Exaggerated sympathetic and cardiovascular responses to dynamic mechanoreflex activation in rats with heart failure: Role of endoperoxide 4 and thromboxane A2 receptors

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

“…Thus, we believe the dynamic hindlimb muscle contraction maneuver is an excellent experimental model that can be used to study the EPR with substantial contribution from the mechanoreflex. In this regard, our present findings that the sympathetic and cardiovascular responses to dynamic muscle contraction were exaggerated in HF-rEF rats compared to SHAM rats builds upon our previous findings which showed that the sympathetic and cardiovascular responses to 1 Hz dynamic skeletal muscle stretch were exaggerated in HF-rEF rats compared to SHAM rats (Butenas, Rollins, et al, 2021). Our findings are also consistent with reports of greater sympathetic responses to single, 1 s hindlimb muscle contractions in HF-rEF rats compared to sham rats (Koba et al, 2008).…”

“…Given we found no difference in TxA 2 -R expression within lumbar DRG or basal COX metabolites within the skeletal muscle interstitial space between SHAM and HF-rEF rats, how may we explain the effect of TxA 2 -R blockade on the sympathetic and cardiovascular responses to hindlimb muscle contraction (present study) and hindlimb muscle stretch (Butenas, Rollins, et al, 2021)? It is possible that the site of amplification of the TxA 2 -R signaling in HF-rEF resides within the intracellular pathways within the sensory neuron endings.…”

“…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). We therefore concluded that TxA 2 -Rs on the sensory endings of thin fiber muscle afferents contribute to a chronic sensitization of the mechanically activated channels that underlie dynamic/rhythmic mechanoreflex activation.…”

“…Several critical extensions of our recent work summarized above (Butenas, Rollins, et al, 2021) remains to be investigated. First, although the hindlimb muscle stretch model of mechanoreflex activation may provide valuable information regarding the presence of chronic mechanoreflex sensitization in rats with HF-rEF, the model activates mechanically activated channels in a nonphysiological manner.…”