SELECTIVE-INHIBITION BY BARBITURATES OF THE SYNTHESIS OF ENDOTHELIUM-DERIVED HYPERPOLARIZING FACTOR IN THE RABBIT CAROTID-ARTERY

1 Several lines of evidence suggest that both volatile and intravenous anaesthetics may interfere with the synthesis and release of endothel ium-derived vasoactive factors. We have investigated the effects of th ree different barbiturates on the release of nitric oxide (NO) and end othelium-derived hyperpolarizing factor (EDHF) in phenylephrine (1 mu M)-preconstricted, endothelium-intact ring segments of the rabbit caro tid artery. The segments were pretreated with the cyclo-oxygenase inhi bitor, diclofenac (1 mu M), to prevent the formation of vasoactive pro stanoids, such as prostacyclin (PGI(2)). 2 Acetylcholine (ACh) elicite d a concentration-dependent relaxation (EC(50) 0.15 mu M) in control s egments which was not significantly different from the relaxant respon ses of segments pretreated with methohexitone (0.03-0.3 mM), phenobarb itone (0.1-0.3 mM) or thiopentone (0.1-0.3 mM). 3 Inhibition of NO syn thesis with N-G-nitro-L-arginine (O.1 mM) significantly reduced the ma ximum relaxant response to ACh from 96 to 40%. This NO/PGI(2)-independ ent relaxation appeared to be mediated by the release of EDHF, since i t was strongly diminished in the presence of the K-ca(+) inhibitors, t etrabutylammonium (1-3 mM) and charybdotoxin (10 nM), following precon striction with potassium calcium (40 mM) or removal of the endothelium . Thiopentone or methohexitone markedly attenuated the EDHF-mediated r elaxant response to ACh, while phenobarbitone had no effect. The endot helium-independent relaxation elicited by sodium nitroprusside (0.01-1 0 mu M), on the other hand, was only marginally affected by these anae sthetics. 4 The cytochrome P450 inhibitor, clotrimazole (3-100 mu M), mimicked the inhibitory effect of thiopentone and methohexitone on the NO/PGI(2)-independent relaxant response to ACh. Moreover the cytochro me P450-catalyzed O-dealkylation of 7-ethoxycoumarin by rabbit liver m icrosomes was inhibited in the presence of thiopentone or methohexiton e (0.3-1 mM), while phenobarbitone was without effect. 5 These finding s suggest that thiopentone and methohexitone selectively attenuate the EDHF-mediated relaxant response to ACh in the rabbit carotid artery, presumably by interfering with its synthesis from arachidonic acid via the cytochrome P450 epoxygenase pathway.