CALCIUM, AGING, AND HYPERTENSION

我们的数据提示了钙拮抗剂在体内的一个重要机制 外周血管药效学效应是通过间接阻断 血管紧张素II(AII)和内皮素-1(E-1)的血管收缩作用。 此外，它还支持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 这些观察结果有助于更好地了解老年高血压的影响 关于这方面钙拮抗剂的药效学和将进行的探索 AII和E-1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 血管收缩对AII和E-1的反应，这种效应是 在老年高血压中保持和/或加重。具体目标#一： 测定和比较AII和E-1介导的逆转作用 钙拮抗剂对青年和老年高血压患者的血管收缩作用 病人。具体目标2：确定这是一种持续的效果 在慢性钙拮抗剂降压治疗期间。 假设2：E-1的血管收缩反应部分 依赖于完整的局部和全身肾素的活性 血管紧张素系统(RAS)部分依赖于完整肾素 血管紧张素系统。钙拮抗剂可阻断这两种成分。 而血管紧张素转换酶抑制剂仅阻断RAS 从属组件。具体目标#3：测定E1值 在前臂局部封锁所有队形的情况下做出反应。 将这与钙存在时的E-1收缩反应进行比较 对抗者。目标4：建立AII和/或 血管紧张素转换酶抑制与E-1介导 血管收缩是相关的。假设3：E-1收缩反应 是直接刺激血管平滑肌和 通过血管内皮细胞的间接作用。受损的内皮细胞 老年高血压的功能增强体内E-1收缩反应， 钙拮抗剂在阻断收缩方面仍然有效。 反应与年龄无关。具体目标5：体内内皮细胞 年轻高血压患者和老年高血压患者的功能比较 病人。在个别患者中，确定的内皮功能将 被评估为个体间e1的变异源 收缩反应。特定目标#6：钙拮抗剂逆转E-1 相同个体的收缩反应将用 预期体内损伤最大的个体 内皮功能将具有最大的E-1收缩反应和 钙对这一反应的最大比例逆转 对抗者。这些研究将扩大对这种机制的理解。 钙拮抗剂药物在衰老过程中的体内血管舒缩作用 高血压患者。此外，它们还将定义 钙通道阻滞剂对最有效的血管收缩激素的作用 已知的AII和E-1，在老年高血压中。

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.