PLATELET A2-ADRENORECEPTOR REGULATION IN HYPERTENSION

我们最近描述了激动剂诱导的α2-肾上腺素受体 正常人完整血小板的脱敏和亲和力降低 在儿茶酚胺的生理浓度下发生的。这些研究 提示循环儿茶酚胺持续调节血小板 α2-肾上腺素受体激动剂的亲和力和敏感性。相比之下，我们的 初步研究表明，高血压病患者很少或根本没有 血小板α2-肾上腺素受体激动剂亲和力的变化 生理刺激和激动剂诱导的脱敏延迟 体外培养。这项授权的目的是进一步定义Alpha中的缺陷 2--高血压中的肾上腺素受体调节。此外，由于Essential 高血压与细胞内钠的异常分布有关 α2-肾上腺素受体激动剂的亲和力受到 钠浓度，我们计划测试受体是否存在缺陷 调节与钠稳态异常有关。 高血压和血压正常的受试者在此之前和 在改变血小板α2-肾上腺素受体的生理刺激后 正常人的激动剂亲和力。聚合响应，Alpha 肾上腺素受体结合特性，与血浆儿茶酚胺 下定决心。钠离子浓度对受体结合的影响 完整和破碎的细胞制剂和激动剂诱导的脱敏 将在体外进行测定。此外，控制钠的摄入量 将在体内评估钠对血小板α2肾上腺素受体的影响 对血小板内钠和钙的敏感性和亲和力调节 浓度，以及可能相互作用的血浆因子的存在 有了这些措施。 这些调查将阐明阿尔法基因的缺陷 2-肾上腺素受体在高血压中的调节是由于鸟嘌呤异常所致 核苷酸调节蛋白功能，钠稳态改变，和/或 A血浆因子(S)。体外钠浓度研究将 区分钠“位置”，一种膜介导钠 浓缩效应，或血浆因子(S)作为血小板的机制 正常血压和高血压患者的α2-肾上腺素受体调节。 这些研究将进一步深入了解人类免疫缺陷病毒的分子机制。 高血压时受体亲和力和调节的改变。

We have recently described agonist induced Alpha 2-adrenoreceptor desensitization and affinity reduction in intact normal human platelets occurring at physiological concentrations of catecholamines. These studies indicate that circulating catecholamines continuously modulate platelet Alpha 2-adrenoreceptor agonist affinity and sensitivity. In contrast, our preliminary studies indicate that essential hypertensives show little or no change in platelet Alpha 2-adrenoreceptor agonist affinity after physiological stimuli and a delay in agonist-induced desensitization in vitro. The purpose of this grant is to define further the defect in Alpha 2-adrenoreceptor regulation in hypertension. In addition, since essential hypertension is associated with abnormal cellular distribution of sodium and Alpha 2-adrenoreceptor agonist affinity is profoundly affected by sodium concentration, we plan to test whether the defect in receptor regulation is associated with abnormal sodium homeostasis. Hypertensive and normotensive subjects will have blood drawn before and after physiological stimuli which alter platelet Alpha 2-adrenoreceptor agonist affinity in normals. Aggregatory responsiveness, Alpha 2-adrenoreceptor binding characteristics, and plasma catecholamines will be determined. The effect of sodium concentration on receptor binding with intact and broken cell preparations and on agonist-induced desensitization will be determined in vitro. In addition, manipulation of sodium intake will assess in vivo effects of sodium on platelet Alpha 2-adrenoreceptor sensitivity and affinity regulation, on intraplatelet sodium and calcium concentration, and on the presence of a plasma factor which may interact with these measures. These investigations will elucidate whether the defect in Alpha 2-adrenoreceptor regulation in hypertension is due to abnormal guanine nucleotide regulatory protein function, altered sodium homeostasis, and/or a plasma factor(s). The in vitro sodium concentration studies will distinguish between a sodium "site," a membrane-mediated sodium concentration effect, or a plasma factor(s) as a mechanism for platelet Alpha 2-adrenoreceptor regulation in normotensives and hypertensives. These studies will yield further insight into the molecular mechanisms of altered receptor affinity and regulation in hypertension.