure caused by vasoconstriction related to radiocontrast agents or cyclosporine can be partly prevented by the administration of a calcium antagonist. Furthermore, in patients with renal artery stenosis, calcium antagonists reduce blood pressure with less renal blood flow impairment than ACE inhibitors. Preliminary clinical studies suggest that verapamil or diltiazem may reduce proteinuria in hypertensive diabetic patients. Whether these compounds can also retard the progression of renal failure in these patients remains to be established with larger trials.

Protective effects of calcium antagonists in different organs and tissues

The therapeutic efficacy of calcium antagonists in ischemic disorders of various tissues is attributed to vasodilator and antivasoconstrictor activities. A direct, energy-conserving, antiischemic effect of certain calcium antagonists has been claimed repeatedly by basic scientists. The clinical value of such effects has been doubtful until recently, when the organ-protective activity of certain calcium antagonists was confirmed in a few large-controlled clinical trials. The following evidence has been presented for the protective activity of calcium antagonists: (1) for the heart, beneficial effects of verapamil and diltiazem have been shown on reinfarction and mortality rates, (2) relative to the brain, the beneficial effect of nimodipine has been shown in preventing neurologic deficits after subarachnoidal hemorrhage, and an antimigraine effect of flunarizine has been demonstrated, (3) concerning the blood vessels, israpidine and lacidipine have been demonstrated to have antiatherogenic potency in animal models, and (4) for the kidneys, an antivasoconstrictor effect occurs at the preglomerular level. In addition, verapamil, diltiazem, and nitrendipine may protect against radiocontrast-induced nephrotoxicity, and verapamil counteracts cyclosporine nephrotoxicity.

Nifedipine and diltiazem reduce pulmonary edema formation during postischemic reperfusion of the rabbit lung.

A protective effect of calcium antagonists in pulmonary preservation for transplantation has been observed recently. This report focuses on the potential use of diltiazem and nifedipine in the early phase of reperfusion after normothermic pulmonary ischemia. Rabbits weighing 4-5 kg were tracheotomized and ventilated with 50% oxygen. In a control group (group I, n = 7), the hilus of the right lung was clamped for 210 min without ischemia of the left lung. Lung ischemia was created in a second group (n = 7) by clamping the left hilum for 2 h. Subsequently, reperfusion of the left lung was maintained for 210 min, while the right hilus was kept occluded. In group III (n = 6) and group IV (n = 8) the conditions were the same as in group II, but either diltiazem (62.5 micrograms/kg i.v., group III) or nifedipine (3 micrograms/kg i.v., group IV) was administered during the first 20 min of reperfusion. After 210 min of reperfusion, the pulmonary vascular resistance was elevated in group II (mean: 5120 dyn.sec.cm-5), group III (5518 dyn.sec.cm-5), and group IV (4324 dyn.sec.cm-5) compared with group I (3390; n.s.). Arterial oxygenation showed no significant differences among group I (mean: 257 mmHg), group II (261 mmHg), group III (208 mmHg), and group IV (247 mmHg). Pulmonary ischemia resulted in an increased extravascular lung water content in group II as compared to group I (73 and 64 g/g wet weight; P less than 0.0125 vs group I). No such increase was seen in groups III and IV (53 and 54 g/g wet weight respectively; P less than 0.001 vs group II).(ABSTRACT TRUNCATED AT 250 WORDS)

The Calcium Antagonist Nisoldipine Improves the Functional Recovery of Reperfused Myocardium Only When Given Before Ischemia

