CALCIUM ANTAGONISTS, AGING, AND HYPERTENSION

钙拮抗剂药物与许多 可能对老年人有害的药效学效应。这些 包括体内活动(负性肌力作用、血管通畅 肌肉松弛，选择性心脏传导障碍， 压力感受性反射活动)，与受损者显著互动 衰老的动态平衡(压力感受器反射活动受损，降低 外周血管的扩张性，对 肾上腺素能刺激)。初步研究表明维拉帕米和 地尔硫卓对老年高血压患者的治疗结果 然而，在没有反射性心动过速的情况下，降压效果增强 降低房室结传导功能障碍。我们假设这些年龄- 药效学的相关变化(1)与这两种变化有关 血管反应性和自主神经稳态反射机制改变； (2)仅部分由药代动力学机制解释，该机制可能是 立体特异性；(3)这3个化学上无关的不同 化合物与其不同程度的官能度和 特殊的肾上腺素能拮抗作用。 具体目标：1.体内外周血管机制的测定 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关系以及他们对 改变后的药效学结果。3.将药效学与 急性与慢性钙拮抗剂暴露的药代动力学 建立青年和老年患者变更的贡献 药代动力学对药效学结果的影响。4.探索 负性肌力作用增强和压力感受性反射功能受损 老年人对钙拮抗剂的较大降压反应 高血压和血压正常的个体。 方法：将正常血压和高血压患者分为3组，青年组和老年组。 20-45岁)、中年(46-岁)和老年人(65岁) 学习。研究的药物将是(+)-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被用来测试 假设。体内外周血管机制，压力反射功能， 心输出量和药效学-药动学关系将是 旨在探讨增龄相关钙拮抗剂作用的变化。 这些研究将建立体内钙变化的机制。 拮抗剂的药效学和体内将探讨与年龄相关的变化 对这些重要药物的直接药物效应和稳态反应 心血管药物。此外，还应理解 每种药物与衰老有关的药效学独特性 并将发展为高血压。

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.