Nitric oxide synthase (NOS) inhibition causes a sustained increase in systemic blood pressure. In this experimental model of hypertension, the rise in blood pressure is mediated by elevated peripheral vascular resistance that requires an intact sympathetic nervous system. However, the mechanism of the elevated resistance has not been clearly defined. Our preliminary evidence suggest that a portion of this resistance is caused by increased a2-adrenoceptor (AR) vasoconstriction and the current proposal will evaluate the role of a2-AR contraction in NOS-inhibition-induced hypertension. The hypothesis proposed is that NOS-inhibition upregulates a2-AR mediated contraction in vascular smooth muscle cells (VSMC). The three specific aims of this proposal are to determine: 1) What is the contribution of vascular VSMC a2-AR to the hypertension and arterial contraction that develop following NOS inhibition?; 2) What is the mechanism of altered vascular smooth muscle a2-AR signaling following in vivo NOS inhibition?; and 3) does NO directly regulate vascular a2-ARs in arterial smooth muscle? Specific Aim 1 will use contractile studies and blood pressure measurements to determine how large of a contribution this upregulation makes.
Specific Aim 2 will measure expression levels to determine if the vascular a2-AR contribution observed under Specific Aim 1 is dependent on elevated receptor expression or on alterations in receptor coupling/signaling. The studies under Specific Aim 3 will determine if NO directly regulates vascular a2-AR or if the changes are an indirect effect of the hypertension that develops during in vivo NOS inhibition. Together, these studies will determine if the mechanism for the elevated resistance in NOS-inhibition-induced hypertension is upregulation of a2-AR signaling in VSMC and if NO regulates this receptor system. The information obtained will increase our understanding of NO regulation of blood pressure and vascular reactivity and will provide important information leading to more effective pharmacological applications of a2-AR ligands. In addition, the new techniques of RT-PCR, flow cytometry measurements, quantitative Western analysis and ligand binding assays will increase the ability of the PI to conduct future studies examining vascular function at the cellular/molecular level.
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