Functional and desensitizing effects of the novel synthetic vanilloid-likeagent 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) in the perfusedrat hindlimb

1 In the present study, the effects of the novel vanilloid agonist, 12-phen ylacetate 13-acetate 20-homovanillate (PPAHV), on oxygen consumption (VO2) and vascular resistance (perfusion pressure, PP) were investigated in the c onstant flow, perfused rat hindlimb. The acute desensitizing properties of this novel synthetic agent were also examined. 2 Maximum stimulation of VO2 was produced by 0.2 muM PPAHV (Delta VO2, 0.83 +/- 0.06 mu mol g(-1) h (1)) and was accompanied by mild vasoconstriction (increase in PP; 8.0 +/- 1.1 mmHg). The highest concentration of PPAHV test ed (2 muM) caused inhibition of VO2 (Delta VO2. -2.73+/-0.51 mu mol g(-1) h (-1)) and strong vasoconstriction (Delta PP, 42.0+/-1.2 mmHg). 3 Capsazepine (10 muM) caused a parallel shift to the right of both VO2 and PP concentration-response curves for PPAHV (pK(b) = 5.00), indicative of c ompetitive binding to vanilloid receptors. 4 The stimulation of VO2 produced by 0.2 muM PPAHV decreased, but was not c ompletely abolished, after repeated infusion of PPAHV (change in VO2, first infusion, 0.66+/- 0.18 mu mol g (1) h (1): sixth infusion, 0.29+/-0.08 mu mol g(-1) h(-1), P<0.05), an acute tachyphylactic response not previously s een with the repeated infusion of other vanilloid analogues. Conversely, th e PP response to repeated PPAHV infusion increased (<Delta>PP, first infusi on, 5.8+/-0.7 mmHg; sixth infusion. 9.0+/-0.6 mmHg, P<0.05). 5 In conclusion, PPAHV produces vasoconstriction and a biphasic effect on V O2 in the perfused rat hindlimb very similar to that induced by naturally o ccurring vanilloids. Both effects are blocked by the competitive antagonist capsazepine. Since, the metabolic response to low concentrations of PPAHV (stimulation of VO2) undergoes tachyphylaxis, the present data suggest that PPAHV desensitizes putative vanilloid receptors in the hindlimb.