Pathogenesis of Exercise Pressor Reflex Dysfunction in Hypertension

高血压运动加压反射功能障碍的发病机制

• 批准号: 7546424
• 负责人: Anna Katherine Leal
• 金额: $ 2.59万
• 依托单位: UT SOUTHWESTERN MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2009-08-12
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7546424
• 关键词: Affect; Age; Arginine; Blood Pressure; Brain Stem; Capsaicin; Cardiovascular system; Chromosome Pairing; Development; Dialysis procedure; Event; Exercise; Exercise Tolerance; Functional disorder; Heart Rate; Hindlimb; Hypertension; Inbred SHR Rats; Inbred WKY Rats; Individual; Knowledge; Laboratories; Lead; Mediating; Medulla Oblongata; Muscle; Myocardial Infarction; Myocardial Ischemia; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase; Nucleus solitarius; Pathogenesis; Patients; Physical Dialysis; Physical activity; Production; Proteins; Rattus; Reflex action; Research; Risk; Role; Sensory; Skeletal Muscle; Staining method; Stains; Stretching; Stroke; Synapses; Testing; Therapeutic; Time; Tissues; Triceps Brachii Muscle; Vascular resistance; Week; base; hemodynamics; hydrochloride arginine methyl ester; infancy; inhibitor/antagonist; male; normotensive; novel; research study; response

DESCRIPTION (provided by applicant): The cardiovascular response to physical activity is exaggerated in hypertension. This enhanced cardiovascular responsiveness is mediated, in part, by the exercise pressor reflex (EPR) and its components, the mechanoreflex and metaboreflex. Within the nucleus tractus solitarius (NTS) of the brainstem, L-arginine is oxidized by nitric oxide synthase (NOS) to produce nitric oxide (NO). Evidence suggests the endogenous production of NO within the NTS modulates the activity of the EPR. In addition, both NOS activity and expression within the NTS of Spontaneously Hypertensive Rats (SHR) have been shown to be normal during infancy, but are altered during the pathogenesis of hypertension. Therefore, we hypothesize that the exaggerated EPR observed in hypertension is mediated by changes in NO activity within the NTS and that these changes are the result of alterations in NOS activity/expression. We also hypothesize that changes in NOS activity/expression within the NTS during the pathogenesis of hypertension are positively correlated to the dysfunction of the EPR and its components, the mechanoreflex and metaboreflex. Using age-matched male normotensive Wistar-Kyoto (WKY) and SHR rats at 4, 8, 12, 16, and 20 weeks old, we will (1) determine the progression of EPR dysfunction during the pathogenesis of hypertension and (2) determine the role of NO and NOS expression/activity within the NTS in the development of EPR dysfunction at these time periods. EPR function will be assessed during electrically-induced static contraction. Mechanoreflex function will be tested through passive hindlimb stretch of the triceps surae muscle. In addition, metaboreflex function will be tested by injecting graded concentrations of capsaicin into the hindlimb arterial supply. Cardiovascular parameters will be recorded during all reflex testing. To evaluate NOS expression in age-matched SHR and WKY rats at the designated time points, brainstem tissue will be stained immunohistochemically for NOS protein. Finally, to determine the effects of NO on EPR function, the NOS inhibitor NG-nitro-L-arginine methyl ester hydrochloride (L-NAME) and the NO precursor L-arginine will be dialyzed into the NTS of age-matched SHR and WKY rats while EPR, mechanoreflex, and metaboreflex testing are repeated. For the beneficial effects of exercise to be realized in hypertension, the mechanism of EPR dysfunction and its progression must be determined. This knowledge may lead to novel treatments that could potentially increase exercise tolerance in hypertensive patients and reduce the risks associated with exercise in hypertension allowing affected individuals to enjoy the therapeutic benefits of physical activity to a greater degree.

描述（由申请人提供）：高血压患者对体力活动的心血管反应被夸大。这种增强的心血管反应性部分地由运动加压反射（EPR）及其组分、机械反射和代谢反射介导。在脑干的孤束核（NTS）内，L-精氨酸被一氧化氮合酶（NOS）氧化产生一氧化氮（NO）。有证据表明，在NTS内的内源性NO的产生调节EPR的活性。此外，在幼年期，自发性高血压大鼠（SHR）的NTS内NOS活性和表达均正常，但在高血压发病过程中发生了改变。因此，我们推测，在高血压中观察到的夸大EPR是由NTS内NO活性的变化介导的，并且这些变化是NOS活性/表达改变的结果。我们还推测，在高血压的发病过程中，在NTS内的NOS活性/表达的变化正相关的EPR及其组件，机械反射和代谢反射的功能障碍。使用4、8、12、16和20周龄的年龄匹配的雄性血压正常的Wistar-Kyoto（WKY）和SHR大鼠，我们将（1）确定高血压发病过程中EPR功能障碍的进展和（2）确定NTS内NO和NOS表达/活性在这些时间段EPR功能障碍发展中的作用。将在电诱导静态收缩期间评估EPR功能。将通过小腿三头肌的被动后肢伸展测试机械反射功能。此外，将通过向后肢动脉供应中注射分级浓度的辣椒素来测试代谢反射功能。将在所有反射测试期间记录心血管参数。为了评估在指定时间点年龄匹配的SHR和WKY大鼠中的NOS表达，将对脑干组织进行NOS蛋白的化学染色。最后，为了确定NO对EPR功能的影响，将NOS抑制剂NG-硝基-L-精氨酸甲酯盐酸盐（L-NAME）和NO前体L-精氨酸透析到年龄匹配的SHR和WKY大鼠的NTS中，同时重复EPR、机械反射和代谢反射测试。为了实现运动对高血压的有益作用，必须确定EPR功能障碍及其进展的机制。这些知识可能会导致新的治疗方法，可能会增加高血压患者的运动耐量，并降低与高血压运动相关的风险，使受影响的个体能够更大程度地享受体力活动的治疗益处。