Nitric oxide activates the sarcolemmal K(ATP) channel 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 (F(I)O2=0.21) or hypoxic (F(I)O2=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 microM and spermine NONOate (50 microM) shortened APD(90) and increased MDP to levels present in chronically hypoxic hearts. This effect was completely abolished by the K(ATP) channel blocker glibenclamide (3 microM) and by a nitric oxide trap, Carboxy-PTIO (100 microM). The NO carrier glutathione (50 microM) and decomposed spermine NONOate had no effect on APD(90) or MDP. GSNO had no effect in hypoxic hearts; however, when GSNO was combined with glibenclamide APD(90) increased, and MDP decreased to normoxic values. 8-Bromo cGMP (100 microM) shortened APD(90) and increased MDP to levels present in chronically hypoxic hearts. This effect was abolished by glibenclamide. A soluble guanylyl cyclase inhibitor, ODQ (10 microM), had no effect on action potentials in normoxic hearts but in hypoxic hearts resulted in an increase in APD(90) 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.
Baker
J E
JE
Division of Pediatric Surgery, Medical College of Wisconsin, Milwaukee, WI 53226, USA. jbaker@mcw.edu
Contney
S J
SJ
Singh
R
R
Kalyanaraman
B
B
Gross
G J
GJ
Bosnjak
Z J
ZJ
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001794:Blood Pressure; D006152:Cyclic GMP / Q000031:analogs & derivatives* / Q000378:metabolism* / Q000494:pharmacology; D004578:Electron Spin Resonance Spectroscopy; D004594:Electrophysiology; D005260:Female; D005978:Glutathione / Q000031:analogs & derivatives* / Q000494:pharmacology; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D000860:Hypoxia; D008297:Male; D008954:Models, Biological; D018696:Neuroprotective Agents / Q000494:pharmacology; D009569:Nitric Oxide / Q000494:pharmacology*; D020030:Nitric Oxide Donors / Q000494:pharmacology; D009589:Nitrogen Oxides; D009603:Nitroso Compounds / Q000494:pharmacology; D010100:Oxygen / Q000378:metabolism*; D015221:Potassium Channels / Q000378:metabolism* / Q000502:physiology*; D011817:Rabbits; D026422:S-Nitrosoglutathione; D012508:Sarcolemma / Q000378:metabolism*; D013096:Spermine / Q000031:analogs & derivatives / Q000494:pharmacology; D013997:Time Factors
D007004:Hypoglycemic Agents; D018696:Neuroprotective Agents; D020030:Nitric Oxide Donors; D009589:Nitrogen Oxides; D009603:Nitroso Compounds; D015221:Potassium Channels; C091861:spermine nitric oxide complex; D013096:Spermine; C016276:8-bromocyclic GMP; D009569:Nitric Oxide; D026422:S-Nitrosoglutathione; D005978:Glutathione; D006152:Cyclic GMP; D010100:Oxygen; D005905:Glyburide