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

Abstract

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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.…”

Effect of Cyclooxygenase Inhibition on Peripheral Venous Distension Reflex in Healthy Humans

“…Cyclooxygenase, the target of nonsteroidal anti-inflammatory drugs, is the enzyme catalyzing the formation of prostaglandin H 2 from arachidonic acid. 25 Prostaglandin H 2 (eg, prostaglandin E 2 , 26 TXA 2 20 ) works as the precursor for prostaglandins and thromboxanes. TXB 2 is a stable inactive metabolite of TXA 2 , which is commonly measured to assess prostaglandin synthesis inhibition.…”

“…We speculate that decreased levels of cyclooxygenase products by ketorolac attenuated the stimulation of afferent group III and IV nerves that innervate the veins. Cyclooxygenase products (eg, prostaglandin E 2 , 26 TXA 2 20 ) are thought to sensitize and directly stimulate afferent group III and IV nerves 3,20 and nociceptors. 26 Interestingly, fluid sheer stress is suggested to induce upregulation of cyclooxygenase and prostaglandins, 32–34 although fluid sheer stress may also induce the deformation of blood vessels.…”

“…15 Metabolites of arachidonic acid produced via the cyclooxygenase enzyme system (ie, prostaglandins and thromboxane) have been recognized to contribute to activation of group III and IV nerve afferents during muscle contraction. 16–18 Notably, cyclooxygenase blockade attenuated sympathetic and BP responses to exercise/muscle contraction in animals 19,20 and in healthy humans. 21,22 However, the effect of cyclooxygenase blockade on the VDR in humans is still unknown.…”