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

Abstract

New Findings 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. Abstract 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 (1 µg) or the TxA2‐R antagonist daltroban (80 µg) into the arterial supply of the hindlimb would reduce the increase in blood pressure and renal sympathetic nerve activity (RSNA) evoked in response to 30 s 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 ± 15 mmHg, 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 ± 13 mmHg, 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.

Thromboxane A 2 receptors contribute to the exaggerated exercise pressor reflex in male rats with heart failure

“…; p = 0.51) within L 4 and L 5 DRG tissue. This was an important reproduction and confirmation of the same findings reported in our recent investigation (Butenas et al, 2020 ).…”

“…We found no difference between SHAM (n = 4) and HF-rEF (n = 4) rats in TxA 2 -R protein within L 4 and L 5 DRG tissue. This was an important reproduction and confirmation of the same findings reported in our recent investigation (Butenas et al, 2020).…”

“…The left ventricular fractional shortening (FS), ejection fraction (EF), end diastolic volume (LVEDV), end systolic volume (LVESV), and stroke volume (SV) were determined by echocardiographic measurements as previously described (Baumfalk et al, 2021). Rats with HF-rEF were required to meet an inclusion criterion of either an FS ≤30% and/or a left ventricular infarct size of ≥15%, which is consistent with values previously reported from our laboratory (Butenas, Colburn, et al, 2021;Butenas et al, 2020;Butenas, Rollins, et al, 2021). We have previously shown that, compared with SHAMoperated healthy control rats, HF-rEF rats that meet similar criterion have a reduced maximal oxygen uptake and time to exhaustion to treadmill running (Butenas, Colburn, et al, 2021).…”

“…Previously, we demonstrated in HF-rEF rats that hindlimb arterial injection of the TxA 2 -R antagonist daltroban reduced the sympathetic and cardiovascular responses to 1 Hz dynamic skeletal muscle stretch (Butenas, Rollins, et al, 2021), but not static hindlimb skeletal muscle stretch (Butenas et al, 2020). We speculated that those contrasting findings in HF-rEF rats pertaining to the role played by TxA 2 -Rs during different mechanoreflex modalities (i.e., static stretch vs. dynamic stretch) were best explained by the fact that these different modalities may activate substantially different classes of mechanically activated channels (for discussion, see: Butenas, Rollins, et al, 2021).…”

“…The mechanically sensitive portion of the EPR (i.e., the mechanoreflex) contributes importantly to the overall EPR exaggeration in HF‐rEF (Butenas et al, 2020 ; Koba et al, 2008 ; Middlekauff et al, 2001 ; Morales et al, 2012 ; Smith et al, 2005 ). Our laboratory has used a dynamic rat hindlimb skeletal muscle stretch experimental model, adapted from Stebbins et al ( 1988 ); (Daniels et al, 2000 ), to study the mechanisms of mechanoreflex activation isolated from contraction‐induced metabolic influence (Butenas et al, 2019 ; Kempf et al, 2018 ; Rollins et al, 2019 , 2020 ; Sanderson et al, 2019 ).…”