Ethanol-induced reduction in myocardial oxygen consumption can be attenuated by inhibiting guanylyl cyclase.
We tested the hypothesis that low-dose ethanol-induced reductions in myocardial metabolism were related to increased cyclic guanosine monophosphate (GMP). Anesthetized open chest rabbits were divided into four groups: control (Ringers lactate and vehicle), ETOH (250 mg/kg i.v. ethanol and vehicle), ODQ (Ringers lactate and 1 H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one, ODQ 10(-4) M ), and ETOH-ODQ (ethanol and ODQ). ODQ, a soluble guanylyl cyclase inhibitor, or vehicle was applied topically to the epicardium for 15 min, while either Ringers lactate or ethanol was administered intravenously. Oxygen consumption (VO2 ) in both the subepicardium (EPI) and subendocardium (ENDO) was determined from coronary blood flow (radioactive microspheres) and O2 extraction (microspectrophotometry). Cyclic GMP was determined by radioimmunoassay. ETOH significantly decreased VO2 in the subepicardium (9.2 +/- 1.0-5.6 +/- 0.7 ml O2 /min/100 g) and subendocardium (9.7 +/- 0.8-7.1 +/- 0.8) and increased cyclic GMP in the subepicardium (10.2 +/- 1.7-13.8 +/- 0.8 pmol/g) and subendocardium (11.0 +/- 0.5-13.7 +/- 0.9). With ODQ, there was no significant change in the subepicardial (9.5 +/- 1.3) or subendocardial (9.0 +/- 0.9) VO2. However, ODQ caused a significant increase in both wall thickening (12.9 +/- 0.9-17.2 +/- 1.2%) and maximal rate of change in wall thickness (10.8 +/- 0.9-16.3 +/- 1.9 mm/s) and decreased subepicardium (8.3 +/- 1.3) and subendocardium (7.8 +/- 1.2) cyclic GMP. The ETOH-ODQ group had cyclic GMP (subepicardium 9.0 +/- 1.8, subendocardium 8.6 +/- 2.4) and VO2 (subepicardium 7.9 +/- 0.5, subendocardium 8.4 +/- 0.4) values similar to control. Thus, the ethanol-induced rise in cyclic GMP was associated with a decrease in myocardial O2 consumption. When this rise was blocked with a soluble guanylyl cyclase inhibitor, the reduction in metabolic demand was also eliminated. This demonstrated that the alcohol-induced reduction in myocardial metabolism was related to increased cyclic GMP and suggests a novel mechanism for the effect of ethanol.
Lazar
M J
MJ
Heart and Brain Circulation Laboratory, Department of Surgery, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey, USA.
Patel
K
K
Scholz
P M
PM
Weiss
H R
HR
D000287:Administration, Topical; D000818:Animals; D002492:Central Nervous System Depressants / Q000008:administration & dosage / Q000494:pharmacology*; D006152:Cyclic GMP / Q000378:metabolism; D004699:Endocardium / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D000431:Ethanol / Q000008:administration & dosage / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D007262:Infusions, Intravenous; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D010101:Oxygen Consumption / Q000187:drug effects* / Q000502:physiology; D010496:Pericardium / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D011817:Rabbits
D002492:Central Nervous System Depressants; D000431:Ethanol; D006162:Guanylate Cyclase; D006152:Cyclic GMP