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.

Blockade of B2 receptors attenuates the responses of group III afferents to static contraction.

Recent evidence has been presented demonstrating that group III mechanoreceptors comprise an important part of the sensory arm of the exercise pressor reflex, which in turn functions to increase arterial blood flow to contracting skeletal muscles. Although group III afferents are stimulated by mechanical distortion of their receptive fields, they are also stimulated by bradykinin, which is produced by skeletal muscle when it contracts. Moreover, blockade of B (bradykinin)2 receptors has been shown to decrease the magnitude of the exercise pressor reflex. Nevertheless, the effect of blockade of B2 receptors on responses of group III afferents to contraction is not known. We therefore determined the effect of B2 receptor blockade with HOE 140 (40µg/kg) on the responses to both static and intermittent contraction of group III afferents with endings in the triceps surae muscle of decerebrated unanesthetized cats. We found that HOE 140 significantly attenuated (P=0.04) the responses of 14 group III afferents to static contraction, but did not significantly attenuate (P=0.16) the responses of 16 group III afferents to intermittent contraction. The attenuation induced by HOE 140 was present throughout the static contraction period, and led us to speculate that blockade of B2 receptors on the endings of group III afferents decreased their sensitivity to mechanical events occurring in the working muscles.

Peripheral δ-opioid receptors attenuate the exercise pressor reflex.

In rats with ligated femoral arteries, the exercise pressor reflex is exaggerated, an effect that is attenuated by stimulation of peripheral µ-opioid receptors on group IV metabosensitive afferents. In contrast, δ-opioid receptors are expressed mostly on group III mechanosensitive afferents, a finding that prompted us to determine whether stimulation of these opioid receptors could also attenuate the exaggerated exercise pressor reflex in "ligated" rats. We found femoral arterial injection of [D-Pen2,D-Pen5]enkephalin (DPDPE; 1.0 µg), a δ-opioid agonist, significantly attenuated the pressor and cardioaccelerator components of the exercise pressor reflex evoked by hindlimb muscle contraction in both rats with ligated and patent femoral arteries. DPDPE significantly decreased the pressor responses to muscle mechanoreflex activation, evoked by tendon stretch, in ligated rats only. DPDPE (1.0 µg) had no effect in either group on the pressor and cardioaccelerator responses to capsaicin (0.2 µg), which primarily stimulates group IV afferents. DPDPE (1.0 µg) had no effect on the pressor and cardioaccelerator responses to lactic acid (24 mM), which stimulates group III and IV afferents, in rats with patent femoral arteries but significantly decreased the pressor response in ligated rats. Western blots revealed the amount of protein comprising the δ-opioid receptor was greater in dorsal root ganglia innervating hindlimbs with ligated femoral arteries than in dorsal root ganglia innervating hindlimbs with patent femoral arteries. Our findings support the hypothesis that stimulation of δ-opioid receptors on group III afferents attenuated the exercise pressor reflex.

Treatment of muscle mechanoreflex dysfunction in hypertension: effects of L-arginine dialysis in the nucleus tractus solitarii.

NEW FINDINGS: 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. The blood pressure response to exercise is exaggerated in hypertension. Recent evidence suggests that an overactive skeletal muscle mechanoreflex contributes significantly to this augmented circulatory responsiveness. Sensory information from the mechanoreflex is processed within the nucleus tractus solitarii (NTS) of the medulla oblongata. Normally, endogenously produced nitric oxide within the NTS attenuates the increase in mean arterial pressure (MAP) induced by mechanoreflex stimulation. Thus, it has been suggested that decreases in NO production in the NTS underlie the generation of mechanoreflex dysfunction in hypertension. Supporting this postulate, it has been shown that blocking NO production within the NTS of normotensive rats reproduces the exaggerated pressor response elicited by mechanoreflex activation in hypertensive animals. What is not known is whether increasing NO production within the NTS of hypertensive rats mitigates mechanoreflex overactivity. In this study, the mechanoreflex was selectively activated by passively stretching hindlimb muscle before and after the dialysis of 1 and 10 µm l-arginine (an NO precursor) within the NTS of decerebrate normotensive Wistar-Kyoto (WKY) rats and spontaneously hypertensive rats (SHRs). Stretch induced larger elevations in MAP in SHRs compared with WKY rats. In both groups, dialysis of 1 µm l-arginine significantly attenuated the pressor response to stretch. However, at the 10 µm dose, l-arginine had no effect on the MAP response to stretch in WKY rats, while it enhanced the response in SHRs. The data demonstrate that increasing NO availability within the NTS using lower doses of l-arginine partly normalizes mechanoreflex dysfunction in hypertension, whereas higher doses do not. The findings could prove valuable in the development of treatment options for mechanoreflex overactivity in this disease.

