KININS--CARDIOPROTECTIVE EFFECTS

激肽——心脏保护作用

• 批准号: 6202209
• 负责人: Oscar A. Carretero
• 金额: $ 19.21万
• 依托单位: HENRY FORD HEALTH SYSTEM
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-15 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6202209
• 关键词: ACE inhibitors; angiotensins; antihypertensive agents; apoptosis; atrial natriuretic peptide; blood pressure; cell growth regulation; disease /disorder model; genetically modified animals; heart failure; heart function; hormone receptor; hormone regulation /control mechanism; kidney function; kidney pharmacology; kinins; laboratory mouse; laboratory rat; myocardial infarction; neprilysin; oxidative stress; prostaglandins; protease inhibitor; receptor expression; renin angiotensin system

Tilting the balance between vasopressors and vasodepressors may result in either a significant hypertensive or antihypertensive effect. The general hypothesis to be tested is that kinins acting as paracrine hormones are an important component of the vasodepressor side of this equilibrium, regulating blood pressure both by decreasing vascular resistance and by acting as renal natriuretic hormones. In specific aim I, we will test the hypothesis that kinins acting as paracrine hormones play a role in the long-term regulation of cardiovascular and renal function and that decreases in kinin activity facilitate the development of hypertension. We propose to study the effect of chronic blockade of kinins in experimental situations which lead to the development of hypertension and in models of low-renin hypertension, using a novel kinin receptor antagonist with more potency than those used previously. In specific aim II we will test the effect of chronic blockade of kinins on the cardiovascular and renal actions of kininase II or angiotensin I-converting enzyme (ACE) inhibitors in various models of hypertension and heart failure in the rat. We hypothesize that ACE inhibitors tilt the balance toward antihypertensive activity, not only because they block angiotensin II formation but also because they inhibit cleavage of paracrine kinins. In specific aim III, we will study the effect of chronic blockade of kinins on the cardiovascular, diuretic and natriuretic actions of an inhibitor of a different kininase, metalloendopeptidase-24.11 (MEP-24.11). These studies will be performed using models of low-renin hypertension and heart failure. We hypothesize that the effects of MEP-24.11 inhibitors are mediated by both ANF and kinins. Kinins appear to play an important role in the acute and pronounced hypotensive effect of an inhibitor of another kininase, metalloendopeptidase 24-15 (MEP-24.15). In specific aim IV we propose to determine whether MEP-24.15 inhibitors have a chronic antihypertensive effect on various models of hypertension, and whether this effect is mediated by kinins and/or ANF. The studies proposed are of importance since they will improve our understanding of the role of kinins in the long-term regulation of cardiovascular and renal function and the mechanism(s) mediating the chronic effects of ACE, MEP-24.11 and MEP-24.15 inhibitors.

倾斜血管升压剂和血管降压剂之间的平衡可能会导致 有显著的降压或降压作用。这位将军 有待检验的假设是，激动素作为旁分泌激素是一种 这一平衡中血管抑制因子的重要组成部分， 通过降低血管阻力和调节血压来调节血压 作为肾性利钠激素。在具体的目标一中，我们将测试 激动素作为旁分泌激素在 心血管和肾功能的长期调节以及 激动素活性的降低有助于高血压的发展。我们 建议在实验中研究慢性阻断激肽的作用 导致高血压发展的情况和在高血压模型中 使用一种新的激动素受体拮抗剂治疗低肾素高血压 比以前使用的更具效力。在《特定目标2》中，我们将测试 慢性阻断激动素对心血管和肾脏的影响 激氨酸酶II或血管紧张素转换酶(ACE)抑制剂的作用 在大鼠高血压和心力衰竭的各种模型中。我们 假设血管紧张素转换酶抑制剂使天平向抗高血压倾斜 活性，不仅是因为它们阻止血管紧张素II的形成，而且还 因为它们能抑制旁分泌激肽的分解。在具体目标三中，我们 将研究长期阻断激动素对心血管的影响， 另一种激氨酸酶抑制剂的利尿和利钠作用， 金属内肽酶-24.11(MEP-24.11)。这些研究将被执行 使用低肾素高血压和心力衰竭模型。我们假设 MEP-24.11抑制剂的作用是由心钠素和 金宁。激肽似乎在急性和非传染性疾病中起着重要作用。 另一种激氨酸酶的抑制剂具有显著的降压作用， 金属内肽酶24-15(MEP-24.15)。在具体目标四中，我们建议 确定MEP-24.15抑制剂是否具有慢性降压作用 对各种高血压模型的影响，以及这种影响是否 由激动素和/或心钠素介导。建议的研究具有重要意义。 因为它们将提高我们对激肽在 心血管和肾功能的长期调节以及 ACE、MEP-24.11和MEP-24.15慢性作用的机制(S) 抑制剂。