Chronic Intermittent Hypobaric Hypoxia Ameliorates Ischemia/Reperfusion-Induced Calcium Overload in Heart via Na+/Ca2+ Exchanger in Developing Rats
Background/Aims: Chronic intermittent hypobaric hypoxia (CIHH) protects the heart against ischemia/reperfusion (I/R) injury. This study investigated the calcium homeostasis mechanism and the role of Na+/Ca2+ exchanger (NCX) in the cardiac protective effect of CIHH in developing rats. Methods: Neonatal male rats received CIHH treatment or no treatment (control) in a hypobaric chamber simulating 3000-meter altitude for 42 days. The left ventricular function of isolated hearts was evaluated after 30 minutes of ischemia and 60 minutes of reperfusion. Myocardial infarct size, intracellular Ca2+ concentration ([Ca2+]i), Na+-Ca2+ exchanger currents (INa/Ca) in ventricular myocytes, and NCX1 protein level in the sarcolemmal membrane were determined. Results: The recovery of cardiac function after I/R was improved, with the myocardial infarct size reduced, in CIHH rats compared with control rats (p<0.05). These effects were attenuated by Bay K8644, an L-type Ca2+ channel agonist, or ryanodine, a sarcoplasmic reticulum Ca2+ channel receptor activator. Furthermore, the increases in [Ca2+]i during I/R were blunted in CIHH rats, but this effect was abolished by Bay K8644 or chelerythrine, a protein kinase C (PKC) inhibitor. The INa/Ca was decreased and the reversal potential of INa/Ca was shifted toward negative potential during simulated ischemia in the control cardiomyocytes (p<0.05). The inhibition of NCX1 protein expression during I/R was smaller in the CIHH rats than in the control rats (p<0.05). Conclusion: These data suggest that CIHH protects developing rat hearts during I/R by enhancing the resistance against calcium overload and by preserving normal INa/Ca and NCX1 protein. PKC activation might be involved in this protective process of CIHH.