Functional and desensitizing effects of the novel synthetic vanilloid-like agent 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) in the perfused rat hindlimb
Griffiths, CD and Keske, MAV and Szallasi, A and Colquhoun, EQ and Geraghty, DP, Functional and desensitizing effects of the novel synthetic vanilloid-like agent 12-phenylacetate 13-acetate 20-homovanillate (PPAHV) in the perfused rat hindlimb, British Journal of Pharmacology, 131, (7) pp. 1408-1412. ISSN 0007-1188 (2000) [Refereed Article]
1. In the present study, the effects of the novel vanilloid agonist, 12-phenylacetate 13-acetate 20-homovanillate (PPAHV), on oxygen consumption (VO 2) and vascular resistance (perfusion pressure, PP) were investigated in the constant flow, perfused rat hindlimb. The acute desensitizing properties of this novel synthetic agent were also examined. 2. Maximum stimulation of VO 2 was produced by 0.2 ╬╝M PPAHV (╬"AVO 2, 0.83┬▒ 0.06 ╬╝mol g -1 h -1) and was accompanied by mild vasoconstriction (increase in PP; 8.0 ┬▒1.1 mmHg). The highest concentration of PPAHV tested (2 ╬╝M) caused inhibition of VO 2 (╬"VO 2, -2.73┬▒0.51 ╬╝mol g -1 h -1) and strong vasoconstriction (╬"PP, 42.0┬▒ 1.2 mmHg). 3. Capsazepine (10 ╬╝M) caused a parallel shift to the right of both VO 2 and PP concentration-response curves for PPAHV (pK(b)= 5.00), indicative of competitive binding to vanilloid receptors. 4. The stimulation of VO 2 produced by 0.2 ╬╝M PPAHV decreased, but was not completely abolished, after repeated infusion of PPAHV (change in VO 2, first infusion, 0.66┬▒ 0.18 ╬╝mol g -1 h -1; sixth infusion, 0.29┬▒0.08 ╬╝mol g -1 h -1, P<0.05), an acute tachyphylactic response not previously seen with the repeated infusion of other vanilloid analogues. Conversely, the PP response to repeated PPAHV infusion increased (╬"PP, first infusion, 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 VO 2 in the perfused rat hindlimb very similar to that induced by naturally occurring vanilloids. Both effects are blocked by the competitive antagonist capsazepine. Since, the metabolic response to low concentrations of PPAHV (stimulation of VO 2) undergoes tachyphylaxis, the present data suggest that PPAHV desensitizes putative vanilloid receptors in the hindlimb.