(Verbatim from the application): Recent data from our laboratory indicated that venous tone is increased in the developmental stages of spontaneous hypertension in the rat. Since the increase in blood pressure in the initial stages of hypertension is characterized by an elevation of cardiac output, veins appear to play an important role in the initiation of the hypertensive process. The development of hypertension is sexually dimorphic. Considerable evidence suggests that estrogen attenuates the development of hypertension. Estrogen has been shown to affect vascular smooth muscle via both endothelial dependent and independent mechanisms and to modulate peripheral and central nervous system function. Veins possess functional estrogen receptors, high estrogen states are associated with changes in venous tone and estrogen modulates neural activity in brain regions involved in the control of venous tone. Thus, estrogen may modulate venoconstrictor tone during the developmental stages of hypertension via effects on venous smooth muscle and/or via effects on sympathetic outflow to veins. Accordingly, the proposed research is aimed at testing the general hypothesis that estrogen reduces venoconstrictor tone during the developmental stages of spontaneous hypertension.
The specific aims of the research will be to determine if I) Estrogen reduces sympathetic venoconstrictor tone in young female SHR. II) Estrogen reduces venous tone via effects on venous smooth muscle responsiveness via an effect on the nitric oxide system, calcium channels or potassium channels. III) Estrogen alters the expression of key proteins involved in the control of venous tone. Experiments will be performed in spontaneously hypertensive (SHR) rats at 6-10 weeks of age, a time point when previous studies have shown elevated venous tone in SHR rats. MAP, HR, and mean circulatory filling pressure, an index of integrated venomotor tone will be measured in conscious rats to determine the effects of estrogen on overall venous tone. Isolated portal and mesenteric veins will be used to assess the effects of estrogen on venous smooth muscle responsiveness and the mechanisms underlying these effects. Western blot techniques will be used to determine if estrogen affects venous tone by altering expression of key protein involved in venous control systems. These studies are expected to show that estrogen attenuates the development of hypertension by reducing venomotor tone and thereby, reduces a major factor contributing to the increase in cardiac output and blood pressure that initiates the hypertensive process.
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