Anna K. Leal

Exercise pressor reflex function is altered in spontaneously hypertensive rats

In hypertension, exercise elicits excessive elevations in mean arterial pressure (MAP) and heart rate (HR) increasing the risk for adverse cardiac events and stroke during physical activity. The exercise pressor reflex (a neural drive originating in skeletal muscle), central command (a neural drive originating in cortical brain centres) and the tonically active arterial baroreflex contribute importantly to cardiovascular control during exercise. Each of these inputs potentially mediates the heightened cardiovascular response to physical activity in hypertension. However, given that exercise pressor reflex overactivity is known to elicit enhanced circulatory responses to exercise in disease states closely related to hypertension (e.g. heart failure), we tested the hypothesis that the exaggerated cardiovascular response to exercise in hypertension is mediated by an overactive exercise pressor reflex. To test this hypothesis, we used a rat model of exercise recently developed in our laboratory that selectively stimulates the exercise pressor reflex independent of central command and/or the arterial baroreflex. Activation of the exercise pressor reflex during electrically induced static muscle contraction in the absence of input from central command resulted in significantly larger increases in MAP and HR in male spontaneously hypertensive rats as compared to normotensive Wistar‐Kyoto rats over a wide range of exercise intensities. Similar findings were obtained in animals in which input from both central command and the arterial baroreflex were eliminated. These findings suggest that the enhanced cardiovascular response to exercise in hypertension is mediated by an overactive exercise pressor reflex. Potentially, effective treatment of exercise pressor reflex dysfunction may reduce the cardiovascular risks associated with exercise in hypertension.

Evidence for functional alterations in the skeletal muscle mechanoreflex and metaboreflex in hypertensive rats

Exercise in hypertensive individuals elicits exaggerated increases in mean arterial pressure (MAP) and heart rate (HR) that potentially enhance the risk for adverse cardiac events or stroke. Evidence suggests that exercise pressor reflex function (EPR; a reflex originating in skeletal muscle) is exaggerated in this disease and contributes significantly to the potentiated cardiovascular responsiveness. However, the mechanism of EPR overactivity in hypertension remains unclear. EPR function is mediated by the muscle mechanoreflex (activated by stimulation of mechanically sensitive afferent fibers) and metaboreflex (activated by stimulation of chemically sensitive afferent fibers). Therefore, we hypothesized the enhanced cardiovascular response mediated by the EPR in hypertension is due to functional alterations in the muscle mechanoreflex and metaboreflex. To test this hypothesis, mechanically and chemically sensitive afferent fibers were selectively activated in normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SHR) decerebrate rats. Activation of mechanically sensitive fibers by passively stretching hindlimb muscle induced significantly greater increases in MAP and HR in SHR than WKY over a wide range of stimulus intensities. Activation of chemically sensitive fibers by administering capsaicin (0.01-1.00 microg/100 microl) into the hindlimb arterial supply induced increases in MAP that were significantly greater in SHR compared with WKY. However, HR responses to capsaicin were not different between the two groups at any dose. This data is consistent with the concept that the abnormal EPR control of MAP described previously in hypertension is mediated by both mechanoreflex and metaboreflex overactivity. In contrast, the previously reported alterations in the EPR control of HR in hypertension may be principally due to overactivity of the mechanically sensitive component of the reflex.

The TRPv1 receptor is a mediator of the exercise pressor reflex in rats

The skeletal muscle exercise pressor reflex (EPR) induces increases in heart rate (HR) and mean arterial pressure (MAP) during physical activity. This reflex is activated during contraction by stimulation of afferent fibres responsive to mechanical distortion and/or the metabolic by‐products of skeletal muscle work. The molecular mechanisms responsible for activating these afferent neurons have yet to be identified. It has been reported that activation of the transient receptor potential vanilloid 1 (TRPv1) receptor within skeletal muscle (localized to unmyelinated afferent fibres) elicits increases in MAP and HR similar to those generated by the EPR. Thus, we hypothesized that stimulation of the TRPv1 receptor during muscle contraction contributes to the activation of the EPR. The EPR was activated by electrically induced static muscle contraction of the hindlimb in decerebrate Sprague–Dawley rats (n= 61) before and after the administration of the TRPv1 receptor antagonists, capsazepine (Capz; 100 μg/100 μl), iodoresinaferatoxin (IRTX; 1 μg/100 μl), or Ruthenium Red (RR; 100 μg/100 μl). Static muscle contraction alone induced increases in both HR (8 ± 2 bpm) and MAP (21 ± 3 mmHg). The HR and MAP responses to contraction were significantly lower (P < 0.05) after the administration of Capz (2 ± 1 bpm; 7 ± 1 mmHg, respectively), IRTX (3 ± 2 bpm; 5 ± 3 mmHg, respectively) and RR (0 ± 1, bpm; 5 ± 2 mmHg, respectively). These data suggest that the TRPv1 receptor contributes importantly to activation of the EPR during skeletal muscle contraction in the rat.

