KININS--CARDIOPROTECTIVE EFFECTS

激肽——心脏保护作用

• 批准号: 6349169
• 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: 2000
• 资助国家: 美国
• 起止时间: 2000-09-01 至 2001-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6349169
• 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.

血管升压药和血管降压药之间的平衡倾斜可能会导致 具有显着的高血压或抗高血压作用。 将军 要检验的假设是，作为旁分泌激素的激肽是一种 这种平衡的血管抑制一侧的重要组成部分， 通过降低血管阻力和调节血压 作为肾钠尿激素。 在具体目标 I 中，我们将测试 假设激肽作为旁分泌激素在 长期调节心血管和肾功能 激肽活性的降低促进高血压的发展。 我们 提议在实验中研究长期阻断激肽的效果 导致高血压发展的情况和模型 低肾素高血压，使用新型激肽受体拮抗剂 比以前使用的效力。 在特定目标 II 中，我们将测试 长期阻断激肽对心血管和肾脏的影响 激肽酶 II 或血管紧张素 I 转换酶 (ACE) 抑制剂的作用 在大鼠的各种高血压和心力衰竭模型中。 我们 假设 ACE 抑制剂使平衡向抗高血压方向倾斜 活性，不仅因为它们阻止血管紧张素 II 的形成，还因为它们 因为它们抑制旁分泌激肽的裂解。 在具体目标 III 中，我们 将研究长期阻断激肽对心血管的影响， 不同激肽酶抑制剂的利尿和利尿钠作用， 金属内肽酶-24.11 (MEP-24.11)。 这些研究将进行 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 ANF 和 激肽。 激肽似乎在急性和 另一种激酶抑制剂具有明显的降血压作用， 金属内肽酶 24-15 (MEP-24.15)。 在具体目标 IV 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，以及这种影响是否是 由激肽和/或 ANF 介导。 提出的研究很重要 因为它们将增进我们对激肽在 对心血管和肾功能的长期调节 介导 ACE、MEP-24.11 和 MEP-24.15 慢性影响的机制 抑制剂。