Nitric Oxide Activates the Sarcolemmal KATPChannel in Normoxic and Chronically Hypoxic Hearts by a Cyclic GMP-dependent Mechanism

Chronic myocardial hypoxia results in elevated nitric oxide (NO) production and increased current through the sarcolemmal KATPchannel. We hypothesized these two processes are related and determined whether NO alters the electrophysiology of Purkinje fibers obtained from rabbits (n=12/group) raised in a normoxic (FIO2=0.21) or hypoxic (FIO2=0.12) environment from birth to 9 days of age. Action potential duration (APD)90was shorter (112±3 ms v 126±3 ms) and maximum diastolic potential (MDP) was more negative (−84±2 mV v−80±1 mV) in hypoxic hearts compared with normoxic controls. In normoxic hearts the NO donors, S-nitrosoglutathione (GSNO) 50 μ and spermine NONOate (50μ M ) shortened APD90and increased MDP to levels present in chronically hypoxic hearts. This effect was completely abolished by the KATPchannel blocker glibenclamide (3 μ M) and by a nitric oxide trap, Carboxy-PTIO (100 μ M). The NO carrier glutathione (50 μ M) and decomposed spermine NONOate had no effect on APD90or MDP. GSNO had no effect in hypoxic hearts; however, when GSNO was combined with glibenclamide APD90increased, and MDP decreased to normoxic values. 8-Bromo cGMP (100 μ M) shortened APD90and increased MDP to levels present in chronically hypoxic hearts. This effect was abolished by glibenclamide. A soluble guanylyl cyclase inhibitor, ODQ (10 μ M), had no effect on action potentials in normoxic hearts but in hypoxic hearts resulted in an increase in APD90to levels present in normoxic hearts and a decrease in MDP. The effect of ODQ could not be reversed by GSNO. We conclude that NO activates the sarcolemmal KATPchannel in normoxic and chronically hypoxic hearts by a cyclic GMP-dependent mechanism.