Can J Physiol Pharmacol. 1992 Sep;70(9):1297-303.  

Inhibition of nitrovasodilator- and acetylcholine-induced relaxation and cyclic
GMP accumulation by the cytochrome P-450 substrate, 7-ethoxyresorufin.

Bennett BM, McDonald BJ, Nigam R, Long PG, Simon WC.

Department of Pharmacology and Toxicology, Faculty of Medicine, Queen's
University, Kingston, Ont., Canada.

We examined the effect of the cytochrome P-450 substrate, 7-ethoxyresorufin
(7-ER), and its corresponding product, resorufin, on nitrovasodilator- and
endothelium-dependent relaxation of isolated rat aorta. The EC50 value for
glyceryl trinitrate (GTN) induced relaxation was increased over 100-fold by 7-ER
and less than 3-fold by resorufin. The EC50 value for sodium nitroprusside (SNP)
induced relaxation was increased approximately 12-fold by 7-ER, acetylcholine
(ACh) induced relaxation was abolished, and relaxation induced by
isopropylnorepinephrine was not significantly affected. GTN-, SNP-, and
ACh-induced increases in cyclic GMP accumulation were inhibited by 7-ER, as were
basal cyclic GMP levels in endothelium-intact, but not endothelium-denuded
tissues. 7-ER decreased GTN biotransformation in intact aorta and decreased the
regioselective formation of glyceryl-1,2-dinitrate. The activation by GTN and
SNP of aortic guanylyl cyclase in broken cell preparations was not affected by
7-ER, indicating that the inhibitory effect of 7-ER is probably not due to a
direct interaction with guanylyl cyclase. The inhibitory effect of 7-ER on
GTN-induced relaxation was not altered by the addition of superoxide dismutase,
suggesting that 7-ER does not act by increasing superoxide anion concentration
(which would serve to increase the degradation of nitric oxide (NO) formed
during vascular GTN biotransformation). Our data provide further evidence for
the role of the cytochrome P-450--cytochrome P-450 reductase system in the
biotransformation of GTN to an activator (presumably nitric oxide) of guanylyl
cyclase. The data are consistent with a mode of action of 7-ER involving either
competitive inhibition of vascular cytochrome P-450 or uncoupling of vascular
cytochrome P-450 reductase from cytochrome P-450. The data also suggest that the
cytochrome P-450 system facilitates NO release from SNP and that 7-ER has an
inhibitory effect on endothelial nitric oxide synthase.

PMID: 1362924 [PubMed - indexed for MEDLINE]