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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Calcium channel blockers such as nicardipine improve outcome after global cerebral ischemia and may attenuate ischemic neuronal injury by preventing calcium influx and binding to calmodulin. We followed the temporal and regional sequence of neuronal calcium-calmodulin binding in normal rats (n = 6), untreated ischemic rats (n = 15), and ischemic rats treated with 0.05 mg/kg/hr s.c. nicardipine (n = 13). After 30 minutes of four-vessel occlusion, 40-microns brain sections were incubated in an anti-calmodulin antibody specific for calmodulin not bound to calcium and brain protein. Light-microscopic sections were examined immediately after ischemia and after 2 and 24 hours of reperfusion. Extensive staining of unbound calmodulin was seen in all hippocampal regions and in the cortex in normal rats. In untreated ischemic control rats, staining was lost, indicating calcium-calmodulin binding immediately after ischemia in all regions. However, after 24 hours, staining returned to normal in the cortex and dentate, and minimal staining returned in CA1 and CA3. Nicardipine-treated animals had significantly less calcium-calmodulin binding in CA1 and in the dentate after 2 hours of reperfusion. This study demonstrates that in clinically relevant doses nicardipine has a limited effect on calcium-calmodulin binding in selectively vulnerable regions after severe ischemia.
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PMID:Calcium-calmodulin binding in ischemic rat neurons after calcium channel blocker therapy. 234 99

Nicardipine has high affinity for the dihydropyridine-binding site and has been shown to inhibit the influx of extracellular calcium through membrane slow channels. The calcium antagonist activity of nicardipine is greater in vascular smooth muscle than in cardiac muscle. Nicardipine has also been shown to possess greater activity in coronary than in peripheral vascular smooth muscle. This in vitro profile accounts for the decreased blood pressure and increased coronary blood flow in animal models in vivo. These pharmacologic properties are the basis for nicardipine's clinical utility in essential hypertension and acute myocardial ischemia. Nicardipine has been shown to be more vascular selective than other calcium antagonists and, therefore, possibly less inclined to produce negative inotropicity. This latter property has been confirmed in human hemodynamic studies. Nicardipine is effective in models of acute myocardial ischemia and hypertension. These results have been confirmed in antianginal and antihypertensive studies in humans. This new calcium antagonist has been shown to limit myocardial infarct size in both dogs and baboons subject to left anterior descending coronary artery ligation and to reduce the extent of ischemia-induced cerebral neuronal death in rats. Other protective effects of nicardipine have been demonstrated in paracetamol overdose in mice, chloroform-induced hepatotoxicity in rats and cerebral ischemia in gerbils and baboons. The mechanism of this cell protection of nicardipine may be related to physicochemical effects.
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PMID:Animal pharmacology of nicardipine and its clinical relevance. 244 Feb 94

In 10 patients undergoing percutaneous transluminal coronary angioplasty of the left anterior descending coronary artery (LAD), the clinical, electrocardiographic and hemodynamic effects of acute intravenous calcium channel antagonism with nicardipine (2 mg over 1 minute, followed by a constant infusion of 25 to 50 micrograms/min) were assessed during temporary LAD occlusion. Onset of myocardial ischemia during coronary occlusion was prevented or delayed after administration of nicardipine in 7 of the 10 patients. During infusion of nicardipine and during LAD occlusion, residual great cardiac vein blood flow increased in 9 of 10 patients compared with residual flow during occlusion before nicardipine (10%, p less than 0.05). Nicardipine also decreased mean aortic pressure, but was associated with a reflex-mediated increase in heart rate. Overall, the double product, an index of global myocardial oxygen demand, decreased 7% (p less than 0.05). Thus, nicardipine usually diminished ischemia induced by acute transient coronary occlusion by increasing collateral flow while oxygen demand decreased.
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PMID:Effect of nicardipine on determinants of myocardial ischemia occurring during acute coronary occlusion produced by percutaneous transluminal coronary angioplasty. 244 86

The effects of calcium channel blockers on myocardial ischemia in humans can be evaluated in studies reporting changes during coronary angioplasty. These studies indicate that the extent and duration of myocardial ischemia in most patients with single vessel coronary artery disease can be improved somewhat by calcium channel blockers. The anti-ischemic effects of intravenous diltiazem, nifedipine, nisoldipine, and nicardipine are discussed. Intravenous diltiazem produces effects similar to intracoronary, but not systemic, nifedipine. Intracoronary nifedipine and nicardipine produce similar degrees of cardioplegia in most studies. Nicardipine and nisoldipine also reduce signs of myocardial ischemia, although different mechanisms are postulated to be involved. Although clinically beneficial in some patients, data indicate that the cardioprotective effect of calcium channel blockers during supply-side ischemia is less potent than reperfusion with blood. For the most part, calcium channel antagonists function through reduction of myocardial oxygen demand with rare agents favorably influencing collateral flow or providing direct myocardial protection. The potential myocardial cellular effects of calcium channel blockers on supply-side ischemia merit further investigation.
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PMID:Influence of calcium channel antagonist therapy on the ischemic response to acute coronary occlusion in humans. 269 Nov 44

