NHLBI FACULTY DEVELOPMENT AWARD

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The objective of this project is to investigate the effect of weberine and its congeners on vascular smooth muscle contractility. Weberine is a cactus plant alkaloid that is structurally related to psychotomimetic agents which are ring substituted phenylalkylamines or indolealkylamines. It has been reported that psychotomimetic agents such as mescaline and lysergic acid diethylamide (LSD) cause severe hypertension. However, the mechanism of action of these agents on hypertension is not clear. Mescaline and LSD act through adrenergic and serotonergic receptors which are linked to Ca2+ influx and phosphotidylinositol. Activation of these receptors found on vascular smooth muscle causes vasoconstriction. Thus, we hypothesize that weberine and its congeners produce aortic smooth muscle contractility by interacting with adrenergic and serotonergic receptors. Furthermore, since adrenergic and serotonergic receptors are linked to Ca2+ influx and phosphoinositol mediated vasoconstriction, we intend to study the effect of weberine, the congeners of weberine and mescaline on rabbit aortic and rat brain tissues. These studies will enable us to determine: 1. the potency of these compounds on vascular smooth muscle contractility, 2. the potency and selectivity of these compounds on alpha1 and 5-HT2 receptors using receptor specific antagonists, 3. the effect(s) of these compounds on extracellular or intracellular calcium-induced contraction, 4. the affinity and selectivity of these compounds for alpha1 and 5-HT2 receptor subtypes using receptor specific radioligand binding assays, and 5. the effect(s) of these compounds on inositol triphosphate levels. We hope that the data obtained from this project will help to provide knowledge to better understand the mechanism of psychotomimetic induced hypertension and thereby aid in the development of potential antagonist(s) that could prevent or reverse the undesirable effects of these psychotomimetic agents.