Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

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

The voltage- and time-dependent slow channels in the myocardial cell membrane are the major pathway by which Ca2+ ions enter the cell during excitation for initiation and regulation of the force of contraction of cardiac muscle. These slow channels appear to behave kinetically, on a population basis, as if their gates open, close, and recover more slowly than those of the fast Na+ channels. In addition, the slow channel gates operate over a less negative (more depolarized) voltage range. Tetrodotoxin does not block the slow channels, whereas the calcium antagonistic drugs, Mn2+, Co2+, and La3+ ions do. The slow channels have some special properties, including functional dependence on metabolic energy, selective blockade by acidosis, and regulation by the intracellular cyclic nucleotide levels. Because of these special properties of the slow channels, Ca2+ influx into the myocardial cell can be controlled by extrinsic factors (such as autonomic nerve stimulation or circulating hormones) and by intrinsic factors (such as cellular pH or ATP level). During transient regional ischemia, the selective blockade of the slow channels, which results in depression of the contraction and work of the afflicted cells, might protect the cells against irreversible damage by helping to conserve their ATP content. Reperfusion arrhythmias may be caused by the breakdown of this protective mechanism, in that, upon reperfusion, the Ca2+ slow channels may recover before the cells are capable of handling the greater Ca2+ influx (Fig. 20). As depicted in this figure, the Ca2+ slow channels may recover their function before the ATP level is sufficiently recovered to allow bail-out of the intracellular Ca2+. In addition, the generation of free radicals upon reperfusion may injure the Ca-ATPase and other enzymes involved in Ca2+ metabolism. The net effect of this would be to cause Ca2+ overload of the cells and SR, with subsequent delayed after-depolarizations (DADs) leading to triggered automaticity and arrhythmias. Following blockade of the fast Na+ channels in myocardial cells with TTX or by voltage-inactivating them in 25 mM (K)0, catecholamines, angiotensin-II, histamine, and methylxanthines rapidly allow the production of slowly-rising Ca2+-dependent action potentials by increasing the number of Ca2+ slow channels available for voltage activation and/or their mean open time. Concomitantly, these compounds rapidly elevate intracellular cyclic AMP levels, suggesting that cyclic AMP is somehow related to the functioning of the slow channels. Exogenous cyclic AMP produces the same effect, but much more slowly.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Regulation of calcium slow channels of cardiac muscle by cyclic nucleotides and phosphorylation. 245 7

In this review the pharmacologic properties of the calcium antagonist bepridil have been reexamined, particularly the evidence for an intracellular locus of action for the drug. Physicochemical properties of bepridil show it to be highly lipophylic, rapidly and extensively taken up, and accumulated in certain tissues. Combined electrophysiologic and mechanical studies have provided convincing, but indirect, evidence for an intracellular action of bepridil in cardiac muscle. Bepridil also fulfills, to a greater or lesser extent, certain important pharmacologic criteria necessary for evoking an intracellular action of a drug in cardiac and vascular smooth muscle: 1. Responses to agonists known to utilize intracellular calcium in the response are inhibited to a similar extent to depolarization-induced K+ responses. 2. Phasic and tonic responses to noradrenaline in vascular tissues are not, or are only to a minor extent, differentially antagonized. 3. Responses to the calcium ionophore A 23187 are antagonized. 4. Activity is retained following removal of the cell membrane by surfactants. 5. Isolated enzyme systems (e.g., calmodulin, myosin light-chain kinase) are affected by the drug at similar concentrations to those that are effective in whole cells or tissues. Finally results obtained with bepridil in ischemic myocardium have been reviewed to ascertain whether its broader pharmacologic spectrum over the calcium-entry blockers is associated with enhanced tissue protective properties. Positive results with bepridil in hypoxic myocytes and ischemic myocardium distinguishes this drug from the classical antianginal agents verapamil, nifedipine, and diltiazem. It is suggested that bepridil, because of its paucity of hemodynamic effects, may be of special therapeutic interest in the management of silent ischemia where cellular mechanisms leading to cytoprotection are more desirable than strong hemodynamic activity.
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PMID:Bepridil: a pharmacological reappraisal of its potential beneficial effects in angina and tissue protection following ischemia. 248 9

