Systolic Cardiac Function in Obesity and Exercise

描述(申请人摘要)：拟议研究的广泛目标是确定心脏反应性降低的机制 肥胖症的β-肾上腺素能刺激及其运动训练机制 在肥胖的发展过程中，可能会减弱这些影响。我们假设 肥胖会导致血流动力学改变，心脏肥厚，心脏 胶原蛋白、激素谱和收缩功能独立于 高血压。为了验证这一假设，我们将比较瘦兔和肥兔。 随着肥胖而发展为高血压的兔子，以及肥胖的兔子 哪种血压可以通过口服控制在肥胖前水平 呋喃西林。我们将使用急性和慢性(遥测)心脏测量 心率和血压，以及有色微球，以研究 血流动力学。我们将使用西方印迹技术，采血，湿和 干心脏重量和朗宁多夫离体心准备情况分析 胶原蛋白，激素谱，心肌肥厚，和收缩功能。我们也 降低心脏对β-肾上腺素能反应性的假说 肥胖的刺激是由于心脏和心脏的异常 β受体和G偶联蛋白级联导致cAMP的形成 以及从肌浆网释放钙。我们将使用适当的 检测和Western blotting技术提供分析的作用 β受体和受体后成分，如β受体/Gs偶联， GS对腺苷环化酶的刺激；cAMP的形成；PKA的激活；以及 肌浆网钙处理对心脏功能的影响 肥胖症的异常。我们假设在运动训练期间 肥胖的发展将1)减轻或预防与肥胖相关的 高血压、静止性心动过速、神经体液激活和心脏 胶原蛋白的形成和2)减轻肥胖相关的反应性下降 对β-肾上腺素能的刺激。久坐肥胖症的异常表现 将兔子与肥胖兔的减肥量进行比较 数周的跑步机运动。还将与适当的 精益控制。最后，我们将确定β-肾上腺素能的机制。 运动介导的反应增强的信号通路 肥胖症中的β-肾上腺素能刺激，使用适当的测定和Western 如上所述的吸墨技术。洞察可能的机制，从而 肥胖会增加患充血性心力衰竭的风险 在预防和治疗方法方面取得重要进展 肥胖患者充血性心力衰竭的治疗。此外，信息 规律耐力运动改善心血管疾病的机制研究 肥胖的风险状况和心脏功能可能有助于降低心血管疾病的风险。因为有这么大一部分人 美国人口超重或肥胖，知识和洞察力来自 这些研究可能会产生深远的影响。

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.