Negative inotropic effect of low-dose ethanol in mouse ventricular myocytes is mediated by activation of endothelial nitric oxide synthase.
Low doses of ethanol can produce negative functional effects in ventricular myocytes. This may be related to the nitric oxide-cyclic GMP signal transduction system. We tested the hypothesis that ethanol stimulated endothelial nitric oxide synthase and this caused the negative functional effects in cardiac myocytes. This hypothesis was tested in ventricular myocytes isolated from endothelial nitric oxide synthase-knockout (eNOS-/-) and wild-type (WT) control mice. Cell function was determined with a video edge detector at 37 degrees C. Myocytes were administered 5 or 10 mM ethanol alone or after 10(-6) M L-nitro-arginine-methyl ester (L-NAME, nitric oxide synthase inhibitor) or 10(-6) M 1H[1,2,4]oxadiazolo[4,3-alpha]quinoxalin-1-one (ODQ, soluble guanylyl cyclase inhibitor). There were no differences in basal perecentage shortening (2.6+/-0.2% WT versus 2.4+/-0.2% eNOS) or maximal rate of shortening (44+/-6 WT versus 47+/-6 microms eNOS) between groups. In the WT mice, 10 mM ethanol significantly decreased percentage shortening (1.8+/-0.1) and maximal rate of shortening (35+/-4). These effects were blocked by L-NAME and ODQ. In the eNOS-/- mice, these values were not affected by ethanol. Similar data were seen for both maximal rate of shortening and relaxation. These data provide both pharmacological and direct genetic proof that these low doses of ethanol act as a stimulator of endothelial nitric oxide synthase, and this leads to the negative functional effects in ventricular myocytes.
Zhang
Shengjun
S
Department of Physiology and Biophysics, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, New Jersey 08854-5635, USA.
Grover
Gary J
GJ
Stokes
Henry
H
Scholz
Peter M
PM
Weiss
Harvey R
HR
D000818:Animals; D000889:Anti-Arrhythmia Agents; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000494:pharmacology; D000431:Ethanol / Q000008:administration & dosage / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D009200:Myocardial Contraction / Q000187:drug effects; D032383:Myocytes, Cardiac / Q000187:drug effects* / Q000201:enzymology*; D019331:NG-Nitroarginine Methyl Ester / Q000494:pharmacology; D052250:Nitric Oxide Synthase Type III / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D010069:Oxadiazoles / Q000494:pharmacology; D011810:Quinoxalines / Q000494:pharmacology
C095284:1H-(1,2,4)oxadiazolo(4,3-a)quinoxalin-1-one; D000889:Anti-Arrhythmia Agents; D004791:Enzyme Inhibitors; D010069:Oxadiazoles; D011810:Quinoxalines; D000431:Ethanol; D052250:Nitric Oxide Synthase Type III; D006162:Guanylate Cyclase; D019331:NG-Nitroarginine Methyl Ester