REGULATION OF CARDIAC SECOND MESSENGERS BY ANGIOTENSIN

肾素-血管紧张素系统是液体和容量的主要调节器 哺乳动物物种的体内平衡。 在病理过程中， 高血压和充血性心力衰竭，抑制血管紧张素 转化酶导致血管紧张素II水平降低， 提供有益的临床效果。 在人类研究中， 血管紧张素II受体拮抗剂，saralasin，用于减少 显示心输出量减少，表明 血管紧张素II可以是心脏收缩功能的体内调节剂。 在心脏组织中，血管紧张素II参与调节 跨膜信号传导和心肌细胞生长。 心脏 血管紧张素II的作用可以通过产生的循环肽介导， 通过外周肾素-血管紧张素系统或局部活性系统， 心脏 肾素血管紧张素前体基因的鉴定 核心系统与可译产品的量化生产 （血管紧张素II）表明，机械和体液调节， 局部肾素血管紧张素系统可能对 血管紧张素II介导的心脏组织反应。 抑制 血管紧张素II介导的新生大鼠肥大反应 心肌细胞的蛋白激酶C抑制剂，星形孢菌素，表明 血管紧张素II刺激第二信使的增加可能是 与心脏生长过程密切相关。 我们建议确定 如果血管紧张素II刺激的细胞内游离Ca 2+、肌醇 磷酸和二酰基甘油-蛋白激酶C是由一种或 多个膜受体，并表征这些的时间过程 应答 假定的鸟嘌呤核苷酸结合蛋白， 血管紧张素II受体对效应器反应的测定将使用 用霍乱和百日咳毒素进行药物处理。 我们有 假设蛋白激酶C参与介导心脏 对血管紧张素II的肥大性生长反应。 康贝特人将以 特异性蛋白激酶C同工酶亚细胞分布及其意义 通过血管紧张素II调节细胞核和细胞骨架组分， 佛波醇酯 这些研究将提供一个更完整的理解 血管紧张素肽在调节心脏功能中的作用 在第二信使的水平上。

The renin-angiotensin system is a major regulator of fluid and volume homeostasis in mammalian species. In pathological processes such as hypertension and congestive heart failure, inhibition of angiotensin converting enzyme results in decreased levels of angiotensin II and provides beneficial clinical effects. Human studies, in which the angiotensin II receptor antagonist, saralasin, was used to decrease vascular resistance, showed reduction in cardiac output indicating that angiotensin II may be an in vivo modulator of cardiac contractile function. In cardiac tissue angiotensin II participates in the regulation of transmembrane signalling and cardiac muscle cell growth. The cardiac effects of angiotensin II could be mediated by circulating peptide produced by the peripheral renin-angiotensin system or a locally active system in the heart. Identification of the precursor genes for the renin angiotensin system in the heart and quantifiable production of translatable product (angiotensin II) suggests that mechanical and humoral regulation of a localized renin angiotensin system could have significant implications for angiotensin II-mediated responses in cardiac tissue. Inhibition of the angiotensin II-mediated hypertrophic response in neonatal rat cardiomyocytes by the protein kinase C inhibitor, staurosporin, suggests that angiotensin II stimulated increases in second messengers may be integrally involved in cardiac growth processes. We propose to determine if the angiotensin II-stimulated increases in cytosolic free Ca2+, inositol phosphates, and diacylglycerol-protein kinase C are mediated by one or multiple membrane receptors, and to characterize the time course for these responses. The putative guanine nucleotide binding proteins that couple angiotensin II receptors to effector responses will be determined using pharmacologic manipulation with cholera and pertussis toxins. We have hypothesized that protein kinase C is involved in mediating the cardiac hypertrophic growth response to angiotensin II. We will determine the subcellular distribution of specific protein kinase C isozymes and their regulation in nuclear and cytoskeletal fractions by angiotensin II and phorbol esters. These studies will provide a more complete understanding of the role of angiotensin peptides in the modulation of cardiac function at the level of second messengers.