Cardioprotection in chronically hypoxic rabbits persists on exposure to normoxia: role of NOS and K_ATP channels

Abstract

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 (K(ATP)) channels. Resistance to myocardial ischemia was determined in rabbits raised from birth to 10 days of age in a normoxic (Fi(O(2)) = 0.21) or hypoxic (Fi(O(2)) = 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, N(G)-nitro-L-arginine methyl ester (200 microM) and glibenclamide (3 microM) 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 K(ATP) channels.

Strategic localization of heart mitochondrial NOS: a review of the evidence

“…Different groups have reported iNOS upregulation during the exposition of rats to chronic hypoxia (62,114). Some reports indicate that eNOS is upregulated during rabbit (47) and rat (48) heart adaptation.…”

Cardioprotective mechanisms ofPrunus cerasus(sour cherry) seed extract against ischemia-reperfusion-induced damage in isolated rat hearts

“…In the search of the mechanisms of ischemiareperfusion-induced pathways that may be amenable to manipulation, a number of potential candidates have been identified and have been the subject of many investigations. It is highly probable that a number of interaction mechanisms combine to determine the damage caused by ischemia-reperfusion in the myocardium, and a variety of such triggers have been postulated, including ionic disturbances and ion channels (30,69), fatty acid metabolism (35), ␣-and ␤-adrenergic receptors (67), various gene expression (53,60,64), platelet-activating factor (6), endothelin (50), nitric oxide (24), heme oxygenase-1 and carbon monoxide (5,61), and free radicals (15,30). It has been also shown that ischemia and reperfusion of the myocardium result in an activation of various pathways including caspase cascade, and it is hypothesized that a degree of caspase inhibition could be related to the recovery of postischemic cardiac function (4,31,57,62,66).…”

Contribution of Opioid Receptors to the Cytoprotective Effect of the Adaptation to Chronic Hypoxia at Anoxia/Reoxygenation of Isolated Cardiomyocytes

“…Signaling mechanisms for implementing protective effect in chronic hypoxia have been hardly studied. We only know that they may include OR [6], protein kinase C [9], NO-synthase [4], mitoBKCa channels (mitochondrial large conductance Ca 2+ -dependent K + -channels) [2], KATP channels [4], and mitochondrial permeability transition (MPT) pore [14]. Analysis of the literature suggests that kinase that are tightly integrated with OR, for example, PI3 protein kinase, Akt, MEK1/2, ERK1/2, Src-protein kinase, and JAK2 may participate in the mechanism of protective action of CCNH [12].…”