Thromboxane A2 Receptors Contribute to the Exaggerated Mechanoreflex in a Rat Model of Peripheral Artery Disease
Authors: Rollins Korynne Sierra , Butenas Alec L. , Felice Kennedy P. , Copp Steven W. 
Published: April 2020

BackgroundThe exercise pressor reflex is evoked by mechanical and metabolic signals associated with skeletal muscle contraction which reflexly increase sympathetic nervous system activity and blood pressure. The reflex is exaggerated in multiple forms of cardiovascular disease. The mechanical portion of the exercise pressor reflex (i.e., the mechanoreflex) specifically contributes to the exaggerated reflex in peripheral artery disease (PAD) which is clinically important because its activation increases a patient’s risk of cardiac ischemia and fibrillation. Our laboratory uses a rat model of simulated PAD in which a femoral artery is ligated for ~72 hours to investigate the mechanisms of mechanoreflex exaggeration in PAD. We found recently that, in the ligated rat model of PAD, cyclooxygenase (COX) inhibition with indomethacin reduced the exaggerated pressor response evoked during 1 Hz dynamic hindlimb skeletal muscle stretch (a model of mechanoreflex activation in the absence of contraction‐induced metabolite production). Indomethacin had no effect in control “freely perfused” rats. What remains unknown are the COX metabolite receptors on muscle afferents that underlie the COX‐mediated mechanoreflex sensitization in the ligated rat model of simulated PAD.Purpose and HypothesisOur purpose was to investigate the role played by the COX metabolite endoperoxide 4 receptors (EP4‐R) and thromboxane A2 receptors (TxA2‐R) in the exaggerated mechanoreflex present in the ligated femoral artery rat model of simulated PAD. We hypothesized that TxA2‐R and EP4‐R blockade would reduce the exaggerated pressor response evoked during 30 s of dynamic hindlimb muscle stretch in rats with a ligated femoral artery. Conversely, we hypothesized no effect of TxA2‐R and EP4‐R blockade in control rats with freely perfused femoral arteries.MethodsWe compared (paired Student’s t‐tests) the pressor response (peak Δ mean arterial blood pressure) evoked during muscle stretch before and after the injection of L161982 (EP4‐R blockade, 1 μg) or daltroban (TxA2‐R blockade, 80 μg) into the arterial supply of the hindlimb circulation of decerebrate, unanesthetized rats.ResultsWe found that EP4‐R blockade had no effect on the pressor response during stretch in either freely perfused (n=6, pre: 14±2, post: 15±2 mmHg, p=0.72) or ligated (n=8, pre: 29±4, post: 29±6 mmHg, p=0.90) rats. In contrast, we found that TxA2‐R blockade had no effect on the pressor response during stretch in freely perfused rats (n=6, pre: 16±3, post: 17±4 mmHg, p=0.85) but reduced the pressor response during stretch in ligated rats (n=11, pre: 29±4, post: 17±5 mmHg, p<0.01).ConclusionWe conclude that TxA2‐R, but not EP4‐R, contribute to the exaggerated mechanoreflex in the ligated rat model of simulated PAD. The present data enhance our understanding of the mechanisms contributing to the exaggerated mechanoreflex, and therefore blood pressure responses, during exercise in PAD patients.Support or Funding InformationNIH grant HL142877 to SWC