Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0151744 (myocardial ischemia)
 31,282 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The aim of this study was to determine whether changes in protein content and/or gene expression of Na+-K+-ATPase subunits underlie its decreased enzyme activity during ischemia and reperfusion. We measured protein and mRNA subunit levels in isolated rat hearts subjected to 30 min of ischemia and 30 min of reperfusion (I/R). The effect of ischemic preconditioning (IP), induced by three cycles of ischemia and reperfusion (10 min each), was also assessed on the molecular changes in Na+-K+-ATPase subunit composition due to I/R. I/R reduced the protein levels of the alpha2-, alpha3-, beta1-, and beta2-isoforms by 71%, 85%, 27%, and 65%, respectively, whereas the alpha1-isoform was decreased by <15%. A similar reduction in mRNA levels also occurred for the isoforms of Na+-K+-ATPase. IP attenuated the reduction in protein levels of Na+-K+-ATPase alpha2-, alpha3-, and beta2-isoforms induced by I/R, without affecting the alpha1- and beta1-isoforms. Furthermore, IP prevented the reduction in mRNA levels of Na+-K+-ATPase alpha2-, alpha3-, and beta1-isoforms following I/R. Similar alterations in protein contents and mRNA levels for the Na+/Ca2+ exchanger were seen due to I/R as well as IP. These findings indicate that remodeling of Na+-K+-ATPase may occur because of I/R injury, and this may partly explain the reduction in enzyme activity in ischemic heart disease. Furthermore, IP may produce beneficial effects by attenuating the remodeling of Na+-K+-ATPase and changes in Na+/Ca2+ exchanger in hearts after I/R.
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PMID:Preconditioning attenuates ischemia-reperfusion-induced remodeling of Na+-K+-ATPase in hearts. 1276 51

Epidemiological data document that regular exercise protects against the morbidity and mortality associated with ischemic heart disease. Therefore, we tested the hypothesis that daily exercise (DE) increases the ventricular arrhythmia threshold (VAT) induced by coronary artery occlusion and alters the expression of calcium regulatory proteins. The VAT was defined as the time from coronary occlusion to sustained ventricular tachycardia resulting in a reduction in arterial pressure. To test this hypothesis, we recorded the VAT in conscious sedentary normotensive, sedentary hypertensive, and DE hypertensive rats, and we associated these thresholds with the protein expression of the L-type calcium channel, Na+/Ca2+ exchanger, phospholamban, and sarco(endo)plasmic reticulum Ca(2+)-ATPase. Results document a significantly reduced time to ventricular arrhythmias (sedentary hypertensive, 3.7 +/- 0.3 min vs. sedentary normotensive, 4.8 +/- 0.3 min), an increased Na+/Ca2+ exchanger protein expression (47%), and a decreased phospholamban protein expression (-34%) in conscious hypertensive rats. DE increased the VAT (5.9 +/- 0.2 min), decreased the protein expression of the Na+/Ca2+ exchanger, and normalized the protein expression of phospholamban in the hypertensive rats. Thus DE may be a primary prevention approach for reducing the incidence of arrhythmias by altering calcium regulatory proteins in hypertensive rats.
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PMID:Daily exercise-induced cardioprotection is associated with changes in calcium regulatory proteins in hypertensive rats. 1547 72

The Ca2+ overload by Ca2+ influx via Na+/Ca2+ exchanger (NCX) is a critical mechanism in myocardial ischemia/reperfusion injury. We investigated protective effects of a novel selective inhibitor of NCX, SEA0400, on cardiac function and energy metabolism during ischemia and reperfusion. Langendorff-perfused rat hearts were exposed to 35 minutes global ischemia and 40 minutes reperfusion. Using 31P nuclear magnetic resonance spectroscopy, cardiac phosphocreatine (PCr), ATP, and pHi were monitored. SEA0400 did not change the basic cardiac function, but improved the recovery of left ventricular developed pressure (LVDP) after reperfusion (27.6 +/- 4.9 mm Hg in control, 101.2 +/- 19.3 mm Hg in 0.1 microM, and 115.5 +/- 13.3 mm Hg in 1 microM SEA0400, means +/- SE, n = 6, P < 0.05). SEA0400 reduced left ventricular end-diastolic pressure and increased coronary flow after reperfusion. SEA0400 improved the recoveries of cardiac phosphocreatine and ATP after reperfusion, but did not affect pHi. There were significant linear correlations between left ventricular developed pressure and cardiac phosphocreatine (r = 0.79, P < 0.05), and left ventricular developed pressure and ATP (r = 0.80, P < 0.05). However, SEA0400 increased the incidence and duration of reperfusion ventricular arrhythmias. SEA0400 added only after reperfusion also improved both the contractile function and energy metabolism. It is concluded that the selective inhibition of NCX may be effective to preserve high-energy phosphates and to improve cardiac function after reperfusion, but may not be able to prevent fatal arrhythmias.
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PMID:A selective inhibitor of Na+/Ca2+ exchanger, SEA0400, preserves cardiac function and high-energy phosphates against ischemia/reperfusion injury. 1649 65

