Effect of thromboxane A2/endoperoxide antagonist SQ29548 on the contractile response to acetylcholine in newborn piglet cerebral arteries.

Abstract

Previous studies have shown that cholinergic stimulation results in a prostanoid-dependent cerebral vasoconstriction in piglets. The present study specifically investigated the contribution of thromboxane A2 (TXA2)/prostaglandin endoperoxide and prostaglandin F2 alpha (PGF2 alpha) to the cerebral vascular response to exogenous acetylcholine (ACh). Effects of TXA2/prostaglandin endoperoxide-receptor antagonist SQ29548 on responsiveness of pial arterioles to ACh (10(-7) and 10(-4) M), PGF2 alpha (10(-7)-10(-5) M), TXA2 mimetic 9,11-methanoepoxy prostaglandin H2 (U46619, 5 and 10 ng/ml), and norepinephrine (10(-6)-10(-4) M) were studied by use of a closed cranial window in 37 anesthetized mechanically ventilated newborn piglets. Pial arteriolar diameter was measured by intravital microscopy. Topical application of exogenous PGF2 alpha and U46619 resulted in dose-dependent cerebral vasoconstriction, and the dose-response curve for each agonist was shifted to the right by the increasing concentrations of SQ29548 (10(-6)-10(-8) M). Topical application of high concentration of ACh (10(-4) M) caused a transient 34 +/- 4% decrease in pial arteriolar diameter from 98 +/- 6 to 65 +/- 5 microns (p less than 0.05). This constriction was attenuated (16 +/- 3%) in the presence of 10(-8) M SQ29548 and abolished with 10(-6) or 10(-4) M SQ29548. SQ29548 (10(-6) M) was without effect on the vasoconstrictor response to exogenous norepinephrine. Low concentration of ACh (10(-7) M) had no consistent effect on pial arterioles in the absence or presence of TXA2/prostaglandin endoperoxide-receptor blockade. The data suggest that vascular prostaglandin/endoperoxide receptors mediate cerebral vasoconstriction upon muscarinic-receptor stimulation.