Cyclooxygenase inhibition does not impact the pressor response during static or dynamic mechanoreflex activation in healthy decerebrate rats

Abstract

Passive limb movement and limb muscle stretch in humans and animals are common experimental strategies used to investigate activation of the muscle mechanoreflex independent of contraction-induced metabolite production. Cyclooxygenase (COX) metabolites, however, are produced by skeletal muscle stretch in vitro and have been found to impact various models of mechanoreflex activation. Whether COX metabolites influence the decerebrate rat triceps surae muscle stretch mechanoreflex model remains unknown. We examined the effect of rat triceps surae muscle stretch on the interstitial concentration of the COX metabolite prostaglandin E2 (PGE2). Interstitial PGE2 concentration was increased above baseline values by 4 min of both static (38% increase, P = 0.01) and dynamic (56% increase, P < 0.01) triceps surae muscle stretch ( n = 10). The 4-min protocol was required to collect enough microdialysis fluid for PGE2 detection. The finding that skeletal muscle stretch in vivo was capable of producing COX metabolites prompted the hypothesis that intra-arterial administration of the COX inhibitor indomethacin (1 mg/kg) would reduce the pressor and cardioaccelerator responses evoked during 30 s (the duration most commonly used in the rat mechanoreflex model) of static and dynamic rat triceps surae muscle stretch. We found that indomethacin had no effect ( P > 0.05, n = 9) on the pressor or cardioaccelerator response during 30 s of either static or dynamic stretch. We conclude that, despite the possibility of increased COX metabolite concentration, COX metabolites do not activate or sensitize thin-fiber muscle afferents stimulated during 30 s of static or dynamic hindlimb skeletal muscle stretch in healthy rats.

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

“…Effect of Indo on the mechanoreflex. Consistent with our recent findings (45), in freely perfused rats (n ϭ 6), the injection of Indo into the arterial supply of the hindlimb had no effect on the pressor or cardioaccelerator response during dynamic stretch (Fig. 1, A-D).…”

“…In a subset of 10 of the 14 rats used in these microdialysis experiments, we subsequently measured microdialysate PGE 2 concentration during stretch of the freely perfused and ligated hindlimb. The 1-Hz dynamic stretch protocols of the freely perfused and ligated hindlimb were performed for 4 min [which was re-quired to collect enough fluid to measure PGE 2 concentration in duplicate (45)], in random order, and with at least 10 min of recovery in between each stretch maneuver. We did not perform the stretch protocols in the four rats in which a superficial epigastric artery catheter and iliac artery and vein snare were previously placed.…”

“…Specifically, in decerebrate, unanesthetized rats with a ligated femoral artery, we tested the hypothesis that local injection of the COX inhibitor indomethacin (Indo) into the arterial supply of a hindlimb would reduce the exaggerated pressor response evoked during 1-Hz dynamic hindlimb muscle stretch. Conversely, based on our recent findings (45), we hypothesized that Indo would have no effect on the pressor response during hindlimb muscle stretch in rats with freely perfused femoral arteries. We also investigated the effect of chronic femoral artery ligation on hindlimb skeletal muscle COX protein expression and activity, skeletal muscle interstitial concentration of the COX metabolite prostaglandin E 2 (PGE 2 ), and protein expression of the COX metabolite receptors endoperoxide (EP) 4 and the thromboxane A2 (TxA 2 ) receptor in L 4 and L 5 DRG.…”

No effect of endoperoxide 4 or thromboxane A2 receptor blockade on static mechanoreflex activation in rats with heart failure

“…Our finding in sham rats that the injection of the EP4-R or the TxA 2 -R antagonist into the arterial supply of the hindlimb had no effect on the pressor, RSNA or cardioaccelerator response to static stretch is consistent with multiple investigations which have shown that COX metabolites are not required to produce reflex cardiovascular responses in healthy subjects (Butenas et al, 2019;Drew, Blaha, Herr, Cui, & Sinoway, 2017;Morales et al, 2012;Muller et al, 2015;Rollins et al, 2019). More specifically, the present lack of effect of the EP4-R antagonist in SHAM rats is consistent with the recent of findings of Yamauchi et al (2013) using the same mode of mechanoreflex activation, and our laboratory using a dynamic mode of mechanoreflex activation (Rollins et al, 2020) in healthy control rats.…”

“…HR was measured by electrocardiogram (ADInstruments, Colorado Springs, CO, USA). The left superficial epigastric artery was cannulated with a PE‐8 catheter whose tip was placed near the junction of the superficial epigastric and femoral arteries and a reversible snare (2‐0 silk suture) was placed around the left iliac artery and vein as previously described (Rollins et al., 2019). The left calcaneal bone was severed and linked by string to a force transducer (Grass FT03; West Warwick, RI, USA), which, in turn, was attached to a rack and pinion.…”