Given the potential clinical benefit of inhibiting Na+/Ca2+ exchanger (NCX) activity during myocardial ischemia reperfusion (I/R), pharmacological approaches have been pursued to both inhibit and clarify the importance of this exchanger. SEA0400 was reported to have a potent NCX selectivity. Thus, we examined the effect of SEA0400 on NCX currents and I/R induced intracellular Ca2+ overload in mouse ventricular myocytes using patch clamp techniques and fluorescence measurements. Ischemia significantly inhibited inward and outward NCX current (from -0.04+/-0.01 nA to 0 nA at -100 mV; from 0.23+/-0.08 nA to 0.11+/-0.03 nA at +50 mV, n=7), Subsequent reperfusion not only restored the current rapidly but enhanced the current amplitude obviously, especially the outward currents (from 0.23+/-0.08 nA to 0.49+/-0.12 nA at +50 mV, n=7). [Ca2+]i, expressed as the ratio of Fura-2 fluorescence intensity, increased to 138+/-7% (P<0.01) during ischemia and to 210+/-11% (P<0.01) after reperfusion. The change of NCX current and the increase of [Ca2+]i during I/R can be blocked by SEA0400 in a dose-dependent manner with an EC50 value of 31 nM and 28 nM for the inward and outward NCX current, respectively. The results suggested that SEA0400 is a potent NCX inhibitor, which can protect mouse cardiac myocytes from Ca2+ overload during I/R injuries.
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PMID:SEA0400, a novel Na+/Ca2+ exchanger inhibitor, reduces calcium overload induced by ischemia and reperfusion in mouse ventricular myocytes. 1649 99

One consequence of elevated afterload pressure is the activation of the angiotensin II type 1 receptor and nonspecific cation channels with subsequent Ca2+ accumulation via the Na+/H(+)-Na+/Ca2+ exchanger combination and the T-type or L-type Ca2+ channels. Intracellular Ca2+ overload is cytotoxic, in part, by inducing the mitochondrial permeability transition (MPT) pore. Therefore, we tested the hypotheses that: (1) increased afterload pressure worsens myocardial ischemia-reperfusion injury in healthy heart, (2) the Na+/H(+)-Na+/Ca2+ exchanger combination and both the T-type and L-type Ca2+ channels are involved in the exacerbating impact of high afterload pressure on infarct size, and (3) elevated afterload enhances infarct size in part via the MPT pore. Accordingly, the effect of candesartan (angiotensin II type 1 receptor antagonist), cariporide (inhibitor of the Na+/H+ exchanger), mibefradil (T-type Ca2+ channel blocker), diltiazem (L-type Ca2+ channel blocker), or cyclosporine A (inhibitor of MPT pore) were examined. The elevation in afterload pressure from 80 to 160 cmH2O increased baseline myocardial performance but caused larger infarcts and worsened recovery of mechanical function after ischemia reperfusion. Whereas mibefradil abrogated the effect of high afterload pressure on infarct size, the other agents reduced infarct size at both afterload pressures. Hearts exposed to mibefradil, diltiazem, or cariporide displayed greater functional recovery than those exposed to candesartan or cyclosporine A, revealing that an uncoupling exists between reduced cell death and recovery of mechanical function of the viable portions of the myocardium. The data also uncovered an important link between pressure-mediated exacerbation of infarct size and T-type Ca2+ channel activity.
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PMID:Mechanisms underlying afterload-induced exacerbation of myocardial infarct size: role of T-type Ca2+ channel. 1650 94