Increased vasoconstriction and impaired vasodilation are complications during the pathogenesis of hypertension. The long term objectives of this proposal are to determine the mechanisms by which hypertension and/or hypercholesterolemia lead to abnormal arterial reactivity. The specific goals will be to determine: 1) How the hypertensive endothelium, by expressing reduced amounts of vasodilators or increased amounts of vasoconstrictors, influences the adrenergic neuroeffector junction and leads to augmented neurogenic arterial contractions; 2) If abnormal expression or function of G proteins leads to abnormal responsiveness to vasodilators or vasoconstrictors in hypertensive arterial smooth muscle and endothelium; and 3) If abnormal growth factor expression alters responsiveness of hypertensive blood vessels. Studies will be conducted on isolated blood vessels from DOC-salt hypertensive rat and one-kidney, one- clip hypertensive rabbit models utilized in Project VI. To determine if arterial reactivity is impaired synergistically by hypercholesterolemia and hypertension, arteries from normotensive and hypertensive Watanabe Heritable Hyperlipidemic (WHHL) rabbits will be studied. Reactivity will be studied by measuring isometric tension in arterial rings and vasoconstriction in perfused segments. Content and release or endogenous norepinephrine, bioassay and radioimmunoassay of vasoactive endothelium- derived vasoactive factors and prostanoids, and assay of smooth muscle cyclic nucleotides, will be indicators of abnormal vasoconstrictors and vasodilators in hypertensive arteries. Expression of G protein mRNA will be determined and G proteins will be measured by immunological and ADP ribosylation procedures. Abnormal expression (Project VI), specific antibodies, and authentic peptides will be used to determine the role of growth factors in the abnormal arterial reactivity in hypertension. Attaining new understanding of the mechanisms involved in the pathogenesis of abnormal arterial reactivity in hypertension and atherosclerosis, which may be accelerated by hypertension, will lead to new treatments.
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