Responses to arachidonic acid and other dilator agonists and their modification by inhibition of prostaglandin synthesis in the canine hindlimb

The influence of indomethacin, in doses that completely inhibit the response to arachidonic acid, has been examined on canine hindlimb vascular responses to intra-arterial administration of bradykinin, histamine, nitroglycerin, isoprenaline and papaverine. The hindlimb was perfused at constant flow. Dose-response curves to intra-arterial administration of arachidonic acid (12 to 200 μg kg^?1), bradykinin (0·4 to 100 ng kg^?1), histamine (1·8 to 120 ng kg^?1), nitroglycerin (15 to 100 ng kg^?1), isoprenaline (12 to 100 ng kg^?1) and papaverine (1·2 to 160 μg kg^?1) (all n = 4) were compared before and 30 min after indomethacin (5 mg kg^?1 i.v.). All the drugs produced dose-related decreases in hindlimb perfusion pressure. After indomethacin, responses for all dilator agonists except arachidonic acid, were significantly greater than control (P < 0·05), both in terms of absolute (mmHg) or percent change. Doseresponse curves after indomethacin had a left upward shift compared with control. Arachidonic acid responses were completely blocked by indomethacin. These findings suggest that indomethacin produces a non-specific increase in responsiveness of the hindlimb vascular bed to dilator substances, except arachidonic acid. The data presented do not support the hypothesis that the peripheral vasodilatation produced by bradykinin, nitroglycerin and histamine could be mediated by endogenous prostaglandin release.