GENDER EFFECTS ON THE CARDIAC TOXICITY OF ETHANOL

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Clinical studies examining the influence of gender on the cardiotoxic effects of chronic ethanol intake are inconclusive with some showing that females are more sensitive to the cardiotoxicity, but others suggesting that men are more sensitive. Unfortunately, corresponding data from animal models, which provide more controlled experimental conditions, are not readily available. Experiments in the proposed project will use a rat model to test the hypotheses that: 1) males respond to chronic ethanol consumption with a more pronounced hypertension that leads to a marked cardiomyopathy; and (2) that this gender-related disparity is mediated, at least in part, by sex hormones and their response to ethanol consumption. Proposed experiments will address the following specific questions: 1) Does gender influence the effects of chronic ethanol intake on measured cardiovascular parameters? 2) Does ethanol intake affect circulating levels of sex hormones? 3) Are gender-related differences observed in castrated animals, and are the effects of castration reversed by hormone-replacement? 4) Are gender-related differences in the cardiomyopathy prevented by maintaining after-load at pre-ethanol levels? Ethanol-preferring male and female P-rats will be allowed free access to either water or an ethanol/water mixture for 16 weeks. Some animals will be castrated, and half of the castrated rats will be treated with sustained-release estradiol (females) or testosterone (males) pellets. In vivo studies examining effects of chronic ethanol intake on blood pressure and heart rate will utilize biotelemetry techniques, while cardiac contractility and vascular responsiveness will be monitored in vitro in tissues isolated after the 16 weeks. Ethanol consumption and body weight will be monitored, and blood ethanol, estradiol levels will be examined. Future experiments will use the established model to examine the cellular and molecular mechanisms underlying observed gender-associated variations. Studies could address possible differences in the effects of ethanol on hormone regulation, blood pressure regulation and/or cardiac function. Gene control, protein expression and cellular function could be examined at any of these sites.