Chronic intermittent hypoxia alters Ca2+ handling in rat cardiomyocytes by augmented Na+/Ca2+ exchange and ryanodine receptor activities in ischemia-reperfusion

This study examined Ca2+ handling mechanisms involved in cardioprotection induced by chronic intermittent hypoxia (CIH) against ischemia-reperfusion (I/R) injury. Adult male Sprague-Dawley rats were exposed to 10% inspired O-2 continuously for 6 h daily from 3, 7, and 14 days. In isolated perfused hearts subjected to I/R, CIH-induced cardioprotection was most significant in the 7-day group with less infarct size and lactate dehydrogenase release, compared with the normoxic group. The I/R-induced alterations in diastolic Ca2+ level, amplitude, time-to-peak, and the decay time of both electrically and caffeine-induced Ca2+ transients measured by spectrofluorometry in isolated ventricular myocytes of the 7-day CIH group were less than that of the normoxic group, suggesting an involvement of altered Ca2+ handling of the sarcoplasmic reticulum (SR) and sarcolemma. We further determined the protein expression and activity of Ca-45(2+) flux of SR-Ca2+-ATPase, ryanodine receptor (RyR) and sarcolemmal Na+/Ca2+ exchange (NCX) in ventricular myocytes from the CIH and normoxic groups before and during I/R. There were no changes in expression levels of the Ca2+-handling proteins but significant increases in the RyR and NCX activities were remarkable during I/R in the CIH but not the normoxic group. The augmented RyR and NCX activities were abolished, respectively, by PKA inhibitor (0.5 mu M KT5720 or 0.5 mu M PKI14-22) and PKC inhibitor (5 mu M chelerythrine chloride or 0.2 mu M calphostin C) but not by Ca2+/calmodulin- dependent protein kinase II inhibitor KN-93 (1 mu M). Thus, CIH confers cardioprotection against I/R injury in rat cardiomyocytes by altered Ca2+ handling with augmented RyR and NCX activities via protein kinase activation.