TRPV1‐mediated sympathetic responsiveness in hindlimb muscle ischemia

Abstract

Muscle metabolic by‐products stimulate thin fiber muscle afferent nerves and evoke reflex increases in blood pressure and sympathetic activity. We report that chemically sensitive transient receptor potential vanilloid type 1 (TRPV1) channels present on sensory muscle afferent neurons have an important impact on sympathetically mediated cardiovascular responses. In turn responses are exaggerated by an ischemic insult to the muscle. Muscle ischemia was induced by the femoral artery ligation in rats. Our data show that 1) ischemia leads to upregulation of TRPV1 expression in the dorsal root ganglion (DRG); 2) the magnitude of the DRG neuron TRPV1 response induced by capsaicin is greater after ischemia (2.9±0.23 in control vs. 3.9±0.31 nA after ischemia, P<0.05); and 3) RSNA and MAP responses to capsaicin are also enhanced after chronic ischemia (54±11%, 9±3 mmHg in controls vs. 98±13%, 33±5 mmHg after ischemia, P<0.05). These results reveal a novel receptor mechanism by which muscle metabolites enhance the reflex sympathetic responses after the induction of chronic ischemia. Thus, alternations in TRPV1 can contribute to enhanced sympathetically mediated vasoconstriction leading to reduced muscle blood flow and exercise intolerance under circumstances of chronic muscle ischemia associated with a number of disorders such as peripheral vascular disease. (Supported by R01 HL075533, R01 HL078866 and R01 HL060800)