Hypertension is a widespread human health problem. It is a complex disease involving interactions between the cardiovascular, nervous, renal and endocrine systems. Most studies of the etiology of hypertension have focused on altered regulation of the arterial vasculature. While arterial resistance is elevated in hypertension, there is also a decrease in venous compliance. There have been few studies of the mechanisms controlling venous smooth muscle contractile activity in hypertension. The overall goal of this proposal is to identify mechanisms causing increased venomotor tone in hypertension. The project is an on-going collaborative effort between two established investigators. A complementary in vitro and in vivo approach will be used in which data obtained with each protocol can guide subsequent studies either at the in vitro or in vivo level. The underlying hypothesis is that increased venomotor tone in the deoxycorticosterone acetate (DOCA)-salt rat model of hypertension is caused partly by increased sensitivity of veins to endothelin-1 (ET-1) and to sympathetic neural input. The mesenteric circulation is a large vascular bed with a significant capacitive function. Therefore, this proposal will focus on studies of mesenteric veins. It is established that ET-1 contracts mesenteric veins via an action at ETA and ETB endothelin receptors. The first specific aim will attempt to identify the electrophysiological correlates of ET-1 induced venoconstriction and to identify the contributions that ETA and ETB receptor activation make to these responses in veins from normotensive and DOCA-salt hypertensive rats.
Specific aim 2 will focus on receptors and electrophysiological mechanisms mediating sympathetic nerve stimulation-induced contractions of mesenteric veins. In addition, this specific aim will also address the mechanisms by which ET-1 facilitates sympathetic neurotransmission to veins. Data from in vitro studies have been used to design related in vivo experiments. The in vivo studies will assess venous tone using repeated within-animal measurements of mean circulatory filling pressure (MCFP), a method recently developed in the PI's lab.
In specific aim 3 the ET receptors mediating increased MCFP in DOCA-salt hypertensive rats will be identified.
Specific aim 4 will determine if endogenous ET-1 induced increases in MCFP in DOCA-salt hypertensive rats indirectly by enhancing sympathetic venoconstriction. The studies in specific aim 5 will determine if ET-1 induced changes in MCFP contribute to the development of DOCA-salt hypertension. This combined in vitro and in vivo research strategy for understanding venous abnormalities in hypertension is innovative and likely to provide new therapeutic approaches to treating venous dysfunction in cardiovascular disease.
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