Nicardipine, a calcium antagonist of the 1:4 dihydropyridine type, has been used to treat angina and hypertension and is currently being examined as an agent for treating ischemia of cerebral and myocardial tissue. Nicardipine shows high affinity for the dihydropyridine binding site (pKi = 9.7) and inhibits the L-type calcium ion channel as demonstrated by its ability to decrease the calcium ion-dependent action potential dose-dependently in ventricular papillary muscle (pIC50 = 7.15). Nicardipine shows greater potency in inhibiting the response of vascular smooth muscle (pIC50 = 8.20) than that of cardiac muscle (pIC50 = 7.15). The nicardipine selectivity for vascular smooth muscle is greater than that shown by other dihydropyridine calcium antagonists such as nifedipine and accounts for the efficacy of nicardipine in the treatment of angina and hypertension. Various mechanisms have been proposed to account for the beneficial action of nicardipine in treating animal models of cerebral ischemia and myocardial infarction. For example, it has been suggested that (1) nicardipine has a specific membrane-stabilizing effect on cell membranes, (2) the compound blocks certain sodium channels, (3) it may become concentrated in ischemic cells, or (4) it may stimulate calcium ion efflux from mitochondria, and these actions may account for the inhibition by nicardipine of veratrine-induced contraction of myocytes. In this study, some of these effects of nicardipine were examined. However, the suggestion that nicardipine concentrates in ischemic cells owing to the tertiary amine structure could not be conclusively demonstrated.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Cellular action of nicardipine. 280 73

The efficacy of intravenous nicardipine in the prevention of vasospasm after subarachnoid hemorrhage has been investigated in a dose escalation study in 67 patients admitted within 1 week of subarachnoid hemorrhage. Favorable outcomes were noted in 52 patients (78%). Vasospasm was found by arteriography in 31 patients (46%). A dose-related trend was noted. At the lower dose levels, angiographic spasm was observed in 68% and symptomatic vasospasm in 27% of 34 patients. Only eight of 33 patients (24%) treated at the highest dose level (approximately 10 mg/hr) developed arteriographic evidence of vasospasm. Symptomatic vasospasm was diagnosed in only two of 33 patients (6%) treated with this dose. No deaths from vasospasm occurred. Verification of changes in tissue calcium has been obtained from the rat middle cerebral artery occlusion model, and we concluded that nicardipine administered after permanent occlusion may offer protection against cerebral ischemia in this animal model. Nicardipine uptake was greater at the infarct site than in surrounding tissue, with the highest concentration in the area of maximal ischemia. Nicardipine appears to affect changes in Ca2+ more than other ions: it significantly reduced Ca2+ accumulation in the territory of the middle cerebral artery by 60% at 6 hours, and significantly reduced Na+ and K+ shifts in the same territory by 40% and 50%, respectively, at 6 hours. Although much research remains to be done, a wide role for the dihydropyridines in a number of cerebrovascular conditions is emerging.
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PMID:The potential use of nicardipine in cerebrovascular disease. 291 83

Nicardipine hydrochloride is the first intravenous dihydropyridine calcium antagonist to become available in the United States. Its chemical structure makes it unique among its drug class and confers clinically useful properties for the treatment of acute cardiovascular conditions, such as ischemia, hypertension, congestive heart failure, cerebrovascular disease, and related disorders. For patients with coronary artery disease, IV nicardipine reduces myocardial oxygen demand by reducing afterload and increases myocardial oxygen supply through coronary vasodilatation. Preliminary data suggest that nicardipine also has cardioprotective and vascular antispastic effects. Nicardipine has been shown to be effective in the treatment of mild to moderate hypertension both as monotherapy and in combination with other antihypertensive agents. In congestive heart failure, nicardipine enhances left ventricular pumping activity and augments coronary blood flow beyond that required by increased myocardial oxygen consumption. Its lack of major effects on sinoatrial and atrioventricular conduction makes it safe for use in patients with certain types of conduction disturbances. Nicardipine's rapid onset and short duration of action are additional advantages for use in the management of acute cardiovascular disorders.
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PMID:Intravenous nicardipine: cardiovascular effects and clinical relevance. 307 10