In the present study we examined three factors affecting the reversal of the ischemia-induced inhibition of the mitochondrial ATPase described by us earlier (W. Rouslin (1983) J. Biol. Chem. 258, 9657-9661). These factors were the pH, the MgATP concentration, and the pCa of the medium in which mitochondria were sonicated following their reenergization in vitro. It was found that the extent of ATPase reactivation, on the one hand, and the extent of inhibitor protein release, on the other, following the reenergization in vitro and subsequent sonication of intact mitochondria isolated from 20-min-ischemic canine cardiac muscle were affected differently by each of the three factors studied. While raising the pH of the medium in which the mitochondria were sonicated subsequent to reenergization from approximately 7.0 to approximately 8.2 resulted in marked parallel increases in both ATPase reactivation and inhibitor protein release, lowering the pH of the medium to approximately 6.4 resulted in a marked decrease in ATPase reactivation but also in the apparent irreversible binding and/or denaturation of a portion of the ATPase inhibitor. Increasing the MgATP concentration of the sonication medium from zero to 2.0 mM resulted in approximately a one-third decrease in ATPase reactivation. The effect upon inhibitor release was more dramatic. MgATP at 2 mM decreased inhibitor release by approximately two-thirds. The pCa of the sonication medium was varied between 9.0 and 3.5 using Ca-ethylenebis(oxyethylenenitrilo)-tetraacetic acid (EGTA) buffers. Decreasing the pCa of the medium from 9.0 to 3.5 had a paradoxical effect. It resulted in increases both in ATPase reactivation and in the amount of inhibitor bound to the particles. Such a paradoxical effect may be explained if one assumes the existence of two kinds of inhibitor-enzyme interaction sites, namely, regulatory and nonregulatory binding sites. Thus, decreasing the pCa may decrease interaction at regulatory sites while enhancing interaction at nonregulatory inhibitor binding sites.
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PMID:Factors affecting the reactivation of the mitochondrial adenosine 5'-triphosphatase and the release of ATPase inhibitor protein during and following the reenergization of mitochondria from ischemic cardiac muscle. 253 91

Impaired left ventricular relaxation and filling is an important pathophysiologic mechanism in hypertrophic cardiomyopathy. To determine whether isoproterenol, known to improve relaxation in isolated cardiac muscle, could favorably modify this effect, we assessed simultaneous left ventricular volume and regional systolic asynchrony (by radionuclide angiography), left ventricular pressure (by micromanometer catheters), and lactate metabolism in 12 patients with hypertrophic cardiomyopathy. Pressure-volume relations were studied during atrial pacing stress to induce myocardial ischemia and during isoproterenol infusion to similar heart rates. Angina occurred in 10 patients with pacing and in 11 patients during isoproterenol infusion; lactate consumption was reduced in nine patients during isoproterenol compared with pacing, including five patients who produced lactate with isoproterenol. During isoproterenol compared with pacing, peak left ventricular pressure was higher (205 +/- 33 vs. 142 +/- 21 mm Hg, p less than 0.001), ejection fraction was higher (77 +/- 10% vs. 71 +/- 12%, p less than 0.02), and regional systolic nonuniformity was diminished. Despite ischemia, these changes in load and nonuniformity during isoproterenol were associated with enhanced diastolic function compared with pacing tachycardia: isoproterenol reduced T 1/2, the half-time of pressure decline after peak negative dP/dt (from 46 +/- 10 to 33 +/- 6 msec, p less than 0.001), shifted the diastolic pressure-volume curve downward and rightward in 10 of 12 patients, and increased end-diastolic volume (from 77 +/- 18% to 100 +/- 11% of control values, p less than 0.001) with no change in end-diastolic pressure (19 +/- 7 to 19 +/- 5 mm Hg, p = NS). Thus, despite ischemia, isoproterenol improved left ventricular relaxation and filling compared with tachycardia in the absence of beta-adrenergic stimulation. Although isoproterenol is detrimental in hypertrophic cardiomyopathy by provoking ischemia, these data suggest that the adverse effects of ischemia on ventricular relaxation and distensibility may be alleviated by beta-adrenergic stimulation, possibly as a result of enhanced inactivation and restored load sensitivity.
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PMID:Beta-adrenergic stimulation with isoproterenol enhances left ventricular diastolic performance in hypertrophic cardiomyopathy despite potentiation of myocardial ischemia. Comparison to rapid atrial pacing. 253 98

Translocation of lipids inside mammalian cells is considered to be facilitated by a number of low-molecular weight lipid binding proteins. An overview of these proteins is given, with particular reference to the heart. Three distinct phospholipid transfer proteins specifically stimulate the net transfer of individual phospholipid classes between membrane structures. In rat cardiac muscle their content is 15-140 pmol/g ww. Fatty acid-binding proteins (FABP) are abundantly present in tissues actively involved in the uptake or utilization of long-chain fatty acids, such as intestine, liver and heart. The four distinct FABP types now identified show a complex tissue distribution with some tissues containing more than one type. Heart (H-) FABP comprises about 5% of the cytosolic protein mass; its content in rat heart is 100 nmol/g ww. Immunochemical evidence has been obtained for the presence of H-FABP in several other tissues, including red skeletal muscle, mammary gland and kidney. Beside long-chain fatty acids FABP binds with similar affinity also fatty acyl-CoA and acyl-L-carnitines. In heart the latter compound may be the primary ligand, since normoxic acyl-L-carnitine levels are several fold higher than those of fatty acids. In addition, H-FABP was found to modulate cardiac energy production by controlling the transfer of acyl-L-carnitine to the mitochondrial beta-oxidative system. H-FABP may also protect the heart against the toxic effects of high intracellular levels of fatty acid intermediates that arise during ischemia.
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PMID:Intracellular transport of lipids. 267 66

