CALCIUM, AGING, AND HYPERTENSION

钙、衰老和高血压

• 批准号: 6029750
• 负责人: JANE E Freedman
• 金额: $ 19.78万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1989
• 资助国家: 美国
• 起止时间: 1989-06-01 至 2001-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6029750
• 关键词: ACE inhibitors; acetylcholine; age difference; aging; angiotensin II; antihypertensive agents; calcium channel blockers; cardiovascular pharmacology; clinical research; diltiazem; enalapril; endothelin; human old age (65+); human subject; hypertension; nitric oxide; renin angiotensin system; vascular endothelium; vascular smooth muscle; vasoconstriction; young adult human (21-34)

Our data suggests an important in vivo mechanism of calcium antagonist peripheral vascular pharmacodynamic effect is via indirect blockade of angiotensin II (AII) and endothelin-1 (E-1) vasoconstrictor effect. Furthermore it supports a close interrelationship between AII and E-1 mediated vasoconstriction. The present proposal will confirm and extend these observations to better understand the effects of aging hypertension on this aspect of calcium antagonist pharmacodynamics and will explore in vivo mechanisms for the observed interrelationship between AII and E-1 mediated vasoconstriction. Hypothesis#1: Calcium antagonists block vascular contractile responses to AII and E-1 and this effect is maintained and/or accentuated in aging hypertension. Specific Aim#I: Determine and compare the reversal of AII and E-1 mediated vasoconstriction by calcium antagonists in younger and older hypertensive patients. Specific Aim#2: Establish that this is a sustained effect during chronic calcium antagonist antihypertensive treatment. Hypothesis#2: Vascular contractile responses of E-1 are partially dependent on the activity of an intact local and systemic renin angiotensin system (RAS) and partially independent of an intact renin angiotensin system. Calcium antagonists block both of these components while angiotensin converting enzyme inhibition blocks only the RAS dependent component. Specific Aim#3: Determine the E1 contractile response in the presence of local forearm blockade of AII formation. Compare this to the E-1 contractile response in the presence of calcium antagonists. Aim#4: Establish the in vivo mechanisms by which AII and/or angiotensin converting enzyme inhibition and E-1 mediated vasoconstriction are related. Hypothesis#3: E-1 contractile responses are the summation of direct stimulation of vascular smooth muscle and indirect effects via the vascular endothelium. Impaired endothelial function in aging hypertension enhances in vivo E-1 contractile response, and calcium antagonists remain effective in blocking the contractile response irrespective of age. Specific Aim#5: In vivo endothelial function will be compared between younger and older hypertensive patients. In individual patients the determined endothelial function will be evaluated as a source of variance for the interindividual E1 contractile response. Specific Aim#6: Calcium antagonist reversal of E-1 contractile response in the same individuals will be determined with the expectation that individuals with the greatest impairment in in vivo endothelial function will have the greatest E-1 contractile response and the greatest proportional reversal of this response by calcium antagonists. These studies will extend understanding of the mechanisms of in vivo vasorelaxant effects of calcium antagonist drugs in aging hypertensive patients. Furthermore they will define the effects of calcium channel blockade on the most potent vasoconstrictor hormones known, AII and E-1, in aging hypertension.

我们的数据表明钙拮抗剂的重要体内机制 外周血管药效作用是通过间接阻断 血管紧张素II (AII) 和内皮素-1 (E-1) 血管收缩作用。 此外，它支持 AII 和 E-1 之间的密切相互关系 介导的血管收缩。本提案将确认并延长 这些观察结果可以更好地了解老年高血压的影响 关于钙拮抗剂药效学这方面的研究并将探索 观察到的 AII 和 E-1 之间相互关系的体内机制 介导的血管收缩。假设#1：钙拮抗剂阻断 对 AII 和 E-1 的血管收缩反应，这种效应是 老年高血压持续和/或加重。具体目标#I： 确定并比较 AII 和 E-1 介导的逆转 钙拮抗剂对年轻和老年高血压患者的血管收缩作用 患者。具体目标#2：确定这是一个持续的效果 长期钙拮抗剂抗高血压治疗期间。 假设#2：E-1 的血管收缩反应部分是 取决于完整的局部和全身肾素的活性 血管紧张素系统（RAS）并且部分独立于完整的肾素 血管紧张素系统。钙拮抗剂阻断这两种成分 而血管紧张素转换酶抑制仅阻断 RAS 依赖组件。具体目标#3：确定 E1 收缩 局部前臂阻断 AII 形成时的反应。 将此与钙存在下的 E-1 收缩反应进行比较 对手。目标#4：建立 AII 和/或 血管紧张素转换酶抑制和 E-1 介导 血管收缩有关系。 假设#3：E-1 收缩反应 是血管平滑肌直接刺激的总和 通过血管内皮的间接作用。内皮细胞受损 老年高血压中的功能增强体内 E-1 收缩反应， 钙拮抗剂仍然能有效阻断收缩 反应不分年龄。具体目标#5：体内内皮细胞 将比较年轻和老年高血压患者的功能 患者。在个别患者中，确定的内皮功能将 被评估为个体间 E1 的方差来源 收缩反应。具体目标#6：钙拮抗剂逆转 E-1 同一个人的收缩反应将由 期望体内损伤最大的个体 内皮功能将具有最大的 E-1 收缩反应 钙对此反应的最大比例逆转 对手。这些研究将加深对机制的理解 钙拮抗剂药物在衰老过程中的体内血管舒张作用的研究 高血压患者。此外，他们将定义以下效果： 对最有效的血管收缩激素的钙通道阻断 已知，AII 和 E-1 治疗老年高血压。