EFFECT OF AGING ON CALCIUM BLOCKER KINETICS/DYNAMICS

衰老对钙阻滞剂动力学/动力学的影响

• 批准号: 3116667
• 负责人: JANICE B SCHWARTZ
• 金额: $ 28.11万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1986
• 资助国家: 美国
• 起止时间: 1986-08-01 至 1994-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3116667
• 关键词: acetylcholine; adenosine; aging; arrhythmia; atrioventricular node; autonomic nervous system; autoradiography; beta antiadrenergic agent; cadmium; calcium channel; calcium channel blockers; cardiovascular disorder chemotherapy; cardiovascular pharmacology; centenarian human (100+); coronary artery; coronary disorder; drug adverse effect; drug metabolism; heart pharmacology; heart rate; human old age (65+); human subject; hypertension; laboratory rat; magnesium; nickel; nifedipine; parasympathetic nervous system; vasodilation; verapamil

Calcium antagonist drugs are efficacious in the management of hypertension, coronary artery disease, and supraventricular arrhythmias. These diseases are among the most frequent in the elderly and calcium antagonists have potential advantages (vasodilation, bronchodilation, lack of CNS effects) over other available drugs for use in the geriatric patient. However, the elimination kinetics and pharmacodynamics of these drugs in the elderly were largely unknown at the time of their release. It was postulated that both 1) drug elimination and 2) dynamic responses to these drugs would be altered in the elderly. Both hypotheses have been confirmed. Racemic verapamil elimination is prolonged in healthy elderly while elimination of diltiazem as a single isomer does not differ markedly in elderly vs younger hypertensives. An aim of this proposal is to determine whether aging alters stereoselective elimination of verapamil by determining the pharmacokinetics of verapamil isomers in healthy young and elderly. Current pilot data suggest verapamil elimination is prolonged to an even greater extent in elderly patients with coronary artery disease vs. healthy elderly. A goal is to determine kinetics and dynamics of verapamil and nifedipine in elderly cardiac patients since this is the group who will be consuming the drug. In studying responses of sinus and atrioventricular (AV) nodes to verapamil, striking differences in heart rate variation and AV conduction were seen in elderly vs younger or middle-aged subjects in the absence of drugs. Data suggest increases in sympathetic and parasympathetic influences with aging. Changes in heart rate and AV conduction with senescence were also seen in beagles after pharmacologic autonomic blockade, and in isolated right atria and Langendorff-perfused hearts from Fischer 344 rats. These findings suggest both the intrinsic function of the sinus and AV nodes, and, autonomic influences on their function are altered with aging. Long-term objectives are to determine potential age-related differences in autonomic regulation of heart rate and AV conduction and function vs. potential age-related changes in activity of the sinus and AV nodal cells. In man, autonomic factors will be evaluated by analyzing heart rate variation and AV conduction before and after beta-adrenergic and parasympathetic blockade, and beta-adrenergic and dopaminergic stimulation. Potential age-related alterations in responses to substances known to directly influence sinus node and AV nodal cell activity (calcium, calcium channel agonists, acetylcholine, cadmium, nickel, Mg++, adenosine) will be studied in the absence of autonomic influences in Langendorff-perfused rat hearts. Potential age-related changes in beta-adrenergic and calcium receptors within the AV node will be studied with quantitative autoradiography of the rat AV node.

钙拮抗剂药物在管理中有效 高血压，冠状动脉疾病和室内心律不齐。 这些疾病是老年人和钙中最常见的疾病 拮抗剂具有潜在的优势（血管舒张，支气管扩张，缺乏 CNS效应）与其他可用药物相比用于老年的药物 病人。 但是，消除动力学和药效学 在释放时，老年人的毒品在很大程度上是未知的。 据推测，两者都消除药物和2）动态反应 这些药物将在老年人中改变。 这两个假设都是 确认的。 健康的老年人延长了消除狂热的维拉帕米 而消除diltiazem作为单个异构体并没有明显差异 在老年人与年轻高血压中。 该建议的目的是 确定衰老是否会改变立体选择性消除维拉帕米 确定健康的年轻人和 老年。 当前的试点数据表明，维拉帕米消除延长至 冠状动脉疾病的老年患者更大程度地 与健康的老年人。 一个目标是确定动力学和动力学 老年心脏患者的维拉帕米和硝苯地平，因为这是 将食用该药物的人群。 研究鼻窦的反应和 对维拉帕米的房室（AV）节点，心脏差异很大 在老年人与年轻人与年轻人或 在没有药物的情况下，中年受试者。 数据表明增加 衰老的交感神经和副交感神经影响。 内心变化 在小猎犬中也可以看到衰老的速率和AV传导 药理学自主性封锁，并在孤立的右心房和 来自Fischer 344只老鼠的Langendorff perfused的心。 这些发现表明 窦和AV节点的内在功能以及自主神经 随着衰老的影响，对其功能的影响会改变。 长期目标 确定自主法规的潜在与年龄相关的差异 心率和AV传导和功能与潜在年龄相关的功能 窦和AV淋巴结细胞活性的变化。 在人类中，自主 将通过分析心率变化和AV来评估因素 β-肾上腺素能和副交感神经封锁之前和之后的传导， 以及β-肾上腺素能和多巴胺能刺激。 潜在与年龄有关的潜在 对已知直接影响鼻窦的物质的反应改变 节点和AV节点细胞活性（钙，钙通道激动剂， 将研究乙酰胆碱，镉，镍，mg ++，腺苷） 在兰戈德夫（Langendorff）丰满的老鼠心脏中没有自主影响。 β-肾上腺素和钙受体的潜在与年龄有关的变化 在AV节点中，将使用定量自身自显影研究 大鼠AV节点。