Nitric oxide activates the sarcolemmal K_ATPchannel 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 K_ATP channel. 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 (F₁O₂ = 0.21) or hypoxic (F₁O₂ = 0.12) environment from birth to 9 days of age. Action potential duration (APD)₉₀ was 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 μM and spermine NONOate (50 μM) shortened APD₉₀ and increased MDP to levels present in chronically hypoxic hearts. This effect was completely abolished by the K_ATP channel blocker glibenclamide (3 μM) and by a nitric oxide trap, Carboxy-PTIO (100 μM). The NO carrier glutathione (50 μM) and decomposed spermine NONOate had no effect on APD₉₀ or MDP. GSNO had no effect in hypoxic hearts; however, when GSNO was combined with glibenclamide APD₉₀ increased, and MDP decreased to normoxic values. 8-Bromo cGMP (100 μM) shortened APD₉₀ and increased MDP to levels present in chronically hypoxic hearts. This effect was abolished by glibenclamide. A soluble guanylyl cyclase inhibitor, ODQ (10 μM), had no effect on action potentials in normoxic hearts but in hypoxic hearts resulted in an increase in APD₉₀ to 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 K_ATP channel in normoxic and chronically hypoxic hearts by a cyclic GMP-dependent mechanism.