Dihydropyridine calcium channel blockers such as nicardipine are under evaluation for treating acute cerebral ischemia because they may increase cerebral blood flow by causing vasodilation and because they may be cytoprotective in part by limiting production of arachidonic acid metabolites. We demonstrated in a previous study that nicardipine improves postischemic neuronal function, as measured by somatosensory evoked potentials, without reducing the extent of light-microscopic CA-1 hippocampal histologic damage. To characterize further the effect of nicardipine on global ischemic injury, we administered the drug beginning 24 hours before 30 minutes of four-vessel ischemia in Wistar rats. We then measured hippocampal ATP, phosphocreatine, and glucose contents immediately and 2 hours after ischemia, and measured learning ability (working and reference errors) on an eight-arm radial maze beginning 30 days after ischemia. To gain insight into the possible mechanism of action, we measured production of arachidonic acid metabolites (eicosanoids: TXB2 and 6-keto-PGF1 alpha) and hemispheric and hippocampal cerebral blood flow by the [14C]butanol indicator fractionation technique immediately and 2 hours after ischemia. Nicardipine was associated with fewer working errors (p less than 0.02) but no difference in reference errors. The drug had no effect on energy metabolites, cerebral blood flow, or eicosanoids immediately after ischemia, but ATP, phosphocreatine, and cerebral blood flow all returned to normal levels significantly more rapidly during reperfusion in treated rats. Nicardipine improves behavioral, electrophysiologic, and mitochondrial function after ischemia without preventing cellular damage and improves postischemic reperfusion. The drug's positive effect appears to occur during reperfusion.
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PMID:Efficacy and mechanism of action of a calcium channel blocker after global cerebral ischemia in rats. 336 73

To define the effects of nicardipine, a new dihydropyridine calcium antagonist drug, on exercise- and pacing-induced myocardial ischemia, 15 men with coronary artery disease were studied during cardiac catheterization. Nicardipine was administered intravenously as a 2-mg bolus followed by an infusion titrated to maintain a 10- to 20-mm Hg decrease in systolic arterial pressure. At rest, nicardipine decreased systemic and coronary vascular resistances, left ventricular end-diastolic pressure and increased coronary blood flow, heart rate and myocardial oxygen consumption. During bicycle exercise-induced myocardial ischemia, nicardipine significantly prolonged exercise duration and time to 1 mm of ST-segment depression. These changes were associated with no alteration in the product of systolic pressure and heart rate, decreased left ventricular end-diastolic pressure, systemic and coronary vascular resistances and increased coronary blood flow, as well as myocardial oxygen consumption. During atrial pacing, the heart rate threshold for myocardial ischemia was not changed by nicardipine administration, despite improvement in the ratio of coronary blood flow to myocardial oxygen consumption and hemodynamic changes otherwise similar to those during exercise. Nicardipine favorably influenced myocardial metabolic state, as indexed by lactate extraction during pacing-induced ischemia. Nicardipine is a potent coronary and systemic vasodilating drug that improves exercise tolerance and myocardial metabolic response to pacing stress, the mechanism for which appears to be partially mediated through increased coronary blood flow.
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PMID:Effects of nicardipine on exercise- and pacing-induced myocardial ischemia in angina pectoris. 363 Sep 28

The effects of the calcium entry blocker nicardipine on CBF, CMRO2, and neurologic outcome following 10 min of complete cerebral ischemia were examined in dogs. In CBF and CMRO2 studies, the CBF in the untreated group (seven dogs) and the nicardipine group (seven dogs; 20 micrograms kg-1 at 30 min postischemia and a subsequent infusion of 2 micrograms kg-1 min-1 for 90 min) initially increased to 300-400% and then returned to preischemic values at 30 min postischemia. Thereafter the CBF in the untreated group significantly decreased to 50% of preischemic values for the following 90-min period (hypoperfusion), while the CBF in the nicardipine group did not differ from preischemic values. The CMRO2 in both groups decreased to approximately 50-80% of preischemic values after 15 min postischemia and did not differ between the groups throughout the study. In neurologic outcome studies, 18 dogs were divided into three groups (of six dogs each): untreated; saline infusion only, posttreated; nicardipine as in CBF and CMRO2 studies, pretreated; nicardipine 20 micrograms kg-1 at 2 min preischemia and a subsequent infusion of 2 micrograms kg-1 min-1 from immediately postischemia to 120 min postischemia. Nicardipine treatment initiated either before or after ischemia failed to improve neurologic outcome at 48 h postischemia. Thus, the increase of postischemic global CBF by nicardipine is not accompanied by neurologic recovery in a canine model of complete cerebral ischemia.
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PMID:Nicardipine increases cerebral blood flow but does not improve neurologic recovery in a canine model of complete cerebral ischemia. 379 4


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