In hypertensive individuals, exercise elicits excessive increases in arterial blood pressure, heart rate and vascular resistance. These potentially dangerous elevations in circulatory hemodynamics increase the risk for adverse cardiac events or stroke during exercise. We have previously established that overactivity of the exercise pressor reflex, a circulatory reflex originating within skeletal muscle, contributes importantly to the generation of these heightened cardiovascular responses. Further, evidence from our laboratory suggests that both the muscle mechanoreflex and metaboreflex, the two functional components of the exercise pressor reflex, drive this overactivity. However, the mechanisms underlying exercise pressor reflex dysfunction in hypertension are not clear. Sensory information generated by activation of the exercise pressor reflex is processed within the nucleus tractus solitarius (NTS) of the medulla oblongata. The activity of neurons within the medulla that receive and process this information can be modulated by the endogenous production of nitric oxide (NO). NO production is mediated by nitric oxide synthase (NOS). Likewise, NO activity within the NTS can be modified by the generation of reactive oxygen species (ROS). Therefore, alterations in either NOS expression/activity or ROS production potentially contribute to changes in NO activity within the NTS. As such, the NO pathway within the NTS represents a viable target for disease induced alterations in exercise pressor reflex function. Based on this knowledge, we hypothesize that the enhanced cardiovascular response to exercise mediated by the exercise pressor reflex in hypertension is induced by alterations in NO activity, changes in NOS expression and/or function as well as alterations in the generation of ROS within the NTS. To test these hypotheses, we will perform physiologic and neuro-biochemical studies in normotensive and hypertensive rats to address the following specific aims: 1) determine the role of NO within the NTS in the generation of exercise pressor reflex, mechanoreflex and metaboreflex overactivity in hypertension;2) determine the role of NOS within the NTS in the generation of exercise pressor reflex, mechanoreflex and metaboreflex overactivity in hypertension;and 3) determine the role of ROS within the NTS in the generation of exercise pressor reflex, mechanoreflex and metaboreflex overactivity in hypertension.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL088422-05
Application #
8257541
Study Section
Hypertension and Microcirculation Study Section (HM)
Program Officer
Ershow, Abby
Project Start
2008-05-01
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
5
Fiscal Year
2012
Total Cost
$388,575
Indirect Cost
$141,075
Name
University of Texas Sw Medical Center Dallas
Department
Other Health Professions
Type
Schools of Allied Health Profes
DUNS #
800771545
City
Dallas
State
TX
Country
United States
Zip Code
75390
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Mizuno, Masaki; Lozano, German; Siddique, Khurrum et al. (2014) Enalapril attenuates the exaggerated sympathetic response to physical stress in prenatally programmed hypertensive rats. Hypertension 63:324-9
Mizuno, Masaki; Siddique, Khurrum; Baum, Michel et al. (2013) Prenatal programming of hypertension induces sympathetic overactivity in response to physical stress. Hypertension 61:180-6
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
Murphy, Megan N; Mizuno, Masaki; Downey, Ryan M et al. (2013) Neuronal nitric oxide synthase expression is lower in areas of the nucleus tractus solitarius excited by skeletal muscle reflexes in hypertensive rats. Am J Physiol Heart Circ Physiol 304:H1547-57
Mizuno, Masaki; Murphy, Megan N; Mitchell, Jere H et al. (2011) Antagonism of the TRPv1 receptor partially corrects muscle metaboreflex overactivity in spontaneously hypertensive rats. J Physiol 589:6191-204
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Mizuno, Masaki; Murphy, Megan N; Mitchell, Jere H et al. (2011) Skeletal muscle reflex-mediated changes in sympathetic nerve activity are abnormal in spontaneously hypertensive rats. Am J Physiol Heart Circ Physiol 300:H968-77
Smith, Scott A; Leal, Anna K; Williams, Maurice A et al. (2010) The TRPv1 receptor is a mediator of the exercise pressor reflex in rats. J Physiol 588:1179-89
Leal, Anna K; Williams, Maurice A; Garry, Mary G et al. (2008) Evidence for functional alterations in the skeletal muscle mechanoreflex and metaboreflex in hypertensive rats. Am J Physiol Heart Circ Physiol 295:H1429-38