CAPSAICIN-INDUCED BIPHASIC OXYGEN-UPTAKE IN RAT MUSCLE - ANTAGONISM BY CAPSAZEPINE AND RUTHENIUM RED PROVIDES FURTHER EVIDENCE FOR PERIPHERAL VANILLOID RECEPTOR SUBTYPES (VN1 VN2)/

Previous studies with the vanilloid spice principle capsaicin have dem onstrated a biphasic VO2 response, with vasoconstriction, in the perfu sed rat hindlimb that has led to suggestions of vanilloid receptor sub types (VN1/VN2) in this preparation (1). In the present study, the kno wn competitive vanilloid antagonist capsazepine inhibited the above ca psaicin-mediated effects in a manner that was indicative of binding at specific vanilloid recognition sites. Low concentrations of capsazepi ne selectively inhibited the increased VO2 produced by the putative VN 1 receptor at submicromolar concentrations of capsaicin, while the inh ibition of VO2 produced by high concentrations of capsaicin (putative VN2) was enhanced. These observations, showing different susceptibilit ies to blockade by capsazepine, further support the presence of two va nilloid receptor subtypes in the rat hindlimb. Schild plots of the dat a yielded variable slopes that approach unity at greater responses to capsaicin (mean K-B = 8.44 +/- 2.08 mu M and 7.28 +/- 0.78 mu M for VO 2 and perfusion pressure curves, respectively). Low concentrations of the capsaicin antagonist ruthenium red selectively blocked the putativ e VN2 receptor-mediated effects produced by high concentrations of cap saicin. The noncompetitive nature of this inhibitor suggests an operat ion through separate receptor-coupled ion channel complexes at high an d low concentrations of the vanilloid. Tetrodotoxin failed to attenuat e any changes produced by capsaicin, suggesting that the mechanism of action of capsaicin in the rat hindlimb may differ from other tissues.