Effect of phenobarbitone pretreatment upon endothelium-dependent relaxation to acetylcholine in rat superior mesenteric arterial bed.

1. Pretreatment of rats for 5 days with phenobarbitone (80 mg kg-1 day-1) enhanced the potency enhanced the potency of acetylcholine in opposing noradrenaline-induced vasoconstriction in the isolated perfused superior mesenteric arterial bed; in 10 saline-pretreated control animals the ED50 was 14.0 +/- 3.9 ng whereas it was 3.23 +/- 1.00 ng in 10 phenobarbitone-pretreated animals. 2. In both saline- and phenobarbitone-pretreated rats acetylcholine was ineffective at opposing noradrenaline vasoconstriction after the mesentery had been perfused for 90s with a 0.3% solution of the detergent CHAPS in distilled water (to remove the endothelium), but pressor responses to noradrenaline were unaffected. 3. Pretreatment with phenobarbitone had no effect on the opposition by sodium nitroprusside of noradrenaline pressor responses. Also, the effects of nitroprusside were not affected by perfusion with CHAPS in either control or barbiturate-pretreated groups. 4. Inclusion of indomethacin (10 microM) in the perfusion fluid had no effect on the enhancement by phenobarbitone pretreatment of the endothelium-dependent opposition by acetylcholine of noradrenaline pressor responses; the ED50 values in the absence and presence of indomethacin were, respectively, 2.40 +/- 0.31 ng and 1.87 +/- 0.27 ng (n = 6). 5. The concentration of cytochrome P450 in the microsomal fraction obtained from the mesenteric preparation was increased from 204 +/- 32 (saline-pretreated; n = 7) to 784 +/- 249 pmol g-1 wet wt (n = 7) by the phenobarbitone pretreatment. 6. It is concluded that the increase in potency of acetylcholine as an endothelium-dependent vasodilator by phenobarbitone pretreatment is most probably at the level of the endothelium rather than the vascular smooth muscle.