NHLBI FACULTY DEVELOPMENT AWARD

本项目的目的是研究小檗碱和 其同系物对血管平滑肌收缩性的影响。 Weberine是一种 一种结构上与拟精神病药有关的仙人掌植物生物碱 试剂是环取代的苯基烷基胺或吲哚烷基胺。 据报道，拟精神病药物如美斯卡林和 麦角酰二乙胺（LSD）可引起严重高血压。 但 这些药物对高血压的作用机制尚不清楚。 Mescaline和LSD通过肾上腺素能和肾上腺素能受体起作用， 与Ca 2+内流和磷脂酰肌醇有关。 激活这些 在血管平滑肌上发现的受体引起血管收缩。 因此，在本发明中， 我们假设小檗碱及其同类物产生主动脉平滑肌， 通过与肾上腺素能受体和肾上腺素能受体相互作用而产生收缩性。 此外，由于肾上腺素能和肾上腺素能受体与Ca 2+相关， 内流和磷酸肌醇介导的血管收缩，我们打算研究 小檗碱及其同系物和美斯卡灵对家兔的作用 主动脉和大鼠脑组织。 这些研究将使我们能够确定： 1.这些化合物对血管平滑肌收缩性的效力， 2.这些化合物对α 1和5-HT 2的效力和选择性 使用受体特异性拮抗剂的受体，3.这些影响 化合物对细胞外或细胞内钙诱导的收缩的影响，4. 这些化合物对α 1和5-HT 2亲和力和选择性 使用受体特异性放射性配体结合测定的受体亚型，和 5.这些化合物对三磷酸肌醇水平的影响。 我们 我希望从这个项目中获得的数据将有助于提供 知识，以更好地了解拟精神病药诱导的机制 高血压，从而有助于开发潜在的拮抗剂 这可以防止或扭转这些不良影响， 拟精神病药物

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.