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.

Blockade of the TP receptor attenuates the exercise pressor reflex in decerebrated rats with chronic femoral artery occlusion.

Cyclooxygenase metabolites stimulate or sensitize group III and IV muscle afferents, which comprise the sensory arm of the exercise pressor reflex. The thromboxane (TP) receptor binds several of these metabolites, whose concentrations in the muscle interstitium are increased by exercise under freely perfused conditions and even more so under ischemic conditions, which occur in peripheral artery disease. We showed that the exercise pressor reflex is greater in rats with simulated peripheral artery disease than in rats with freely perfused limbs. These findings prompted us to test the hypothesis that the TP receptor contributes to the exaggerated exercise pressor reflex occurring in a rat model of peripheral artery disease. We compared the cardiovascular responses to static contraction and stretch before and after femoral arterial injections of daltroban (80 µg), a TP receptor antagonist. We performed these experiments in decerebrate rats whose femoral arteries were ligated 72 h before the experiment (a model of simulated peripheral artery disease) and in control rats whose hindlimbs were freely perfused. Daltroban reduced the pressor response to static contraction in both freely perfused (n = 6; before: Δ12 ± 2 mmHg, after: Δ6 ± 2 mmHg, P = 0.024) and 72-h-ligated rats (n = 10; before: Δ25 ± 3 mmHg, after: Δ7 ± 4 mmHg, P = 0.001). Likewise, daltroban reduced the pressor response to stretch in the freely perfused group (n = 9; before: Δ30 ± 3 mmHg, after: Δ17 ± 3 mmHg, P < 0.0001) and in the ligated group (n = 11; before: Δ37 ± 5 mmHg, after: Δ23 ± 3 mmHg, P = 0.016). Intravenous injections of daltroban had no effect on the pressor response to contraction. We conclude that the TP receptor contributes to the pressor responses evoked by contraction and stretch in both freely perfused rats and rats with simulated peripheral artery disease.

Dorsal root tetrodotoxin-resistant sodium channels do not contribute to the augmented exercise pressor reflex in rats with chronic femoral artery occlusion.

We investigated the contribution of tetrodotoxin (TTX)-resistant sodium channels to the augmented exercise pressor reflex observed in decerebrated rats with femoral artery ligation. The pressor responses to static contraction, to tendon stretch, and to electrical stimulation of the tibial nerve were compared before and after blocking TTX-sensitive sodium channels on the L3-L6 dorsal roots of rats whose hindlimbs were freely perfused and rats whose femoral arteries were ligated 72 h before the start of the experiment. In the freely perfused group (n=9), pressor (Δ22±4 mmHg) and cardioaccelerator (Δ32±6 beats/min) responses to contraction were attenuated by 1 µM TTX (Δ4±1 mmHg, P<0.05 and Δ17±4 beats/min, P<0.05, respectively). In the 72 h ligated group (n=9), the augmented pressor response to contraction (32±4 mmHg) was also attenuated by 1 µM TTX (Δ8±2 mmHg, P<0.05). The cardioaccelerator response to contraction was not significantly attenuated in these rats. In addition, TTX suppressed the pressor response to tendon stretch in both groups of rats. Electrical stimulation of the tibial nerve evoked similar pressor responses between the two groups (freely perfused: Δ74±9 mmHg and 72 h ligated: Δ78±5 mmHg). TTX attenuated the pressor response to the tibial nerve stimulation by about one-half in both groups. Application of the TTX-resistant sodium channel blocker A-803467 (1 µM) with TTX (1 µM) did not block the pressor response to tibial nerve stimulation to any greater extent than did application of TTX (1 µM) alone. Although the contribution of TTX-resistant sodium channels to the augmented exercise pressor reflex may be slightly increased in rats with chronic femoral artery ligation, TTX-resistant sodium channels on dorsal roots do not play a major role in the augmented exercise pressor 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 microg/100 microl), iodoresinaferatoxin (IRTX; 1 microg/100 microl), or Ruthenium Red (RR; 100 microg/100 microl). 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.

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.

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.