Modulation of arteriolar blood flow by inhibitors of arachidonic acid oxidation after thermal injury: possible role for a novel class of vasodilator metabolites.
To examine the contribution of arachidonic acid (AA) metabolites to the maintenance of cutaneous vasomotor tone after thermal injury, enzyme inhibitors were topically applied to the hamster cheek pouch before and after a spot burn. By use of video microscopy, blood flow was measured in adjacent arterioles that supplied the injured site. Ringer's solutions containing no drug (vehicle), indomethacin (cyclooxygenase inhibitor), BW755c (cyclooxygenase/lipoxygenase inhibitor), or ketoconazole (lipoxygenase/cytochrome P450 inhibitor) continuously suffused the entire tissue. There were no effects of these drugs on preburn blood flow at concentrations that blocked the vascular effects evoked by topical AA. In all groups, blood flow transiently increased after burn and thereafter decreased to levels that were altered by treatment. These results could not be attributed to alterations in vascular reactivity because neither the burn nor the drugs altered the vasodilation evoked by adenosine or prostacyclin. Relative to Ringer's, indomethacin had no effect, BW755c caused vasodilation, and ketoconazole caused vasoconstriction, which suggests that cytochrome P450 products might be vasoactive mediators in injured tissue. Therefore, purified synthetic compounds were compared with known vasodilators. The potency was prostacyclin greater than 12R-hydroxyeicostetraenoic acid greater than adenosine = 5,6 epoxyeicosatrienoic acid greater than AA, which supports the hypothesis that AA can be the source of a novel class of nonprostaglandin vasodilator compounds. In addition, at least one of the vasodilator responses was stereospecific. Nevertheless, the exact explanation for the differential effects of AA inhibitors on postburn blood flow is unknown.
D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D000818:Animals; D001095:Arachidonic Acids / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D001160:Arterioles / Q000187:drug effects; D002056:Burns / Q000503:physiopathology*; D002610:Cheek / Q000098:blood supply / Q000187:drug effects / Q000293:injuries; D006224:Cricetinae; D003577:Cytochrome P-450 Enzyme System / Q000494:pharmacology; D007213:Indomethacin / Q000494:pharmacology; D007511:Ischemia / Q000503:physiopathology; D007654:Ketoconazole / Q000494:pharmacology; D008297:Male; D009061:Mouth Mucosa / Q000098:blood supply* / Q000187:drug effects / Q000293:injuries; D010084:Oxidation-Reduction; D011720:Pyrazoles / Q000494:pharmacology; D012039:Regional Blood Flow / Q000187:drug effects; D014661:Vasoconstriction / Q000187:drug effects; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology*
D001095:Arachidonic Acids; D011720:Pyrazoles; D014665:Vasodilator Agents; D015772:4,5-Dihydro-1-(3-(trifluoromethyl)phenyl)-1H-pyrazol-3-amine; D003577:Cytochrome P-450 Enzyme System; D007654:Ketoconazole; D007213:Indomethacin