Nitric oxide activates the sarcolemmal KATPchannel in normoxic and chronically hypoxic hearts by a cyclic GMP-dependent mechanism

John E. Baker, Stephen J. Contney, Ravinder Singh, B. Kalyanaraman, Garrett J. Gross, Zeljko J. Bosnjak

Research output: Contribution to journalArticle

37 Scopus citations

Abstract

Chronic myocardial hypoxia results in elevated nitric oxide (NO) production and increased current through the sarcolemmal KATP 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 KATP 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 KATP channel in normoxic and chronically hypoxic hearts by a cyclic GMP-dependent mechanism.

Original languageEnglish (US)
Pages (from-to)331-341
Number of pages11
JournalJournal of Molecular and Cellular Cardiology
Volume33
Issue number2
DOIs
StatePublished - Jan 1 2001

Keywords

  • Action potential
  • Cyclic GMP
  • Electron spin resonance spectroscopy
  • Glibenclamide
  • S-nitrosoglutathione

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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