RECEPTOR-SECOND MESSENGER MODULATION IN HYPERTROPHY

心脏对慢性压力超负荷的适应导致心脏 肥大和信号转导-第二信使的改变 瀑布 对儿茶酚胺的反应可以维持， 受体下调和流量储备损失，但这并不 总是发生。 正补偿是通过调整 细胞内后受体系统。 本提案的目的是 第一，确定积极和消极的补偿变化， 第二信使cGMP与心肌肥厚中cAMP的关系，以及 评价这些变化对局部心肌功能的影响， 02成本。 第二，目标是提高薪酬和效率 通过受体介导的变化的慢性药理学调节， cAMP/cGMP途径。 所有实验将在麻醉的， 诱导肥大（主动脉瓣狭窄）后6个月开胸犬 模型），以及来自类似动物的细胞。 局部心肌功 使用超声波尺寸从节段长度测量进行评估 晶体和收缩力测定微型测力计。 同一段的O2消耗量将根据区域 心肌血流量（放射性微球）和局部O2 血红蛋白饱和度（显微分光光度法）和p02 分离的细胞悬浮液中的电极。 这些生理测量 将结合β肾上腺素能和 毒蕈碱受体数量和亲和力，腺苷酸和鸟苷酸环化酶 活性、cAMP、cGMP水平以及cAMP和cGMP特异性 磷酸二酯酶在体外和体内。 目的是确定 肥大心脏对受体介导和直接作用的反应 cGMP水平在cAMP控制局部功能和O2方面的变化 成本 β肾上腺素能和毒蕈碱受体特异性拮抗剂， 激动剂将用于上调和下调受体数量， 为了通过调制补偿和恢复效率， cAMP/cGMP途径。 最终目的是为了更好地了解 控制肥大补偿的细胞机制。 提高肥厚心脏保存功能的能力 较低的O2成本应该对充血性心力衰竭的发展产生积极影响， 压力性心肌病患者心力衰竭与生存率 超载。

Adaption of the heart to chronic pressure overload leads to cardiac hypertrophy and alterations in signal transduction-second messenger cascades. Responsiveness to catecholamine can be maintained despite receptor down regulation and loss of flow reserves, but this does not always occur. The positive compensation is achieved by readjusting intracellular post receptor systems. The objective of this proposal is first to determine the positive and negative compensatory changes in the second messenger cGMP in relation to cAMP in cardiac hypertrophy, and to evaluate the effect of these changes on local myocardial function and its 02 costs. Secondly, the goal is to enhance compensation and efficiency by chronic pharmacological modulation of receptor mediated changes in cAMP/cGMP pathways. All experiments will be conducted in anesthetized, open-chest dogs 6 months after induction of hypertrophy (aortic stenosis model), and on cells from similar animals. Regional myocardial work will be assessed from segment length measurements using ultrasonic dimension crystals and contractile force determinations by miniature force gauges. O2 consumption of the same segment will be determined from regional myocardial blood flow (radioactive microspheres) and regional O2 saturation of hemoglobin (microspectrophotometry) and with a p02 electrode in isolated cell suspensions. These physiological measurements will be combined with biochemical assays of beta adrenergic and muscarinic receptor number and affinity, adenyl and guanyl cyclase activity, cAMP, cGMP levels as well as cAMP and cGMP specific phosphodiesterase in vitro and in vivo. The aim is to determine the response of the hypertrophied heart to receptor mediated and direct changes in cGMP levels in terms of cAMP control of local function and 02 costs. Beta adrenergic and muscarinic receptor specific antagonists and agonists will be used to up and down regulate receptor numbers in order to improve compensation and restore efficiency through modulation of the cAMP/cGMP pathways. The ultimate goal is to gain a better understanding of the cellular mechanisms that control compensation in hypertrophy. Improving the ability of the hypertrophied heart to preserve function at lower 02 costs should impact positively on the development of congestive heart failure and survival in patients with cardiomyopathy of pressure overload.