Date of Award

Spring 1-1-2011

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 R. Mazzeo

Abstract

Prehypertension, defined as systolic blood pressure between 120-139 mm Hg and/or diastolic blood pressure between 80-89 mm Hg, is a common condition that affects ~30% of the US adult population. It is increasingly recognized that prehypertension is not only an independent risk factor for the development of clinical hypertension (blood pressure ≥ 140/90 mm Hg), but also cardiovascular disease and its clinical consequences, such as myocardial infarction, stroke, and congestive heart failure. The increased cardiovascular risk associated with prehypertension may be mediated, at least in part, by vascular endothelial dysfunction, a critical etiological event in the pathogenesis and progression of atherosclerotic vascular disease. However, the impact of blood pressure in the prehypertensive range on the vascular endothelium is currently unclear. Accordingly, the purpose of this dissertation was to determine: 1) if prehypertension is associated with impaired nitric oxide (NO)-mediated endothelium-dependent vasodilation; 2) whether endothelin (ET)-1 vasoconstrictor tone is elevated in prehypertensive adults; and, if so, 3) whether the increase in ET-1-mediated vasoconstriction contributes to endothelial vasodilator dysfunction in prehypertensive adults. To address these aims, venous occlusion plethysmography was used to measure forearm blood flow responses to intra-arterial acetylcholine, sodium nitroprusside, and selective and non-selective ET-1 receptor blockade in normotensive and prehypertensive adults. In addition, forearm blood flow responses to acetylcholine were determined with concomitant endothelial NO synthase inhibition and selective ET-1 receptor blockade. The results of these studies indicate that: 1) prehypertension is associated with impaired NO-mediated endothelium-dependent vasodilation; 2) ET-1 vasoconstrictor tone is greater in prehypertensive compared with normotensive adults; and 3) the elevation in ET-1-mediated vasoconstriction contributes to impaired endothelium-dependent vasodilation with prehypertension. Collectively, these findings demonstrate that blood pressure in the prehypertensive range, independent of other cardiovascular risk factors, is associated with impaired endothelial vasomotor function. Reduced NO-mediated endothelium-dependent vasodilation and elevated ET-1-mediated vasoconstrictor tone represent an atherogenic endothelial phenotype that may contribute to the elevated risk of clinical hypertension and acute vascular events in prehypertensive adults.

Share

COinS