Thromboxane A ₂ Receptors Contribute to the Exaggerated Exercise Pressor Reflex in Rats with Heart Failure

Abstract

Background Mechanical and metabolic signals associated with skeletal muscle contraction stimulate the sensory endings of thin fiber skeletal muscle afferents. During exercise, stimulation of these afferents initiates a reflex, termed the exercise pressor reflex (EPR), which contributes importantly to reflex increases in sympathetic nerve activity (SNA) and mean arterial blood pressure (MAP). In patients and animals with heart failure with reduced ejection fraction (HF‐rEF), activation of the EPR contributes to exaggerated increases in SNA and is linked to decreased exercise tolerance and increased mortality. The exaggerated EPR in HF‐rEF is attributed, at least in part, to an increased responsiveness of thin fiber skeletal muscle afferents produced by cyclooxygenase (COX) products of arachidonic metabolism. However, the COX metabolite receptors on the sensory endings that mediate the COX‐induced afferent sensitization in HF‐rEF are unknown. Purpose & Hypothesi The purpose of this investigation was to determine the role played by one of the major receptors for products of COX metabolism present on sensory neurons, namely thromboxane A2 receptors (TxA2‐Rs), in the exaggerated EPR in HF‐rEF rats. We tested the hypothesis that injection of the TxA2‐R antagonist daltroban (80μg) into the arterial supply of the hindlimb would reduce the reflex increase in renal SNA (RSNA) and MAP evoked in response to 30 seconds of 1 Hz dynamic hindlimb muscle contraction in HF‐rEF rats, but not control rats. Methods Experiments were performed on male Sprague‐Dawley rats subjected to either a coronary artery ligation surgery to produce myocardial infarction and HF‐rEF or a sham ligation. At least six weeks after the initial surgery, in decerebrate, unanesthetized rats we compared the EPR evoked by electrically induced hindlimb skeletal muscle contraction before and after injection of daltroban into the arterial supply of the hindlimb. Results Ejection fraction was significantly reduced in HF‐rEF (47±3%) compared to sham (84±1%, p<0.01). We found that daltroban reduced the EPR response in HF‐rEF (n=8; peak ΔMAP pre: 17±4; post: 12±2mmHg; P=0.04; peak ΔRSNA pre: 135±55; post: 46±13%; P=0.07), but not in SHAM rats (n=10; peak ΔMAP pre: 13±3; post: 11±2mmHg; P=0.48; peak ΔRSNA pre: 64±17; post: 63±15%; P=0.96;) rats. In a separate group of HF‐rEF rats (n=4), we determined whether systemic circulation of daltroban accounted for the attenuating effects on EPR activation seen when daltroban was injected into the hindlimb arterial supply. We found that intravenous injection of daltroban had no effect on the EPR (peak ΔMAP pre: 26±7; post: 25±7mmHg; P=0.50). In these same four HF‐rEF rats we also found that hindlimb arterial injection of the vehicle for daltroban (0.4mL saline containing 1% DMSO) had no effect on the EPR (peak ΔMAP pre: 23±8; post: 20±6mmHg; P=0.40). Conclusions These data suggest that that TxA2‐R receptors on the sensory endings of muscle afferents contribute to the exaggerated EPR in HF‐rEF. Our data enhance the understanding...

Novel mechanosensory role for acid sensing ion channel subtype 1a in evoking the exercise pressor reflex in rats with heart failure

“…The present study was powered only to investigate the effect of ASIC1a blockade within the SHAM and HF‐rEF groups and the across‐group comparisons were left underpowered. Importantly, the available literature consistently demonstrates that, compared to SHAM counterparts, the reflex responses to hindlimb muscle contraction and stretch are exaggerated in the rat myocardial infarction‐induced model of HF‐rEF (Butenas et al., 2020, 2021b, 2021c; Koba et al., 2008, 2009, 2010; Morales et al., 2012; Smith et al., 2003; Smith, Mitchell et al., 2005; Smith, Williams et al., 2005; Wang, Pan et al., 2010). We do report the statistical comparison of the pressor response to lactic acid injection between SHAM and HF‐rEF groups because, to our knowledge, this is the first investigation to report the reflex pressor and RSNA response to a bolus injection of lactic acid into the arterial supply of the hindlimb of HF‐rEF rats.…”

“…In comparison to healthy subjects, activation of the exercise pressor reflex in patients/animals with heart failure with reduced ejection fraction (HF‐rEF) results in an exaggerated increase in SNA (Butenas et al., 2021c; Koba et al., 2008; Middlekauff et al., 2004; Wang, Pan et al., 2010) and altered cardiovascular responses (Amann et al., 2014; Ansorge et al., 2004; Hammond et al., 2000; Piepoli et al., 1996; Sterns et al., 1991), which include augmented peripheral (Amann et al., 2014; Smith et al., 2020) and coronary (Ansorge et al., 2004) vasoconstriction. Thus, whereas activation of the exercise pressor reflex in healthy subjects supports exercise performance (Amann, Blain et al., 2011; O'Leary et al., 1999), activation of the reflex in HF‐rEF patients likely contributes to exacerbated fatigue, exercise intolerance and elevated cardiovascular risk.…”