Effects of prolonged exposure to ethanol in vivo on functional parameters and sensitivity to nitrendipine in the isolated rat heart.
This study investigated the possibility that previously reported marked upregulation of binding sites for the dihydropyridine calcium channel antagonist nitrendipine in heart tissue during the development of ethanol dependence in the rat may represent functional L-type voltage-operated calcium channels (L-VOCCs). Isolated hearts obtained from adult Sprague-Dawley rats, which received intoxicating concentrations of ethanol for 6-10 days, by inhalation, were perfused with Krebs-Henseleit solution in the Langendorff mode. Basic measurements of cardiac function were compared with hearts from control rats not exposed to ethanol vapor. In another study, concentration-response curves were constructed for nitrendipine at concentrations in the range of 10(-10)-10(-6) M for hearts obtained from control and ethanol-exposed animals. Changes in measured cardiac parameters such as R-wave amplitude, heart rate, diastolic and systolic pressure, and (+)dP/dt(max) and coronary flow were recorded. All comparisons were made between preparations set to a similar left ventricular end-diastolic pressure. Under these conditions, there were no significant differences in R-wave amplitude, but isolated hearts from ethanol-dependent rats showed significantly greater indices of myocardial contraction than did controls. These included increased systolic and developed ventricular pressure and increased (+)dP/dt(max). Coronary flow also was significantly greater in hearts from ethanol-dependent rats compared with controls. Heart rate was higher in the alcohol-exposed group, but this difference did not achieve significance. When nitrendipine was added to the perfusate at concentrations between 10(-10) and 10(-6) M, hearts from ethanol-dependent animals showed a greater sensitivity to the effects of the drug on heart rate and systolic pressure. Effects on R-wave amplitude and (+)dP/dt(max) were less clear but also suggested a greater sensitivity to nitrendipine in hearts from ethanol-exposed rats. Effects on coronary flow were small and did not differ significantly between preparations from control and ethanol-dependent rats. The results suggest that the increase in Bmax of DHP binding previously observed in hearts from ethanol-dependent animals might represent an increase in L-VOCCs, which alters physiologic function, and pharmacologic responses in the isolated heart. These changes may represent the exposure of an adaptive mechanism designed to overcome the generally depressant effects of ethanol on cardiac function in vivo.
Guppy
L J
LJ
Department of Basic Medical Sciences, Faculty of Medical Sciences, University of The West Indies, Mona, Kingston, Jamaica. ljguppy@uwimona.edu.jm
Littleton
J M
JM
D000818:Animals; D002121:Calcium Channel Blockers / Q000494:pharmacology*; D020746:Calcium Channels, L-Type / Q000187:drug effects / Q000378:metabolism; D004095:Dihydropyridines / Q000378:metabolism*; D004347:Drug Interactions; D000431:Ethanol / Q000009:adverse effects / Q000494:pharmacology*; D006321:Heart / Q000187:drug effects* / Q000503:physiopathology; D008297:Male; D009206:Myocardium / Q000378:metabolism; D009568:Nitrendipine / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013375:Substance Withdrawal Syndrome / Q000378:metabolism*
D002121:Calcium Channel Blockers; D020746:Calcium Channels, L-Type; D004095:Dihydropyridines; D000431:Ethanol; C038806:1,4-dihydropyridine; D009568:Nitrendipine