Thromboxane A2 receptors mediate chronic mechanoreflex sensitization in a rat model of simulated peripheral artery disease

Abstract

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 patients with peripheral artery disease (PAD) 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 h 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 Δmean 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. NEW & NOTEWORTHY We demonstrate that thromboxane A₂ receptors, but not endoperoxide 4 receptors, on the sensory endings of thin fiber muscle afferents contribute to the chronic sensitization of the muscle mechanoreflex in rats with a ligated femoral artery (a model of simulated peripheral artery disease). The data may have important implications for our understanding of blood pressure control during exercise in patients with peripheral artery disease.