title: Effect of calcium, Bay K 8644, and reduced perfusion on basic indices of myocardial function in isolated hearts from rats after prolonged exposure to ethanol.
abstract: We previously reported findings consistent with a marked upregulation in functional L-type voltage-operated calcium channels (L-VOCCs) in hearts obtained from rats exposed over the long term to ethanol. These experiments were undertaken to establish whether detrimental effects on cardiac function were associated with excess calcium entry into the myocardium in these hearts. Isolated hearts from adult male Sprague-Dawley rats received intoxicating concentrations of ethanol for 6-10 days by inhalation, were perfused with Krebs-Henseleit buffer by a modified Langendorff technique, and several functional parameters were assessed continuously. In some experiments, the calcium concentration in the perfusate was first reduced from the physiologic range (1.2 mM) to 0.15 mM and then increased in a step-wise fashion to 4 mM. In other experiments, hearts were exposed to buffer containing concentrations of the L-VOCC activator, (+/-)Bay K 8644, increasing from 10(-9) to 10(-6) M. These perfusion protocols were repeated in hearts from treated animals subject to reduced coronary flow because of induction of partial left ventricular ischemia. There were some close similarities in the effects of these different stimuli. When the calcium concentration in the perfusate exceeded a physiologic level, there were signs of decreased function relative to controls in the hearts from ethanol-exposed rats. Thus R-wave amplitude and systolic pressure were lower, diastolic pressure also was reduced, but heart rate was elevated above that of controls. Similarly the presence of (+/-)Bay K 8644 in the perfusate caused a decrease in systolic and diastolic pressure and an increase in heart rate in hearts from ethanol-exposed rats. When cardiac perfusion was reduced in vitro by inflation of a balloon in the left ventricle, some of the effects of excess calcium and (+/-)Bay K 8644 were reproduced in control hearts. However, imposition of this "ischemic" stress did not appear to exacerbate the effects of prior exposure to ethanol. In general, in control hearts, indices of contractility were increased across the range of calcium concentration or by perfusing with (+/-)Bay K 8644. Hearts from ethanol-exposed rats, however, showed no further increase in these parameters once physiologic levels of calcium were exceeded, or showed inhibition of contractility in the presence of (+/-)Bay K 8644. The results are consistent with calcium entry through L-VOCCs in hearts from ethanol-exposed animals having detrimental effects on cardiac function once physiologic levels are exceeded. However, it is possible that these channels also may be involved in maintenance of cardiac function at hypocalcemic levels.
authors.affiliation: Department of Basic Medical Sciences, University of the West Indies, Mona, Kingston, Jamaica. ljguppy@uwimona.edu.jm
authors.forename: L J
authors.initials: LJ
authors.lastname: Guppy
authors.forename: J M
authors.initials: JM
authors.lastname: Littleton
mesh_terms: D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002118:Calcium / Q000502:physiology*; D015220:Calcium Channels / Q000502:physiology*; D003326:Coronary Circulation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004562:Electrocardiography / Q000187:drug effects; D000431:Ethanol / Q000633:toxicity*; D006321:Heart / Q000187:drug effects*; D066298:In Vitro Techniques; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D017202:Myocardial Ischemia / Q000139:chemically induced; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D015220:Calcium Channels; D000431:Ethanol; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002118:Calcium