CALCIUM ANTAGONISTS, AGING, AND HYPERTENSION

钙拮抗剂药物已与许多 可能对老年人有害的药效学作用。 这些 包括体内活性（负性肌力作用、血管平滑 肌肉松弛，选择性心脏传导障碍， 压力反射活动），其与受损的 老化的稳态（受损的压力反射活性，降低 外周血管系统的扩张性，对 肾上腺素能刺激）。 初步研究表明维拉帕米和 对老年高血压患者给予地尔硫卓导致 然而，降压作用增加，但没有反射性心动过速 房室结传导受损减少。 我们假设这些年龄- 药效学的相关变化（1）与两种改变有关 血管反应性和改变的自主稳态反射机制; (2)仅部分由药代动力学机制解释， 立体特异性;（3）在这3种化学上不相关的物质中不同 化合物与其不同程度的功能和 特异性肾上腺素能拮抗作用。 具体目标：1。体内外周血管机制的确定 对钙拮抗剂的反应。 2.这些机制的比较 青年和老年高血压患者之间的差异及其对 改变药效学结果。 3.药效学与 急性与慢性钙拮抗剂暴露的药代动力学 年轻和老年患者建立的贡献改变 药代动力学到药效学结果。 4.探索角色 负性肌力作用增加，压力反射功能受损， 老年人对钙拮抗剂的反应更大， 高血压和血压正常个体。 方法：正常血压和高血压患者分为3组，青年组（老年组 20-45岁）、中年（46-64岁）和老年人（>65岁） 研究了 研究药物为（+）-维拉帕米、d-顺式地尔硫卓和 硝苯地平。 急性和慢性药物暴露将用于测试 假设 体内外周血管机制，压力反射功能， 心输出量和药效学-药代动力学关系将 建立以探索钙拮抗剂作用的年龄相关变化。 这些研究将建立体内钙改变的机制， 拮抗剂药效学，并将在体内探索年龄相关的变化， 直接的药物作用和稳态反应，这些重要的 心血管药物 此外，了解 每种药物与衰老相关的药效学独特性 高血压也会发生

Calcium antagonist drugs have been associated with a number of pharmacodynamic effects that may be deleterious in the elderly. These include in vivo activities (negative inotropic effects, vascular smooth muscle relaxation, selective impairment of cardiac conduction, changes in baroreflex activity) which significantly interact with the impaired homeostasis of aging (impaired baroreflex activity, decreased distensibility in peripheral vasculature, decreased sensitivity to adrenergic stimuli). Preliminary studies indicate verapamil and diltiazem administration to elderly hypertensive patients results in increased hypotensive effect without reflex tachycardia, however decreased impairment in A-V nodal conduction. We hypothesize these age- related changes in pharmacodynamics are (1) associated with both altered vascular reactivity and altered autonomic homeostatic reflex mechanisms; (2) only in part explained by a pharmacokinetic mechanism which may be stereospecific; (3) different among these 3 chemically unrelated compounds in relation to their different degrees of functional and specific adrenergic antagonism. Specific Aims: 1. Determination of in vivo peripheral vascular mechanisms of response to calcium antagonists. 2. Comparison of these mechanisms between young and elderly hypertensive patients and their contribution to the altered pharmacodynamic outcome. 3. Relating pharmacodynamics to pharmacokinetics in acute versus chronic calcium antagonist exposure in young and elderly patients to establish the contribution of altered pharmacokinetics to pharmacodynamic outcome. 4. Explore role of increased negative inotropic effect and impaired baroreflex function in the greater hypotensive response to calcium antagonists in aged hypertensive and normotensive individuals. Methods: Normotensive and hypertensive patients in 3 groups, young (aged 20-45 years), middle-aged (46-64 years), and elderly (>65 years) will be studied. Drugs studied will be (+)-verapamil, d-cis diltiazem, and nifedipine. Acute and chronic drug exposure will be used to test the hypotheses. In vivo peripheral vascular mechanisms, baroreflex function, cardiac output, and pharmacodynamic-pharmacokinetic relationships will be established to probe age-related changes in calcium antagonist effect. These studies will establish in vivo mechanisms of altered calcium antagonist pharmacodynamics and will probe in vivo age-related changes in direct drug effect and homeostatic responses for these important cardiovascular drugs. Furthermore an understanding of the pharmacodynamic uniqueness of each of the drugs as it relates to aging and hypertension will be developed.