Six hours of coronary occlusion has been thought to produce extensive and irreversible transmural damage and no possibility of salvage by reperfusion. This has been based on findings of adenosine triphosphate depletion and histochemical (triphenyltetrazolium chloride nonstaining) and ultrastructural changes (conventional preparatory techniques). This study tests the hypothesis that, in contrast to conventional wisdom, considerable structural and mitochondrial functional integrity remains in cardiac muscle subjected to 6 hours of regional ischemia. Twenty open-chest anesthetized dogs underwent isolation of the left anterior descending coronary artery and were observed for 6 hours. Eight of the 20 did not undergo ischemia and served as controls. Twelve underwent 6 hours of proximal ligation of the left anterior descending coronary artery (30% +/- 2% area at risk). Transmural biopsy specimens were analyzed. Coronary occlusion reduced regional blood flow (radioactive microspheres) to less than 10 ml/100 gm/min (p less than 0.05) and dyskinesia persisted in the area at risk for 6 hours. High-energy phosphates (adenosine triphosphate and creatine phosphate) declined to negligible levels and histochemical damage occurred (49% +/- 12% triphenyltetrazolium chloride non-staining). Mitochondrial ultrastructural changes (low protein denaturation embedding technique) were mild (the integrity of the inner and outer mitochondrial surface membranes and crystal membranes was maintained and myofibrillar degeneration did not occur). Mitochondrial oxidative phosphorylation rate remained at 63% of control levels, respiratory control index remained at 77%, and adenosine diphosphate/oxygen ratio was maintained at 96%. Mitochondrial Ca++ increased with lanthanum (from 26 to 46 nmol/mg protein, p less than 0.05), but irreversible calcium precipitation did not occur; calcium could be mobilized to normal levels (i.e., 13 nmol/mg protein) by ethylenediaminetetraacetic acid chelation. These data support our inference that necrosis does not occur after 6 hours of coronary occlusion and suggest that muscle salvage by reperfusion is possible after at least 6 hours of regional myocardial ischemia.
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PMID:Studies on prolonged acute regional ischemia. I. Evidence for preserved cellular viability after 6 hours of coronary occlusion. 281 16

Published evidence suggests that ischemia-induced cell swelling renders myocytes vulnerable to plasmalemmal disruption and consequent cell death. Alterations to the myocyte cytoskeleton may be involved in the pathogenesis of this plasmalemmal injury. One putative cytoskeletal structure in cardiac muscle that has received little consideration is the subplasmalemmal network of periodic densities with linking microfilaments termed leptomeres or leptofibrils. We demonstrate these structures in dog heart papillary muscle and describe the improvement in their definition brought about by tissue fixation at 37 degrees C in 2% glutaraldehyde with addition of 0.05 M lysine-HCl, followed by brief postfixation with osmium tetroxide. Alterations to leptomeres during ischemic injury were examined in myocardium subjected to total in vitro ischemia for 30-180 min at 37 degrees C. Leptomeres showed little morphological alteration during the first 90-120 min, after which leptomere periodic densities (striae) increased in size, from 10-20 to 50-80 nm, and were more densely stained. The leptomeres eventually (150-180 minutes) lose definition. The course of these alterations coincided with the appearance of ultrastructural evidence of irreversible ischemic injury to the myocytes.
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PMID:Alterations to subplasmalemmal leptomeres in adult canine myocytes during total in vitro ischemia. 275 77

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

By using a novel approach for the study of the effects of pH variation in skinned myocardium, the present experiments were aimed to provide new insights into the mechanism of ischemia. Ca2+ sensitivity is decreased by acid pH, but the effect is more than double in cardiac myofilaments than that in fast-twitch skeletal muscle fibers. With the technique of troponin C exchange in myocytes, we find here that the effect of pH is the same with cardiac or skeletal troponin C. These results rule out a direct H+-Ca2+ competition on the Ca2+-binding sites of troponin C as a significant mechanism of ischemia. The findings provide conclusive evidence in favor of the idea that acidosis modulates the protein-protein interactions in the regulatory complex in cardiac muscle.
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PMID:Effect of acidosis on Ca2+ sensitivity of skinned cardiac muscle with troponin C exchange. Implications for myocardial ischemia. 292 25


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