The Effect Of Calcium Channel Blockers On Contractile Dysfunction By Low K~+Perfusion

Hypokalemia is one of the most important trigger contributing to suddencardiac death, however, the underlying mechanism remains to be elucidated. Ourprevious studies showed that low K⁺perfusion exacerbated ischemia/reper-fusion-induced myocardial dysfunction, and increased serious calciumoscillations. The purpose of this study was to evaluate the effect of calciumchannel blocker and calpain on myocardial contractile changes induced by lowK⁺perfusion.Objectives1. To compare the effects of perfusion by3.1mM K⁺and standard KH solutioncontaining5.9mM K⁺on the post ischemic myocardial contractile function.2. To observe the low Ca²⁺solution containing0.5mM Ca²⁺on the post ische-mic contractile function in hearts perfused by3.1and5.9mM K⁺.3. To observe the effects of nifedipine, a calcium channel blocker, on the postischemic contractile function in heart perfused by3.1and5.9mM K⁺.4. To observe the effects of MDL-28170, a calpain inhibitor, on thepostischemic contractile function in heart perfused by3.1and5.9mM K⁺.5. To investigate the effects of perfusion by3.1and5.9mM K⁺on thedegradation of cTnI with and without the low Ca²⁺solution. MethodsAfter stabilization, isolated rat hearts were subjected to1h global ischemiafollowed by1h reperfusion, and the LVP of left ventricle was recorded byAcqKnowledge acquiring system. Contractile performance of the left ventriclewas evaluated on the basis of its LVDP, LVEDP, dp/dt and-dp/dt. At the end ofthe experiment, left myocardium from each heart was homogenized to detect thedegradation of cTnI by using western blot.Results1. In heart perfused by5.9mM K⁺（standard KH solution）, after1hreperfusion, the LVDP, dp/dt, and-dp/dt was recovered to60.9±8.3%,56.2%±7.8%,59.2%±5.0%of that before ischemia respectively, the LVEDPwas increased to22.1±4.2mmHg. In contrast, In hearts perfused by3.1mMK⁺, the recovery of LVDP, dp/dt, and-dp/dt were lower than that in standardKH solution group （p<0.05）, and the LVEDP was increased （p<0.01）. Theseresults suggest that perfusion by low K⁺aggravated postischemic contractiledysfunction.2. The low Ca²⁺solution containing0.5mM Ca²⁺, increased the recovery ofLVDP, dp/dt and-dp/dt respectively in heart perfused with standard buffer.And the LVEDP was decreased. In hearts perfused by3.1mM K⁺, therecovery of LVDP, dp/dt and-dp/dt by low Ca²⁺solution were significantlyhigher than that in standard KH solution group. The low Ca²⁺solution alsosignificantly decreased the elevation of LVEDP. These results indicate Ca²⁺mediates postischemic contractile dysfunction induced by low K⁺.3. MDL-28170, at the concentration of3μM, significantly attenuated thepostischemic contractile dysfunction in hearts perfused by both standardbuffer and3.1mM K⁺,while MDL-28170, at the concentration of10μM, significantly aggravated the postischemic contractile dysfunction in heartsperfused by both standard buffer and3.1mM K⁺.However, there is nosignificantly difference in the increased/reduced recovery ratio byMDL-28170between two groups, suggesting that calpain may not involvedin the aggravated postischemic contractile dysfunction induced by low K⁺.4. Nifedinpine, which was administered during the first10min reperfusion,significantly increased the level of LVEDP. In addition, nifedinpineproduced a trend of decrease in LVDP and±dp/dt, although no statisticalsignificance was reached.5. Compared with the heart perfused by standard KH solution, low K⁺significantly increased the degradation of cTnI, which was attenuated by lowCa²⁺solution. We propose that increased the degradation of cTnI contributeto the aggravated effects induced by low K⁺.Conclusion1. Our results demonstrated that the low potassium perfusion aggravate thepostischemic contractile dysfunction for the isolated rat heart thataccompanied with increased degradation of cTnI.And confirm that calciumoverload mediates ischemia/reperfusion–induced contractile dysfunction inheart perfused with low potassium,2. Calpain may not contribute to this effect by low K⁺.3. Our results suggest that nifedipine produces exacerbated effect on theischemic heart.