It is unclear whether the protective effects of calcium antagonists on reperfused myocardium are secondary to increased blood flow during ischemia (anti-ischemic action) or reperfusion (Gregg phenomenon), or are mediated through altered calcium kinetics in ischemic or reperfused myocardium. To study the effect of the calcium antagonist nisoldipine on the functional recovery of stunned myocardium, 32 enflurane-anesthetized dogs were subjected to 15 min of occlusion of the left circumflex coronary artery and subsequent 4 h of reperfusion. Eight dogs served as placebo controls (group I), and eight dogs received nisoldipine (5 micrograms/kg i.v.) before occlusion (group II), eight dogs at 10 min of occlusion (group III), and eight dogs at 4 min of reperfusion (group IV). The mean aortic pressure was kept constant with an intra-aortic balloon, and the heart rate did not change. In group I, posterior systolic wall thickening (WT, sonomicrometry) decreased from 18.3 +/- 2.4% (mean +/- SD) during control conditions to -3.0 +/- 2.0% at 13 min of occlusion. At 10 min of reperfusion, WT was 1.7 +/- 3.9% and did not recover further (-1.2 +/- 3.7% at 4 h of reperfusion). Posterior transmural blood flow (BF, colored microspheres) decreased from 1.42 +/- 0.43 ml/min/g during control conditions to 0.26 +/- 0.08 ml/min/g at 13 min of occlusion. BF was 2.07 +/- 0.93 ml/min/g at 10 min and 0.95 +/- 0.31 ml/min/g at 4 h of reperfusion. In groups III and IV, the WT and BF were not different from those in group I throughout the experimental protocol. In group II, however, the WT, although similar to the WT of group I before and during ischemia, recovered from 2.7 +/- 4.3% at 10 min to 11.8 +/- 6.0% at 4 h of reperfusion (p less than 0.05 vs. groups I, III, and IV). The BF in group II decreased from 2.52 +/- 0.66 ml/min/g after administration of nisoldipine to 0.22 +/- 0.14 ml/min g at 13 min of occlusion. The BF was 1.31 +/- 0.51 ml/min/g at 10 min and 1.33 +/- 0.43 ml/min/g at 4 h of reperfusion. Nisoldipine exerts no beneficial effect when given immediately before or after the onset of reperfusion. The improved functional recovery of reperfused myocardium in dogs pretreated with nisoldipine cannot be attributed to an increased regional myocardial blood flow during ischemia or reperfusion. The better myocardial recovery, therefore, appears to be related to an attenuated myocardial calcium overload during the first few minutes of ischemia.

The restoration of ATP synthesis may explain the protective effect of calcium antagonists against cyclosporine a nephrotoxicity

Cyclosporine A at pharmacological doses decreases the rate and yield of ATP synthesis in rat mitochondria. This action seems to be due to the mitochondrial calcium storage induced by the drug. If such an effect occurs in vivo, the ATP deficit will affect calcium extrusion pumps, so triggering vasoconstruction which is the major side effect of Cyclosporine A. Calcium antagonists (Nifedipine and Verapamil) at least partially correct this effect on ATP synthesis : this finding may be related with the beneficial clinical effect conferred on Cyclosporine A toxicity by calcium antagonists. This effect of calcium antagonists may be due to an interaction with Cyclosporine A at the level of mitochondrial calcium efflux.

Myocardial Stunning Following Coronary Angioplasty

The beneficial effects of calcium-channel blockers against myocardial stunning have been tested in experimental studies, showing that, when added before or during ischemia, a protective effect against postischemia stunning is achieved. The present study was undertaken to test and compare the protective effect of calcium antagonists [nisoldipine (NIS) and nifedipine (NIF)] and nitrates (NIT) against myocardial stunning in patients with coronary artery disease undergoing percutaneous transluminal coronary angioplasty (PTCA) with prolonged inflation as PTCA represents a model of induced acute and severe ischemia for a brief period and might cause myocardial stunning. The study included 30 patients between the ages of 42 and 67 years, all with exercise-induced angina and single-vessel disease, with severe stenosis (80% to subtotal occlusion) localized on the left anterior descending artery and with the absence of collaterals on the coronary angiograms. Moreover, all patients had normal left ventricular (LV) overall function, as well as normal systolic thickening of the anterior wall, supplied by the diseased artery. Patients were randomized to a pre-PTCA treatment with NIT, 80-120 mg/day (10 patients), NIF, 40-60 mg/day (10 patients), and NIS, 10-20 mg/day (10 patients). Pre-PTCA treatment was initiated 7 days before the procedure and continued after. During the PTCA, at the first balloon inflation, an additional dose of 300 micrograms of NIT was injected into the left anterior descending artery through the balloon catheter in the patients in the NIT group, as well as 0.2 mg of NIF in NIF group patients and 0.05 mg of NIS in NIS group patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Protective Effects of Calcium Antagonists on Energy and Substrate Metabolism During Ischemia and Reperfusion in Hypertensive Myocardial Hypertrophy

