Chronic Ablation of TRPV1 Sensitive Skeletal Muscle Afferents Attenuates the Muscle Metaboreflex
Exercise intolerance is a hallmark symptom of cardiovascular disease and likely occurs via enhanced activation of muscle metaboreflex- induced vasoconstriction of the heart and active skeletal muscle which, thereby limits cardiac output and peripheral blood flow. Muscle metaboreflex vasoconstrictor responses occur via activation of metabolite-sensitive afferent fibers located in ischemic active skeletal muscle, some of which express Transient Receptor Potential Vanilloid 1 (TRPV1) cation channels. Local cardiac and intrathecal administration of an ultra-potent noncompetitive, dominant negative agonist resiniferatoxin (RTX) can ablate these TRPV1 sensitive afferents. This technique has been used to attenuate cardiac sympathetic afferents and nociceptive pain. We investigated whether intrathecal administration (L4-L6) of RTX (2 μg/kg) could chronically attenuate subsequent muscle metaboreflex responses elicited by reductions in hindlimb blood flow during mild exercise (3.2 km/h) in chronically instrumented conscious canines. RTX significantly attenuated metaboreflex induced increases in mean arterial pressure (27 ± 5.0 mmHg vs. 6 ± 8.2 mmHg), cardiac output (1.40 ± 0.2 L/min vs. 0.28 ± 0.1 L/min) and stroke work (2.27 ± 0.2 L*mmHg vs. 1.01 ± 0.2 L*mmHg). Effects were maintained until 78 ± 14 days post RTX at which point the efficacy of RTX injection was tested by intra-arterial administration of capsaicin (20 μg/kg). A significant reduction in the mean arterial pressure response (+45.7 ± 6.5 mmHg pre RTX vs +19.7 ± 3.1mmHg post RTX) was observed. We conclude that intrathecal administration of RTX can chronically attenuate the muscle metaboreflex and could potentially alleviate enhanced sympatho-activation observed in cardiovascular disease states.