Cardioprotection in chronically hypoxic rabbits persists on exposure to normoxia: Role of NOS and K ATP channels

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 plus or minus 4%) than normoxic controls (43 plus or minus 4%). At 10 days of age, NG-nitro-L-arginine methyl ester (200 uM) and glibenclamide (3 u) abolished the cardioprotective effects of chronic hypoxia (45 plus or minus 4% and 46 plus or minus 5%, respectively) but had no effect on normoxic hearts. At 30 days of age resistance to ischemia in normoxic hearts declined (36 plus or minus 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 plus or minus 4%). L-NAME or glibenclamide abolished cardioprotection in previously hypoxic hearts (37 plus or minus 4% and 39 plus or minus 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. [PUBLICATION ABSTRACT]