The hypotensive action of endoperoxide analogues in the rat

The endoperoxide analogues U46619 and U44069 when injected intravenously (i.v.), into the femoral artery or directly into the aortic arch in chloralose-anaesthetised rats, decreased arterial blood pressure dose-dependently. Treatment i.v. 30 min beforehand with indomethacin (8-15 mg/kg) or atropine (2 mg/kg) attenuated the hypotensive effect of U46619 or U44069, but methysergide (5 mg/kg) was ineffective. Combined pretreatment with indomethacin and atropine reduced further the hypotensive action of the endoperoxide analogues, but was unable to block the effect completely. However, pretreatment i.v. with AH23848, a specific thromboxane A2 (TXA2)-receptor antagonist, completely abolished the depressor responses to U46619 and U44069. Bilateral vagotomy did not change the hypotensive effect of both endoperoxide analogues. These findings suggest that the vasodepressor action of U46619 or U44069 is not a reflex mechanism, nor is it related to 5-hydroxytryptamine release. This effect appears to be mediated via TXA2-receptor stimulation, with the liberation of prostacyclin and/or acetylcholine or possibly an endothelium-derived relaxing factor (EDRF), all of which produce vasodilatation.