Pathogenesis of Exercise Pressor Reflex Dysfunction in Hypertension

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在一定程度上是由运动加压反射（EPR）及其组成部分机械反射和代谢反射介导的。在脑干孤束核（NTS）内，l -精氨酸被一氧化氮合酶（NOS）氧化生成一氧化氮（NO）。有证据表明，NTS内源性NO的产生调节了EPR的活性。此外，自发性高血压大鼠（SHR） NTS内NOS活性和表达在婴儿期正常，但在高血压发病过程中发生改变。因此，我们假设高血压患者EPR的升高是由NTS内NO活性的变化介导的，而这些变化是NOS活性/表达改变的结果。我们还假设在高血压发病过程中NTS内NOS活性/表达的变化与EPR及其成分（机械反射和代谢反射）功能障碍呈正相关。使用年龄匹配的雄性正常血压Wistar-Kyoto （WKY）和SHR大鼠，分别在4、8、12、16和20周龄时，我们将(1)确定高血压发病过程中EPR功能障碍的进展，(2)确定NTS内NO和NOS表达/活性在这些时期EPR功能障碍发展中的作用。EPR功能将在电致静态收缩期间进行评估。机械反射功能将通过后肢肱三头肌表面肌的被动拉伸来测试。此外，代谢反射功能将通过向后肢动脉供应注射不同浓度的辣椒素来检测。在所有反射测试中，将记录心血管参数。为评价年龄匹配的SHR和WKY大鼠在指定时间点的NOS表达，对脑干组织进行NOS蛋白免疫组织化学染色。最后，为了确定NO对EPR功能的影响，我们将NOS抑制剂ng -硝基- l -精氨酸甲酯盐化（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。为了使运动对高血压的有益作用得以实现，必须确定EPR功能障碍的机制及其进展。这一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受性，降低高血压患者运动相关的风险，使受影响的个体在更大程度上享受体育活动的治疗益处。

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.