Systolic Cardiac Function in Obesity and Exercise

描述（申请人摘要）：所提出的申请的广泛目标 研究旨在确定降低心脏反应性的机制， 肥胖症中的β-肾上腺素能刺激和运动训练的机制 在肥胖症的发展过程中可能会减弱这些影响。我们假设 肥胖会导致血液动力学的改变，心脏肥大， 胶原蛋白，激素分布和收缩功能，独立于 高血压为了验证这一假设，我们将比较瘦兔子和肥胖兔子。 沿着发展为高血压的兔子，以及 使用口服药物将血压控制在肥胖前值， 肼苯哒嗪我们将使用心脏的急性和慢性（遥测）测量 速率和血压，以及彩色微球，以研究 血流动力学我们将使用蛋白质印迹技术，血液采样，湿， 心脏干重和Langendorff离体心脏制备物进行分析 胶原蛋白、激素分布、心脏肥大和收缩功能。我们也 假设心脏对β-肾上腺素能的反应性降低 肥胖症的刺激是由于心脏 β-受体和G-偶联蛋白级联导致cAMP形成 和肌浆网中钙的释放。我们将使用适当的 分析和蛋白质印迹技术，以分析 β-受体和受体后组分如β-受体/Gs偶联， Gs刺激腺苷酸环化酶; cAMP的形成; PKA的活化，以及 肌浆网钙处理在心脏 肥胖症的异常我们假设， 肥胖症的发展将1）减弱或防止肥胖相关的 高血压、静息心动过速、神经体液激活和心脏 胶原蛋白形成和2）减弱肥胖相关的反应性降低 β肾上腺素能刺激久坐型肥胖者发生的厌食症 兔子将与它们在经历12个月的肥胖兔子中的减少进行比较。 数周的跑步机锻炼。还将与适当的 精益控制。最后，我们将确定β-肾上腺素能神经元 信号通路负责运动介导的反应性增加， 肥胖症患者β-肾上腺素能刺激，使用适当的测定和西方 如上所述的印迹技术。深入了解可能的机制 肥胖会增加充血性心力衰竭的风险， 导致预防和治疗方法的重要进展， 治疗肥胖患者的充血性心力衰竭。此外，信息 定期耐力运动可以改善心血管疾病的机制 肥胖者的风险状况和心脏功能可能有助于降低风险 心血管疾病的发展。因为如此大的一部分 美国人口超重或肥胖，知识和洞察力从 这些研究可以产生深远的影响。

DESCRIPTION (Applicant's abstract): The broad objectives of the proposed research are to determine mechanisms for reduced responsiveness to cardiac Beta-adrenergic stimulation in obesity and mechanisms whereby exercise training during the development of obesity may attenuate these effects. We hypothesize that obesity causes alterations in hemodynamics, cardiac hypertrophy, cardiac collagen, hormonal profile, and systolic function that are independent of hypertension. To test this hypothesis, we will compare lean rabbits with obese rabbits that develop hypertension along with obesity, and obese rabbits in which blood pressure will be controlled at pre-obese values using oral Hydralazine. We will use acute and chronic (telemetry) measurement of heart rate and blood pressure, as well as colored microspheres, to study hemodynamics. We will use western blotting techniques, blood sampling, wet and dry cardiac weights, and the Langendorff isolated heart preparation to analyze collagen, hormonal profile, cardiac hypertrophy, and systolic function. We also hypothesize that decreased cardiac responsiveness to Beta-adrenergic stimulation in obesity is due to abnormalities both at the cardiac Beta-receptor and in the G-coupled protein cascade leading to cAMP formation and calcium release from the sarcoplasmic reticulum. We will use appropriate assay and western blotting techniques to provide an analysis of the role of beta-receptor and post-receptor components such as Beta-receptor/Gs coupling, Gs stimulation of adenylate cyclase; formation of cAMP; activation of PKA, and sarcoplasmic reticulum calcium handling in contributing to cardiac abnormalities in obesity. We hypothesize that exercise training during development of obesity will 1) attenuate or prevent obesity-related hypertension, resting tachycardia, neurohumoral activation, and cardiac collagen formation and 2) attenuate obesity-related decreases in responsiveness to Beta-adrenergic stimulation. Abnormalities occurring in sedentary obese rabbits will be compared with their reduction in obese rabbits that undergo 12 weeks of treadmill exercise. Comparisons will also be made with appropriate lean controls. Finally, we will determine mechanisms within the Beta-adrenergic signaling pathway responsible for exercise-mediated increased responsiveness to Beta-adrenergic stimulation in obesity, using appropriate assay and western blotting techniques as noted above. Insight into possible mechanisms whereby obesity causes increased risk for development of congestive heart failure may lead to important advances in therapeutics modalities for prevention and treatment of congestive heart failure in obese patients. Further, information on mechanisms whereby regular endurance exercise may improve cardiovascular risk profile and cardiac performance in obesity may help reduce risk development of cardiovascular disease. Because such a large segment of the American population is overweight or obese, knowledge and insight gained from these studies can have far-reaching effects.