The incidence of cardiovascular disease in women increases dramatically following menopause. This is, most likely, triggered by estrogen deprivation. The proposed collaborative project is designed to expand Dr. Clark's scientific armament so as to enable a successful transition to mainstream funding for his studies of neuroendocrine regulation of cardiovascular and sexual function during aging. Very few studies of neural control of the cardiovascular system have employed middle-aged rats that are most at risk for the hypertension and stroke, and none have carefully considered the potential collaborative contribution between the sympathetic nervous system and the cardiovascular system in the generation of stroke. This is especially important, because even a short term excess of vasoconstriction could greatly increase the mortality or morbidity associated with stroke. The proposed studies will test the hypothesis that the loss of normal and hypertensive female rats, thus allowing sympathetic nervous system response to increase. Further, the role of estrogen also increases the contractile responses of cerebral arteries to noradrenergic (sympathetic) stimulation. We hypothesize that these responses are potentiated in the stroke-prone rat.
Our specific aims are to test the hypotheses that, in middle-aged female rats: [1] estrogen deprivation will result in decreased norepinephrine release in pre-optic- anterior hypothalamic area. This will be associated with increased blood pressure in normotensive and hypertensive female rats; [2] the interaction between estrogen and the nervous system occurs in specific areas relevant to blood pressure control, namely the organum vaculosum of the lamina terminalis, the subfornical organ, and the median pre-optic nucleus. Neuronal projections from these areas utilize angiotensin II and are responsive to estradiol; and [3] hypothalamic neurons, and in AT-1 gene expression in noradrenergic projections to the preoptic-anterior hypothalamic area. The anti-hypertensive effects of AT-1 receptor blockade will be attenuated in estrogen deprived middle-aged female rats. Taken together, these studies will provide important new information regarding the role of protective estrogens in neural regulation of blood pressure, and damage due to stroke, in stroke-prone hypertensive rats.
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