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

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 patients with peripheral artery disease (PAD) 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 patients with PAD, but the specific mechanism(s) of the COX-mediated exaggeration are 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. NEW & NOTEWORTHY We demonstrate that the mechanoreflex is sensitized by the cyclooxygenase (COX) pathway within hindlimb skeletal muscles in the rat chronic femoral artery ligation model of simulated peripheral artery disease (PAD). The mechanism of sensitization appears attributable to increased receptors for COX metabolites on sensory neurons and not increased concentration of COX metabolites. Our data may carry important clinical implications for patients with PAD who demonstrate exaggerated increases in blood pressure during exercise compared with healthy counterparts.

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

“…(2014) compared values between exercise trained and untrained HF‐rEF patients, whereas we compared values between healthy control and HF‐rEF rats, must also be considered. Interestingly, we have reported recently that, compared to control rats, rats with simulated peripheral artery disease develop COX‐mediated chronic mechanoreflex sensitization concurrent with increased EP4‐R and TxA 2 ‐R protein expression in lumbar DRG (Butenas et al., 2019). Considered in conjunction with those recent findings (Butenas et al., 2019), the present results indicate that different rat models of cardiovascular disease ( i.e ., heart failure vs .…”

“…Interestingly, we have reported recently that, compared to control rats, rats with simulated peripheral artery disease develop COX‐mediated chronic mechanoreflex sensitization concurrent with increased EP4‐R and TxA 2 ‐R protein expression in lumbar DRG (Butenas et al., 2019). Considered in conjunction with those recent findings (Butenas et al., 2019), the present results indicate that different rat models of cardiovascular disease ( i.e ., heart failure vs . simulated peripheral artery disease) demonstrate different effects on EP4‐R and TxA 2 ‐R expression in DRG and different mechanisms of COX‐mediated chronic mechanoreflex sensitization.…”

“…Upon completion of in vivo experiments, the left and right L 4 and L 5 DRG and muscle tissue samples (∼20 mg) from the soleus and the white portion of the gastrocnemius muscle of the right hindlimb ( i.e ., the hindlimb not studied in vivo ) were harvested as described previously (Butenas et al., 2019). DRG and muscle tissues were collected in both successful and unsuccessful in vivo experiments resulting in a tissue bank from a total of 54 rats.…”

“…Specifically, we tested the hypothesis that hindlimb arterial injection of either the EP4‐R antagonist L‐161,982 or the TxA 2 ‐R antagonist daltroban would reduce the exaggerated increase in mean arterial pressure (MAP), RSNA and heart rate (HR) during 30 s of static hindlimb skeletal muscle stretch in rats with HF‐rEF, but not healthy (SHAM operated) rats. Furthermore, greater expression of EP4‐Rs and TxA 2 ‐Rs in L 4 and L 5 dorsal root ganglia (DRG) has been implicated in the COX‐mediated exaggeration of the EPR in rats with simulated peripheral artery disease (Butenas et al., 2019; Yamauchi et al., 2013). Thus, we also sought to determine whether rats with HF‐rEF would have greater EP4‐R and TxA 2 ‐R mRNA and protein expression in L 4 and L 5 DRG compared to SHAM rats.…”

“…Prostaglandin E 2 (PGE 2 ) accounts for the largest proportion of COX‐2 products of arachidonic metabolism within skeletal muscle (Berlin, Cronestrand, Nowak, Sonnenfeld, & Wennmalm, 1979). PGE 2 is known to interact with endoperoxide 4 receptors (EP4‐R; Southall & Vasko, 2001) and thromboxane A 2 receptors (TxA 2 ‐R; Gluais, Lonchampt, Morrow, Vanhoutte, & Feletou, 2005), both of which are found on sensory neurons (Butenas, Hopkins, Rollins, Felice, & Copp, 2019; Kopp et al., 2004; Southall & Vasko, 2001; Yamauchi, Kim, Stone, Ruiz‐Velasco, & Kaufman, 2013), and have been demonstrated to play a role in the exaggerated EPR found in a rat model of simulated peripheral artery disease (Leal, McCord, Tsuchimochi, & Kaufman, 2011; Yamauchi et al., 2013). However, the extent to which the receptors contribute to the COX‐mediated chronic mechanoreflex sensitization in HF‐rEF is unknown.…”