The exercise pressor reflex is a feedback autonomic and cardiovascular control mechanism evoked by mechanical and metabolic signals within contracting skeletal muscles. The mechanically sensitive component of the reflex (the mechanoreflex) is exaggerated in peripheral artery disease (PAD) patients and in a rat model of simulated PAD in which a femoral artery is chronically ligated. Products of cyclooxygenase enzyme activity have been shown to chronically sensitize the mechanoreflex in PAD but the identity of the muscle afferent receptors that mediate the sensitization is unclear. We hypothesized that injection of the endoperoxide 4 receptor (EP4-R) antagonist L161982 or the thromboxane A2 receptor (TxA2-R) antagonist daltroban into the arterial supply of the hindlimb would reduce the pressor response to repetitive, dynamic hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in rats with a femoral artery that was ligated ~72 hours before the experiment but not in rats with freely perfused femoral arteries. We found that EP4-R blockade had no effect on the pressor response (peak Δ mean arterial pressure) to stretch in "freely perfused" (n=6, pre: 14±2, post: 15±2 mmHg, p=0.97) or "ligated" (n=8, pre: 29±4, post: 29±6 mmHg, p=0.98) rats. In contrast, TxA2-R blockade had no effect on the pressor response to stretch in freely perfused rats (n=6, pre: 16±3, post: 17±4 mmHg, p=0.99) but significantly reduced the response in ligated rats (n=11, pre: 29±4, post: 17±5 mmHg, p<0.01). We conclude that TxA2-Rs contribute to chronic mechanoreflex sensitization in the chronic femoral artery ligated rat model of simulated PAD.

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New Findings What is the central question of this study?Do endoperoxide 4 and thromboxane A2 receptors, which are receptors for cyclooxygenase products of arachidonic metabolism, on thin fibre muscle afferents play a role in the chronic mechanoreflex sensitization present in rats with heart failure with reduced ejection fraction (HF‐rEF)? What is the main finding and its importance?The data do not support a role for endoperoxide 4 receptors or thromboxane A2 receptors in the chronic mechanoreflex sensitization in HF‐rEF rats. Abstract We investigated the role of cyclooxygenase metabolite‐associated endoperoxide 4 receptors (EP4‐R) and thromboxane A2 receptors (TxA2‐R) on thin fibre muscle afferents in the chronic mechanoreflex sensitization in rats with myocardial infarction‐induced heart failure with reduced ejection fraction (HF‐rEF). We hypothesized that injection of either the EP4‐R antagonist L‐161,982 (1 µg) or the TxA2‐R antagonist daltroban (80 µg) into the arterial supply of the hindlimb would reduce the increase in blood pressure and renal sympathetic nerve activity (RSNA) evoked in response to 30 s of static hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in decerebrate, unanaesthetized HF‐rEF rats but not sham‐operated control rats (SHAM). Ejection fraction was significantly reduced in HF‐rEF (45 ± 11%) compared to SHAM (83 ± 6%; P < 0.01) rats. In SHAM and HF‐rEF rats, we found that the EP4‐R antagonist had no effect on the peak increase in mean arterial pressure (peak ΔMAP SHAM n = 6, pre: 15 ± 7, post: 15 ± 9, P = 0.99; HF‐rEF n = 9, pre: 30 ± 11, post: 32 ± 15 mmHg, P = 0.84) or peak increase in RSNA (peak ΔRSNA SHAM pre: 33 ± 14, post: 47 ± 31%, P = 0.94; HF‐rEF, pre: 109 ± 47, post: 139 ± 150%, P = 0.76) response to stretch. Similarly, in SHAM and HF‐rEF rats, we found that the TxA2‐R antagonist had no effect on the peak ΔMAP (SHAM n = 7, pre: 13 ± 7, post: 19 ± 14, P = 0.15; HF‐rEF n = 14, pre: 24 ± 13, post: 21 ± 13 mmHg, P = 0.47) or peak ΔRSNA (SHAM pre: 52 ± 43, post: 57 ± 67%, P = 0.94; HF‐rEF, pre: 108 ± 93, post: 88 ± 72%, P = 0.30) response to stretch. The data do not support a role for EP4‐Rs or TxA2‐Rs in the chronic mechanoreflex sensitization in HF‐rEF.

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Background Mechanical and metabolic signals associated with skeletal muscle contraction stimulate the sensory endings of thin fiber skeletal muscle afferents. During exercise, stimulation of these afferents initiates a reflex, termed the exercise pressor reflex (EPR), which contributes importantly to reflex increases in sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP). In patients and animals with heart failure with reduced ejection fraction (HF‐rEF), activation of the EPR contributes to exaggerated increases in SNA and is linked to decreased exercise tolerance and increased mortality. The exaggerated EPR in HF‐rEF is attributed, at least in part, to an increased responsiveness of thin fiber skeletal muscle afferents produced by cyclooxygenase (COX) products of arachidonic metabolism. However, the COX metabolite receptors on the sensory endings that mediate the COX‐induced afferent sensitization in HF‐rEF are unknown. Purpose & Hypothesi The purpose of this investigation was to determine the role played by one of the major receptors for products of COX metabolism present on sensory neurons, namely thromboxane A2 receptors (TxA2‐Rs), in the exaggerated EPR in HF‐rEF rats. We tested the hypothesis that injection of the TxA2‐R antagonist daltroban (80μg) into the arterial supply of the hindlimb would reduce the reflex increase in renal SNA (RSNA) and MAP evoked in response to 30 seconds of 1 Hz dynamic hindlimb muscle contraction in HF‐rEF rats, but not control rats. Methods Experiments were performed on male Sprague‐Dawley rats subjected to either a coronary artery ligation surgery to produce myocardial infarction and HF‐rEF or a sham ligation. At least six weeks after the initial surgery, in decerebrate, unanesthetized rats we compared the EPR evoked by electrically induced hindlimb skeletal muscle contraction before and after injection of daltroban into the arterial supply of the hindlimb. Results Ejection fraction was significantly reduced in HF‐rEF (47±3%) compared to sham (84±1%, p<0.01). We found that daltroban reduced the EPR response in HF‐rEF (n=8; peak ΔMAP pre: 17±4; post: 12±2mmHg; P=0.04; peak ΔRSNA pre: 135±55; post: 46±13%; P=0.07), but not in SHAM rats (n=10; peak ΔMAP pre: 13±3; post: 11±2mmHg; P=0.48; peak ΔRSNA pre: 64±17; post: 63±15%; P=0.96;) rats. In a separate group of HF‐rEF rats (n=4), we determined whether systemic circulation of daltroban accounted for the attenuating effects on EPR activation seen when daltroban was injected into the hindlimb arterial supply. We found that intravenous injection of daltroban had no effect on the EPR (peak ΔMAP pre: 26±7; post: 25±7mmHg; P=0.50). In these same four HF‐rEF rats we also found that hindlimb arterial injection of the vehicle for daltroban (0.4mL saline containing 1% DMSO) had no effect on the EPR (peak ΔMAP pre: 23±8; post: 20±6mmHg; P=0.40). Conclusions These data suggest that that TxA2‐R receptors on the sensory endings of muscle afferents contribute to the exaggerated EPR in HF‐rEF. Our data enhance the understanding...