Article date: December 2000
By: Cory D Griffiths, Michelle A Vincent, Arpad Szallasi, Eric Q Colquhoun, Dominic P Geraghty in Volume 131, Issue 7, pages 1408-1412
In the present study, the effects of the novel vanilloid agonist, 12‐phenylacetate 13‐acetate 20‐homovanillate (PPAHV), on oxygen consumption (VO2) 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.
Maximum stimulation of VO2 was produced by 0.2 μM PPAHV (ΔVO2, 0.83±0.06 μmol 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 μM) caused inhibition of VO2 (ΔVO2, −2.73±0.51 μmol g−1 h−1) and strong vasoconstriction (ΔPP, 42.0±1.2 mmHg).
Capsazepine (10 μM) caused a parallel shift to the right of both VO2 and PP concentration‐response curves for PPAHV (pKb=5.00), indicative of competitive binding to vanilloid receptors.
The stimulation of VO2 produced by 0.2 μM PPAHV decreased, but was not completely abolished, after repeated infusion of PPAHV (change in VO2, first infusion, 0.66±0.18 μmol g−1 h−1; sixth infusion, 0.29±0.08 μmol 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 (ΔPP, first infusion, 5.8±0.7 mmHg; sixth infusion, 9.0±0.6 mmHg, P<0.05).
In conclusion, PPAHV produces vasoconstriction and a biphasic effect on VO2 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 VO2) undergoes tachyphylaxis, the present data suggest that PPAHV desensitizes putative vanilloid receptors in the hindlimb.
In the present study, the effects of the novel vanilloid agonist, 12‐phenylacetate 13‐acetate 20‐homovanillate (PPAHV), on oxygen consumption (VO2) 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.
Maximum stimulation of VO2 was produced by 0.2 μM PPAHV (ΔVO2, 0.83±0.06 μmol 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 μM) caused inhibition of VO2 (ΔVO2, −2.73±0.51 μmol g−1 h−1) and strong vasoconstriction (ΔPP, 42.0±1.2 mmHg).
Capsazepine (10 μM) caused a parallel shift to the right of both VO2 and PP concentration‐response curves for PPAHV (pKb=5.00), indicative of competitive binding to vanilloid receptors.
The stimulation of VO2 produced by 0.2 μM PPAHV decreased, but was not completely abolished, after repeated infusion of PPAHV (change in VO2, first infusion, 0.66±0.18 μmol g−1 h−1; sixth infusion, 0.29±0.08 μmol 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 (ΔPP, first infusion, 5.8±0.7 mmHg; sixth infusion, 9.0±0.6 mmHg, P<0.05).
In conclusion, PPAHV produces vasoconstriction and a biphasic effect on VO2 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 VO2) undergoes tachyphylaxis, the present data suggest that PPAHV desensitizes putative vanilloid receptors in the hindlimb.
British Journal of Pharmacology (2000) 131, 1408–1412; doi:10.1038/sj.bjp.0703702
DOI: 10.1038/sj.bjp.0703702
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