Responses of chronically hypoxic rat hearts to ischemia: KATP channel blockade does not abolish increased RV tolerance to ischemia. Am J Physiol Heart Circ Physiol 286: H545-H551, 2004. First published October 9, 2003 10.1152/ajpheart.00022.2003.-Chronic hypoxia may precondition the myocardium and protect from ischemia-reperfusion damage. We therefore examined the recovery of left and right ventricular function after ischemia and reperfusion (15 min each) in isolated blood-perfused working hearts from normoxic (Norm) and hypoxic (Hypo; 14 days, 10.5% O2) adult rats. In addition, the mRNA expression of hypoxia-inducible factor (HIF)-1␣ and the protein expression of endothelial nitric oxide synthase (eNOS) were measured. Postischemic left ventricular function recovered to 66 Ϯ 6% and 67 Ϯ 5% of baseline in Norm and Hypo, respectively. In contrast, postischemic right ventricular function was 93 Ϯ 2% of baseline in Hypo vs. 67 Ϯ 3% in Norm (P Ͻ 0.05). Improved postischemic right ventricular function in Hypo (93 Ϯ 2% and 96 Ϯ 2% of baseline) was observed with 95% O 2 or 21% O2 in the perfusate, and it was not attenuated by glibenclamide (5 and 10 mol/l) (86 Ϯ 4% and 106 Ϯ 6% recovery). HIF-1␣ mRNA and eNOS protein expression were increased in both left and right hypoxic ventricles. In conclusion, postischemic right, but not left, ventricular function was improved by preceding chronic hypoxia. ATP-sensitive K ϩ channels are not responsible for the increased right ventricular tolerance to ischemia after chronic hypoxia in adult rat hearts. chronic hypoxia; glibenclamide; hypoxia-inducible factor-1␣; endothelial nitric oxide synthase ISCHEMIC PRECONDITIONING protects myocardium against subsequent ischemia-reperfusion injury (19). Protection is evident by limitation of infarct size (19,22), better recovery of myocardial contractile function in some models (8), preservation of high-energy phosphate levels (13), and attenuation of arrhythmias (23). ATP-sensitive K ϩ (K ATP ) channels are crucially involved in the protection of ischemic preconditioning (10).Chronic hypoxic preconditioning also increases the tolerance of the myocardium to ischemia. In an isolated adult rat heart model, chronic hypoxia improved postischemic systolic function and protected against prolonged periods of ischemia (27). Although similarities of the phenomena of hypoxic and ischemic preconditioning have been found in protecting the myocardium, the additive cardioprotective effects of hypoxic and ischemic preconditioning suggest different mechanisms of protection (27). Baker et al. (3,4) reported that the increased tolerance to ischemia in isolated crystalloid-perfused immature rabbit hearts exposed to chronic hypoxia is associated with an activation of the K ATP channels. The beneficial effects of chronic hypoxic preconditioning on left and right ventricular (RV) developed pressure were abolished by the K ATP channel antagonist glibenclamide. The K ATP channel agonist bimakalim enhanced postischemic left ventricular (LV) function in normoxic heart...

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