Chronic Ablation of Hindlimb Afferents Containing TRPV1 Receptors Attenuates Cardiovascular Responses to Muscle Metaboreflex Activation

Increases in sympathetic nerve activity during exercise occur, in part, due to activation of the muscle metaboreflex – a pressor reflex triggered via stimulation of type III and IV skeletal muscle afferents. Some of these afferents express capsaicin sensitive transient receptor potential vanilloid 1 (TRPV1) channels. Epicardial and intrathecal administration of resiniferatoxin (RTX), an ultra‐potent analog of capsaicin, attenuates responses to cardiac sympathetic afferent activation and provides relief of limb pain due to bone cancer. We investigated whether administration of intrathecal RTX (2μg/kg, L4–L6) would attenuate the muscle metaboreflex (induced by partial reductions in hindlimb blood flow during steady‐state mild exercise; 3.2 km/h). Experiments were performed using conscious, chronically instrumented canines before and 10–42 days after RTX. RTX markedly attenuated metaboreflex‐induced increases in mean arterial pressure (+27.0 ± 5.0 mmHg vs. +5.9 ± 8.2 mmHg) and cardiac output (+1.40 ± 0.20 l/min vs. +0.28 ± 0.12 l/min). Terminal experiments under isoflurane anesthesia performed 78 ± 14 days after RTX showed attenuated pressor responses to hindlimb intra‐arterial infusion of 20μg/kg capsaicin (+45.7 ± 6.5 mmHg pre RTX vs. +19.7 ± 3.1 mmHg post RTX). We conclude that intrathecal RTX chronically attenuates muscle metaboreflex pressor responses. Thus, RTX could be an effective treatment to reduce excessive sympatho‐activation often seen during exercise in patients with heart failure or other diseases when the metaboreflex is overstimulated due to underperfusion of the active skeletal muscle. Support or Funding Information HL‐55473, HL‐126706, HL‐120822 and GM‐058905