ET-1 System Activity, Cardiovascular Disease Risk Factors and Pharmacologic Intervention

Diehl, Kyle James

Graduate Thesis Or Dissertation

ET-1 System Activity, Cardiovascular Disease Risk Factors and Pharmacologic Intervention Public Deposited

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Citeable URL: https://scholar.colorado.edu/concern/graduate_thesis_or_dissertations/dv13zt32q

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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