Exercise Pressor Reflex Dysfunction in Hypertension

The exercise pressor reflex and its components, the muscle mechanoreflex and the metaboreflex, are overactive in hypertension. The mechanoreflex and metaboreflex are feedback mechanisms originating in skeletal muscle that increase mean arterial pressure (MAP) and heart rate (HR) during exercise. In hypertensive individuals, mechanoreflex and metaboreflex overactivity can cause dangerous elevations in MAP and HR during physical activity, creating risks for adverse cardiac events. Mechanoreflex (predominantly group III) and metaboreflex (predominantly group IV) afferent fibers, which are activated by mechanical stress and the metabolic byproducts of working muscle, respectively, project to the nucleus tractus solitarius (NTS) in the brainstem. Within this nucleus, nitric oxide (NO) is produced from L-arginine via the enzymatic activity of nitric oxide synthase (NOS). Brainstem NO has been shown to modulate exercise pressor reflex-driven changes in MAP and HR. Therefore, we hypothesized that a decrease in NO production/availability within the NTS is involved in mediating both mechanoreflex and metaboreflex dysfunction in hypertension. To test this, we microdialyzed a NOS inhibitor, L-nitro-arginine methyl ester (L-NAME), and the NO precursor, L-arginine, into the NTS of normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) rats to experimentally alter endogenous NO production during preferential activation of mechanically and metabolically sensitive skeletal muscle afferents. Passive hindlimb muscle stretch was the maneuver used to simulate mechanoreflex activation while metabolically sensitive afferents were activated by hindlimb intra-arterial capsaicin injections. Capsaicin binds to transient potential 1 (TRPv1) receptors, which are primarily localized to group IV afferents. We found that blocking NO production via L-NAME within the NTS of normotensive WKY rats recapitulates the exaggerated cardiovascular response elicited by both mechanically and metabolically sensitive afferent neurons in hypertension. Importantly, we demonstrated that experimentally increasing NO production within the NTS of hypertensive SHR rats partially corrects the enhanced cardiovascular response to activation of both mechanically and metabolically sensitive afferent neurons. These findings provide evidence that a decrease in NO production/availability within the brainstem contributes to mechanoreflex and metaboreflex dysfunction in hypertension. Future utilization of this research could lead to effective treatment options for hypertensive individuals, allowing them to engage in physical activity without the associated hemodynamic risks.