Testosterone has been identified as a potential cardiovascular risk factor for males. The prevalence of cardiovascular disease is greater in men compared to premenopausal women. Heart attacks and strokes have been reported in young males athletes abusing anabolic steroids. Thromboxane A2(TXA2) aggregates platelets, constricts vascular smooth muscle and its synthesis is increased in acute coronary artery syndromes. Aspirin inhibits the synthesis of TXA2 by platelets and is beneficial in the treatment of coronary artery disease. These observations have supported the notion that TXA2 plays an important pathophysiologic role in coronary artery disease. Treatment of cultured rat thoracic aortic smooth muscle cells (RASMC) or rats with testosterone results in a significant increase in RASMC, aortic membrane and platelet TXA2 receptors and their responses to TXA2. Castration of male rats resulted in a significant decrease in aortic TXA2 receptor density and to TXA2 mimetic induced increase in coronary artery pressure and significantly lowered the threshold dose compared to controls. Treatment of normal male volunteers with testosterone doubled their platelet TXA2 receptor density. This proposal will test the hypothesis that testosterone regulates the expression of TXA2 receptors in human platelets and vascular smooth muscle. The effects of administration of testoterone to normal male volunteers and chemical and surgical castration in prostatic cancer patients on platelet TXA2 receptor density and aggregation response will be measured. The effect of the administration of testosterone to normal male volunteers on the dorsal hand vein vascoconstrictor responses to prostaglandin F2a,, a surrogate TXA2 mimetic, will be determined. We will also determine the effects of puberty on the density of platelet TXA2 receptors in boys and girls and if there are differences in platelet TXA2 receptors and aggregation response in pre- and post- menopausal females and age matched males. These studies should provide new information concerning the potential role of testosterone to regulate the expression of TXA2 receptors and modulate platelet and vascular reactivity. The results may also further our understanding of the mechanism(s) by which testosterone acts as a risk factor for cardiovascular disease.
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