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

Abstract

What is the central question of this study? Do endoperoxide 4 and thromboxane A2 receptors, which are receptors for cyclooxygenase products of arachidonic metabolism, on thin fibre muscle afferents play a role in the chronic mechanoreflex sensitization present in rats with heart failure with reduced ejection fraction (HF-rEF)? What is the main finding and its importance? The data do not support a role for endoperoxide 4 receptors or thromboxane A2 receptors in the chronic mechanoreflex sensitization in HF-rEF rats. We investigated the role of cyclooxygenase metabolite-associated endoperoxide 4 receptors (EP4-R) and thromboxane A2 receptors (TxA2 -R) on thin fibre muscle afferents in the chronic mechanoreflex sensitization in rats with myocardial infarction-induced heart failure with reduced ejection fraction (HF-rEF). We hypothesized that injection of either the EP4-R antagonist L-161,982 (1µg) or the TxA2 -R antagonist daltroban (80µg) into the arterial supply of the hindlimb would reduce the increase in blood pressure and renal sympathetic nerve activity (RSNA) evoked in response to 30s of static hindlimb skeletal muscle stretch (a model of isolated mechanoreflex activation) in decerebrate, unanaesthetized HF-rEF rats but not sham-operated control rats (SHAM). Ejection fraction was significantly reduced in HF-rEF (45±11%) compared to SHAM (83±6%; P<0.01) rats. In SHAM and HF-rEF rats, we found that the EP4-R antagonist had no effect on the peak increase in mean arterial pressure (peak ΔMAP SHAM n=6, pre: 15±7, post: 15±9, P=0.99; HF-rEF n=9, pre: 30±11, post: 32±15mmHg, P=0.84) or peak increase in RSNA (peak ΔRSNA SHAM pre: 33±14, post: 47±31%, P=0.94; HF-rEF, pre: 109±47, post: 139±150%, P=0.76) response to stretch. Similarly, in SHAM and HF-rEF rats, we found that the TxA2 -R antagonist had no effect on the peak ΔMAP (SHAM n=7, pre: 13±7, post: 19±14, P=0.15; HF-rEF n=14, pre: 24±13, post: 21±13mmHg, P=0.47) or peak ΔRSNA (SHAM pre: 52±43, post: 57±67%, P=0.94; HF-rEF, pre: 108±93, post: 88±72%, P=0.30) response to stretch. The data do not support a role for EP4-Rs or TxA2 -Rs in the chronic mechanoreflex sensitization in HF-rEF.