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Hypoxia from birth increases resistance to myocardial ischemia in infant rabbits. We hypothesized that increased cardioprotection in hearts chronically hypoxic from birth persists following development in a normoxic environment and involves increased activation of nitric oxide synthase (NOS) and ATP-dependent K (KATP) channels. Resistance to myocardial ischemia was determined in rabbits raised from birth to 10 days of age in a normoxic (FiO2 = 0.21) or hypoxic (FiO2 = 0.12) environment and subsequently exposed to normoxia for up to 60 days of age. Isolated hearts ( n = 8/group) were subjected to 30 min of global ischemia followed by 35 min of reperfusion. At 10 days of age, resistance to myocardial ischemia (percent recovery postischemic recovery left ventricular developed pressure) was higher in chronically hypoxic hearts (68 ± 4%) than normoxic controls (43 ± 4%). At 10 days of age, NG-nitro-l-arginine methyl ester (200 μM) and glibenclamide (3 μM) abolished the cardioprotective effects of chronic hypoxia (45 ± 4% and 46 ± 5%, respectively) but had no effect on normoxic hearts. At 30 days of age resistance to ischemia in normoxic hearts declined (36 ± 5%). However, in hearts subjected to chronic hypoxia from birth to 10 days and then exposed to normoxia until 30 days of age, resistance to ischemia persisted (63 ± 4%). l-NAME or glibenclamide abolished cardioprotection in previously hypoxic hearts (37 ± 4% and 39 ± 5%, respectively) but had no effect on normoxic hearts. Increased cardioprotection was lost by 60 days. We conclude that cardioprotection conferred by adaptation to hypoxia from birth persists on subsequent exposure to normoxia and is associated with enhanced NOS activity and activation of KATP channels.

Isoflurane mimics the cardioprotective effect of acute ischemic preconditioning with an acute memory phase. We determined whether isoflurane can induce delayed cardioprotection, the involvement of ATP-sensitive potassium (KATP) channels, and cellular location of the channels. Neonatal New Zealand White rabbits at 7–10 days of age ( n = 5–16/group) were exposed to 1% isoflurane-100% oxygen for 2 h. Hearts exposed 2 h to 100% oxygen served as untreated controls. Twenty-four hours later resistance to myocardial ischemia was determined using an isolated perfused heart model. Isoflurane significantly reduced infarct size/area at risk (means ± SD) by 50% (10 ± 5%) versus untreated controls (20 ± 6%). Isoflurane increased recovery of preischemic left ventricular developed pressure by 28% (69 ± 4%) versus untreated controls (54 ± 6%). The mitochondrial KATP channel blocker 5-hydroxydecanoate (5-HD) completely (55 ± 3%) and the sarcolemmal KATPchannel blocker HMR 1098 partially (62 ± 3%) attenuated the cardioprotective effects of isoflurane. The combination of 5-HD and HMR-1098 completely abolished the cardioprotective effect of isoflurane (56 ± 5%). We conclude that both mitochondrial and sarcolemmal KATP channels contribute to isoflurane-induced delayed cardioprotection.