Gender-related differences in risk for cardiovascular disease are prominent prior to the climacteric; however, the influence of gender on vascular reactivity and the nature of the hormones responsible are not well understood. Using the Fischer 344 rat model, we will measure in vitro vascular reactivity to adrenergic nerve stimulation and to the pineal hormone melatonin as well as the vascular distribution of gonadal steroid hormone receptors to test the following specific hypotheses: 1. Greater sensitivity to adrenergic nerve stimulation seen in male vasculature in vitro compared to female can be accounted for by a difference in adrenergic nerve function. We will measure vascular norepinephrine content, stimulation-evoked norepinephrine release, and the influence of antagonists of the co-transmitters ATP and neuropeptide Y and adrenergic receptor antagonists on contractile responses to adrenergic nerve stimulation to determine how gender and possibly stage of the estrous cycle influence vascular reactivity. 2. There is a correlation between presence of melatonin binding sites and effects of melatonin on vascular sensitivity, and both vary with gender, estrous cycle stage and vascular bed. Circadian variation in the onset of acute cardiovascular disease, vascular reactivity and levels of sympathetic activity has been well described, and the circadian hormone melatonin appears to influence vascular reactivity. Therefore we will investigate the functional response of the vasculature to melatonin, specificity for vessels involved in thermoregulation, distribution of vascular melatonin binding sites, and variation with stage of the estrous cycle or gender. 3. Gonadal steroid hormones are important in maintaining gender-related differences in vascular reactivity, and their effects can be correlated with distribution of hormone receptors in the vasculature. Vascular reactivity of ovariectomized females and castrated males will be studied with and without hormone replacement. Autoradiography will be used to define the vascular distribution of relevant steroid hormone receptors. Better understanding of the basis of gender-related differences in vascular reactivity will shed new light on the sexual dimorphism in incidence and characteristics of cardiovascular disease.
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