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. ? ? ?
| Leal, Anna K; Mitchell, Jere H; Smith, Scott A (2013) Treatment of muscle mechanoreflex dysfunction in hypertension: effects of L-arginine dialysis in the nucleus tractus solitarii. Exp Physiol 98:1337-48 |
