RECEPTOR-SECOND MESSENGER MODULATION IN HYPERTROPHY

心脏对慢性压力超负荷的适应导致心脏 肥大与信号转导的改变--第二信使 瀑布。对儿茶酚胺的反应性可以保持，尽管 受体下调和流动储备的损失，但这不是 总是会发生的。正向补偿是通过调整来实现的 细胞内受体后系统。这项提议的目标是 第一，确定经济增长中的积极和消极补偿变化 第二信使cGMP与cAMP在心肌肥厚中的关系 评价这些改变对局部心肌功能的影响及其临床意义 02成本。其次，目标是提高补偿和效率 通过慢性药物调节受体介导的改变 CAMP/cGMP途径。所有实验都将在麻醉状态下进行， 诱导肥厚(主动脉狭窄)6个月后开胸犬 模型)，以及来自类似动物的细胞。地区性心肌工作将 通过使用超声波尺寸测量管段长度进行评估 用微型测力计测定晶体和收缩力。 同一细分市场的氧气消耗量将由地区确定 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 分离细胞悬浮液中的电极。这些生理测量 将与β-肾上腺素能和生化测定相结合 M受体数目和亲和力、腺苷和鸟苷环化酶 活性、cAMP、cGMP水平以及cAMP和cGMP特异性 体外和体内的磷酸二酯酶。其目的是确定 肥厚心脏对受体介导和直接作用的反应 CGMP水平的变化与cAMP对局部功能的控制和02 成本。β肾上腺素能和M受体特异性拮抗剂和 激动剂将被用来按顺序上调和下调受体数量 要提高补偿和恢复效率，通过调节 CAMP/cGMP途径。最终目的是为了更好地理解 控制肥大补偿的细胞机制。 改善肥厚心脏保护心脏功能的能力 较低的O2成本应该会对充血性心脏病的发展产生积极影响 压力型心肌病患者心力衰竭与生存的关系 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.