The aim of the present study was to define the protective effects of verapamil and nifedipine on mechanical performance and energy and substrate metabolism of the postischemically reperfused myocardium in a chronic pressure overload cardiac hypertrophy model. The isolated beating rat heart preparation was used and left ventricular pressures and high-energy phosphates were continuously monitored during 30 min of global ischemia and reperfusion, respectively. Recovery of mechanical performance and high-energy phosphate and sugar monophosphate metabolism was significantly impaired in untreated hypertrophied hearts compared with normal control hearts and hypertrophied hearts treated with calcium antagonists. In hypertrophied hearts with chronic verapamil treatment, recovery was significantly improved compared to acute verapamil treatment, nifedipine treatment, and normal control hearts. Thus, verapamil and nifedipine exerted a protective effect on the postischemic recovery of the hypertrophied myocardium that was most prominent following long-term pretreatment with verapamil. Prolonged maintenance of adequate plasma levels and tissue distribution of calcium antagonists before an ischemic event may improve the postischemic prognosis in the presence of pressure-induced myocardial hypertrophy.

Protective Effects of Calcium Antagonists on Energy and Substrate Metabolism During Ischemia and Reperfusion in Hypertensive Myocardial Hypertrophy

Protective Effects of Calcium Antagonists on Energy and Substrate Metabolism During Ischemia and Reperfusion in Hypertensive Myocardial Hypertrophy

Calcium Antagonists Prevent Monocyte and Endothelial Cell-Induced Modification of Low Density Lipoproteins

Low density lipoprotein (LDL) incubated in the presence of the calcium antagonists verapamil, nifedipine and flunarizine were more resistant than control LDL to human monocyte- or endothelial cell-induced modification, as assessed by electrophoretic mobility in agarose gel, thiobarbituric acid reactive substance content, and degradation by J774 macrophages. The efficiency of the drugs was: flunarizine greater than nifedipine greater than verapamil. Moreover, a 24 h preculture with calcium antagonists significantly impaired the ability of cells to modify LDL in the absence of the drugs. All the studied drugs also inhibited copper-induced autooxidation of LDL. None of the studied calcium antagonists, at concentrations up to 10(-4) M, significantly reacted with free radicals as assessed by the 1,1-diphenyl-2-picrylhydrazyl test. It is suggested that such a protective effect of calcium antagonists against LDL peroxidation could play a role in the previously reported antiatherogenic effect of these drugs.

Protection by Bepridil Against Myocardial ATP-Catabolism Is Probably Due to Negative Inotropy

The protective effect of calcium antagonists on ischemic heart has been attributed to decreased energy expenditure. We administered one of the newer calcium antagonists, DL-bepridil (0.1-10 microM), to Langendorff rat hearts 10 or 15 min before ischemia (flow reduction approximately 80%). Vasodilation during normoxia was already observed with 0.3 microM DL-bepridil (flow increase 34%, p less than 0.005). This concentration decreased normoxic contractility and ischemic purine release, a marker for ATP breakdown. In the absence of bepridil, purine release of hearts that were made ischemic was 8.5-fold higher than that of normoxic control hearts. With 1 microM bepridil, the ischemic purine efflux was suppressed by 55% (p less than 0.05), with negative inotropy (p greater than 0.05) during normoxia. At 3 and 10 microM, bepridil decreased normoxic contractility by 40 and 75%, respectively (p less than 0.001), concomitant with a decrease in ischemic purine release by 80 and 76%, respectively (p less than 0.01). At the end of ischemia, myocardial ATP and creatine phosphate had decreased by 22 and 55%, respectively (p less than 0.05), and ADP, AMP, and creatine had increased 1.5-3.5-fold (p less than 0.05). Bepridil (3 microM) normalized the adenine nucleotide values; creatine and creatine phosphate approached control levels. The dose-dependent protection of the ischemic heart by bepridil appears to arise from its negative inotropic action during normoxia.