Endoperoxide 4 receptor inhibition has no effect on the pressor response evoked during isolated mechanoreflex activation in rats with heart failure
Authors: Butenas Alec Lloyd Edward , Rollins Korynne S. , Felice Kennedy P. , Ade Carl J. , Musch Timothy I. , Copp Steven W. 
Published: April 2020

BackgroundThe stimulation of primarily mechanically sensitive group III and primarily metabolically sensitive group IV muscle afferents during skeletal muscle contractions evokes reflex increases in blood pressure (i.e., the exercise pressor reflex) and facilitates exercise performance. Heart failure patients with reduced ejection fraction (HF‐rEF) exhibit an exaggerated exercise pressor reflex, leading to excessive peripheral vasoconstriction and impaired limb blood flow during exercise. The exaggerated exercise pressor reflex in HF‐rEF is attributed, at least in part, to an exaggeration of the mechanically sensitive portion of the reflex (i.e., the mechanoreflex). Furthermore, multiple lines of evidence suggest that, in HF‐rEF, the mechanoreflex sensitization is attributable to the cyclooxygenase products of arachidonic acid metabolism. For example, recent evidence in a rat model of HF‐rEF induced by myocardial infarction demonstrated that the exaggerated rise in renal sympathetic nerve activity during hindlimb muscle stretch (a model of mechanoreflex activation) was significantly reduced following inhibition of the COX‐2 isoform that predominately produces prostaglandin E2 (PGE2). However, the COX metabolite receptor on sensory neurons that mediated the PGE2‐induced mechanoreflex sensitization in HF‐rEF is not known.Purpose & HypothesisOur purpose was to determine the effect of inhibition of the PGE2 receptor endoperoxide 4 (EP4) on mechanoreflex activation in rats with HF‐rEF. We hypothesized that hindlimb arterial injection of the EP4 receptor antagonist L‐161,982 would reduce the exaggerated increase in MAP during 30 s of static hindlimb muscle stretch in rats with HF‐rEF, but not in healthy control rats.MethodsWe utilized a rat model of HF‐rEF in which the left main coronary artery is ligated with 5‐0 suture to induce myocardial infarction (n=7). Control rats (n=3) were subjected to a sham ligation in which the suture was passed under the artery but not tied. At least four weeks after the initial surgery, in decerebrate, unanesthetized rats we compared (paired Student’s t‐tests) the pressor response (peak ΔMAP) evoked during muscle stretch before and after the injection of L‐161,982 (1 μg) into the arterial supply of the hindlimb circulation.ResultsEjection fraction determined via echocardiography was significantly reduced in HF‐rEF rats (35±6%) compared to sham rats (82±2%, p<0.01, unpaired Student’s t‐test). We found that EP4 receptor inhibition had no effect during hindlimb muscle stretch on the peak ΔMAP in either HF‐rEF rats (pre: 24±4; post: 26±6mmHg; p=0.74) or sham rats (pre: 13±3; post: 11±2mmHg; p=0.23). Moreover, western blot analysis revealed no difference between HF‐rEF and sham rats in protein expression of EP4 receptor within the L4 and L5 dorsal root ganglia (unpaired Student’s t‐test; p=0.25).ConclusionsThe present data suggest that that EP4 receptors do not contribute to the exaggerated mechanoreflex evoked in rats with HF‐rEF. Our data enhance the understanding of the blood pressure control during exercise in the ~6 million Americans currently diagnosed with HF‐rEF.Support or Funding InformationNational Institutes of Health Grant HL‐142877 to SWC