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Investigation of the mechanisms of cyclooxygenase-mediated mechanoreflex sensitization in a rat model of simulated peripheral artery disease.

Alec L. E. Butenas,Tyler D. Hopkins,K. Rollins,Kennedy P. Felice,Steven W Copp

Published 2019 in American Journal of Physiology. Heart and Circulatory Physiology

ABSTRACT

Mechanical and metabolic stimuli within contracting skeletal muscles reflexly increase sympathetic nervous system activity and blood pressure. That reflex, termed the exercise pressor reflex, is exaggerated in peripheral artery disease (PAD) patients and in a rat PAD model with a chronically ligated femoral artery. The cyclooxygenase (COX) pathway contributes to the exaggerated pressor response during rhythmic skeletal muscle contractions in PAD patients but the specific mechanism(s) of the COX-mediated exaggeration is not known. In decerebrate, unanesthetized rats with a chronically ligated femoral artery ("ligated" rats), we hypothesized that hindlimb arterial injection of the COX inhibitor indomethacin would reduce the pressor response during 1 Hz dynamic hindlimb skeletal muscle stretch; a model of the activation of the mechanical component of the exercise pressor reflex (i.e., the mechanoreflex). In ligated rats (n=7), indomethacin reduced the pressor response during stretch (control: 30±4, indomethacin: 12±3 mmHg; p<0.01) whereas there was no effect in rats with "freely perfused" femoral arteries (n=6, control: 18±5, indomethacin: 17±5 mmHg; p=0.87). In ligated rats (n=4), systemic indomethacin injection had no effect on the pressor response during stretch. Femoral artery ligation had no effect on skeletal muscle COX protein expression or activity, or concentration of the COX metabolite prostaglandin E2. Conversely, femoral artery ligation increased expression of the COX metabolite receptors endoperoxide 4 and thromboxane A2-R in dorsal root ganglia tissue. We conclude that, in ligated rats, the COX pathway sensitizes the peripheral endings of mechanoreflex afferents which occurs principally as a result of increased expression of COX metabolite receptors.

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