KININS--CARDIOPROTECTIVE EFFECTS

改变血管加压药和血管抑制药之间的平衡可能导致 显著的高血压或抗高血压作用。 总 有待检验的假设是，作为旁分泌激素的激肽是一种 这种平衡的血管抑制剂的重要组成部分， 通过降低血管阻力和 作为肾利钠激素。 在具体目标I中，我们将测试 假设激肽作为旁分泌激素发挥作用， 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 建议在实验中研究激肽的慢性阻断作用， 导致高血压发展的情况，以及 低肾素高血压，使用一种新的激肽受体拮抗剂， 比以前使用的更有效。 在具体目标II中，我们将测试 慢性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倾斜 活性，不仅因为它们阻断血管紧张素II的形成， 因为它们抑制旁分泌激肽的分裂。 在具体目标三中，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钠作用， 金属内肽酶-24.11（MEP-24.11）。 这些研究将在 使用低肾素高血压和心力衰竭的模型。 我们假设 MEP-24.11抑制剂的作用是由ANF和 激肽 激肽似乎在急性和慢性炎症中起重要作用， 另一种激肽酶抑制剂的显著抑制作用， 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 由激肽和/或ANF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 长期调节心血管和肾功能， 介导ACE、MEP-24.11和MEP-24.15慢性效应的机制 抑制剂的

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.