Date of Award

Spring 1-1-2015

Document Type

Dissertation

Degree Name

Doctor of Philosophy (PhD)

Department

Integrative Physiology

First Advisor

Christopher A. DeSouza

Second Advisor

Robert S. Mazzeo

Third Advisor

Monika Fleshner

Fourth Advisor

Kenneth P. Wright Jr.

Fifth Advisor

Brian Stauffer

Abstract

Endothelin (ET)-1 is a potent vasoconstrictor peptide produced and released by the vascular endothelium. In combination with the endothelial vasodilator nitric oxide, ET-1 plays a central role in the regulation of vascular tone. In addition to its vasoregulatory actions, there is considerable evidence supporting the involvement of ET-1 in the pathogenesis of atherosclerotic vascular disease and its associated risk factors, most notably elevated blood pressure. Nebivolol, a third generation beta-blocker with high selectivity for beta-1-adrenergic receptors, has proven to be highly effective in treating hypertension. A distinguishing feature of nebivolol from other beta-blockers is its positive effects on hemodynamic profile, particularly nitric oxide bioavailability. The effects of nebivolol, however, on ET-1-mediated vasoconstrictor tone are unclear. Accordingly, the primary hypotheses associated with this dissertation are: 1) chronic nebivolol treatment will reduce ET-1-mediated vasoconstrictor tone in adult humans with elevated blood pressure; and 2) reduced ET-1 vasoconstrictor activity contributes to the improvement in endothelial vasodilator function associated with nebivolol. To address these hypotheses, we employed a 3-month randomized, double-blind placebo controlled study to determine the effects of nebivolol, metoprolol and placebo on ET-1 vasoconstrictor tone in adults with suboptimal blood pressure. Venous occlusion plethysmography was used to measure forearm blood flow (FBF) responses to intra-arterial acetylcholine, sodium nitroprusside, and selective and non-selective ET-1 receptor blockade. FBF responses to acetylcholine were also determined with the co-infusion of non-selective ET-1 receptor blockade. The results of this study indicate that although both nebivolol and metoprolol reduced blood pressure to a similar extent: 1) nebivolol, but not metoprolol, treatment reduced both ETA and ETB receptor mediated ET-1 vasoconstrictor tone in adult humans with elevated blood pressure; and 2) the reduction in ET-1-mediated vasoconstrictor tone contributes to the nebivolol-induced enhancement in endothelial vasodilator function. Collectively, these findings demonstrate direct effects of nebivolol, independent of reducing blood pressure, on ET-1 system activity. Diminished ET-1 system activity represents a favorable pleiotropic effect of chronic nebivolol treatment independent of blood pressure lowering.

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