AUTONOMIC RECEPTOR FUNCTION IN LV HYPERTROPHY & FAILURE

这项资助的目标是研究贝塔病毒远端的机制- 肾上腺素能受体介导的β-肾上腺素能受体环化酶改变 心力衰竭与儿茶酚胺脱敏的偶联作用。这是有计划的 重点研究两种模型，即起搏诱导的心力衰竭和 儿茶酚胺脱敏伴或不伴心脏失神经。这些 模型之所以特别强大，有三个原因：1)它们允许 大动物模型中生化和分子机制的研究 这些生理特征可以被描述为意识状态，2)它们 允许研究疾病状态发展过程中的系列变化 从最初的变化到更长期的状态，其特征是 失代偿；3)疾病状态是可逆的。四个假设 将会受到考验。第一种假设是联结中的异常 β-肾上腺素能受体对腺苷酸环化酶的作用发生在 左心室(LV)失代偿的进展及这些 异常反映了受体与鸟嘌呤的解偶联 核苷酸刺激蛋白(Gs)，β1和β1比例的变化 β2受体，或腺苷环化酶催化单位的缺陷。 第二个假设是，在起搏诱导的心力衰竭模型中 在儿茶酚胺脱敏模型中，正性肌力 对儿茶酚胺的反应严重抑制，Gs活性 保持，但GI得到增强，并有助于受损的一代 腺酰环化酶对交感神经刺激的反应。第三 假设心脏神经损害，例如去神经，是 细胞表面β-肾上腺素能受体下调所需 心力衰竭或儿茶酚胺脱敏。第四个假设是 在衰竭的心脏中，β-肾上腺素能受体的占有率更高 导致维持环磷酸腺苷水平 尽管β-肾上腺素能刺激通路受损。因此， 通过在心力衰竭模型中检验这些假说 脱敏，将有可能更好地了解生化和 致抑郁的生理反应的分子机制 体内交感神经刺激。

The goal of this grant is to investigate mechanisms distal to the beta- adrenergic receptor mediating altered beta-adrenergic receptor-cyclase coupling in heart failure and catecholamine desensitization. It is planned to focus on two models, i.e., pacing-induced heart failure and catecholamine desensitization with or without cardiac denervation. These models are particularly powerful for three reasons: 1) they allow the study of biochemical and molecular mechanisms in larger animal models in which the physiology can be characterized in the conscious state, 2) they allow the study of serial changes during progression of the disease state from initial changes to more chronic states characterized by decompensation, and 3) the disease states are reversible. Four hypotheses will be tested. The first hypothesis is that abnormalities in the coupling of the beta-adrenergic receptor to adenylyl cyclase occur prior to the development of left ventricular (LV) decompensation and that these abnormalities reflect either uncoupling of the receptor from the guanine nucleotide stimulatory protein (Gs), changes in proportions of beta1 and beta2 receptors, or to a defect in the adenylyl cyclase catalytic unit. The second hypothesis is that in the pacing-induced model of heart failure and in the catecholamine desensitization model where the inotropic response to catecholamines is profoundly depressed, Gs activity is maintained, but Gi is enhanced and contributes to impaired generation of adenylyl cyclase in response to sympathetic stimulation. The third hypothesis is that cardiac neural impairment, e.g., denervation, is required for downregulation of cell surface beta-adrenergic receptors in heart failure or catecholamine desensitization. The fourth hypothesis is that in the failing heart, beta-adrenergic receptor occupancy is higher than in the normal heart resulting in maintenance of cyclic AMP levels despite the impairment in the beta-adrenergic stimulatory pathway. Thus, by examination of these hypotheses in models of heart failure and desensitization, it will be possible to better understand biochemical and molecular mechanisms responsible for depressed physiological responses to sympathetic stimulation in vivo.