TREATMENT OF MUSCLE MECHANOREFLEX DYSFUNCTION IN HYPERTENSION: EFFECTS OF L-ARGININE DIALYSIS IN THE NUCLEUS TRACTUS SOLITARII

•  What is the central question of this study? Does increasing NO production within the nucleus tractus solitarii (NTS) affect mechanoreflex function in normotensive and hypertensive rats? •  What is the main finding and its importance? Dialysis of 1 μm l‐arginine, an NO precursor, within the NTS significantly attenuated the pressor response to muscle stretch in normotensive and hypertensive rats. In contrast, 10 μm l‐arginine had no effect in normotensive animals, while increasing and decreasing the pressor and tachycardic responses to stretch, respectively, in hypertensive rats. This suggests that increasing NO within the NTS using lower doses of l‐arginine can partly normalize mechanoreflex overactivity in hypertensive rats, whereas the effects of larger doses are equivocal.

A role for nitric oxide within the nucleus tractus solitarii in the development of muscle mechanoreflex dysfunction in hypertension

Evidence suggests that the muscle mechanoreflex, a circulatory reflex that raises blood pressure and heart rate (HR) upon activation of mechanically sensitive afferent fibres in skeletal muscle, is overactive in hypertension. However, the mechanisms underlying this abnormal reflex function have yet to be identified. Sensory input from the mechanoreflex is processed within the nucleus tractus solitarii (NTS) in the medulla oblongata. Within the NTS, the enzymatic activity of nitric oxide synthase produces nitric oxide (NO). This centrally derived NO has been shown to modulate muscle reflex activity and serves as a viable candidate for mediating the mechanoreflex dysfunction that develops in hypertension. We hypothesized that mechanoreflex dysfunction in hypertension is mediated by abnormal alterations in NO production in the NTS. Mechanically sensitive afferent fibres were stimulated by passively stretching hindlimb muscle before and after blocking the endogenous production of NO within the NTS via microdialysis of the NO synthase inhibitor l‐NAME (1 and 5 mm) in normotensive Wistar–Kyoto rats and spontaneously hypertensive rats (SHRs). Changes in HR and mean arterial pressure in response to stretch were significantly larger in SHRs compared with Wistar–Kyoto rats prior to l‐NAME dialysis. Attenuating NO production via l‐NAME in normotensive rats recapitulated the exaggerated cardiovascular response to stretch observed in SHRs. Dialysing l‐NAME in SHRs further accentuated the increases in HR and mean arterial pressure elicited by stretch. These findings support the contention that reductions in NO production within the NTS contribute to the generation of abnormal cardiovascular control by the skeletal muscle mechanoreflex in hypertension.

Muscle mechanoreflex overactivity in hypertension: A role for centrally-derived nitric oxide

The cardiovascular response to exercise is abnormally large in hypertension. Over the past decade, it has become clear that the exercise pressor reflex (a peripheral feed-back mechanism originating in skeletal muscle) contributes significantly to the generation of this hyper-responsiveness. Further, it has been determined that overactivity of the mechanically (muscle mechanoreflex) and chemically (muscle metaboreflex) sensitive components of the exercise pressor reflex underpin its dysfunction. Given the recent attention in the literature, this review focuses upon the aberrant function of the muscle mechanoreflex in this disease. Evidence supporting a role for the mechanoreflex in the pathogenesis of the exaggerated cardiovascular response to physical activity is highlighted. The peripheral and central mechanisms that may be responsible for mechanoreflex overactivity in hypertension are likewise discussed. Particular attention is given to emerging evidence implicating a role for centrally-derived nitric oxide in this process.