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Vol. 56, Issue 2, 243-253, August 1999
The Wolfson Institute for Biomedical Research, University College
London, London, United Kingdom (M.F.); Department of Pharmacology and
Toxicology, Julius-Maximilians-University, Würzburg, Germany
(P.K., H.H.H.W.S.); and Institute of Pharmacy,
Christian-Albrecht-University, Kiel, Germany (J.S., B.C.)
Soluble guanylyl cyclase (sGC) is an important effector for
nitric oxide (NO). It acts by increasing intracellular cyclic GMP
(cGMP) levels to mediate numerous biological functions. Recently, 1H-[1,2,4]oxadiazolo[4,3,-a]quinoxalin-1-one
(ODQ) was identified as a novel and selective inhibitor of this enzyme.
Therefore, ODQ may represent an important pharmacological tool for
differentiating cGMP-mediated from cGMP-independent effects of NO. In
the present study, we examined the inhibitory action of ODQ both
functionally and biochemically. In phenylephrine-preconstricted,
endothelium-intact, isolated aortic rings from the rat, ODQ, in a
concentration-dependent manner, increased contractile tone and
inhibited relaxations to authentic NO with maximal effects at
3 µM. Pretreatment of vascular rings with ODQ induced a
parallel, 2-log-order shift to the right of the concentration-response
curves (CRCs) to histamine, ATP, NO, the NO-donors
S-nitrosoglutathione,
S-nitroso-N-acetyl-D,L-penicillamine, and spermine NONOate [N-[4-[1-(3-amino
propyl)-2-hydroxy-2-nitroso hydrazino]butyl]-1,3-propane diamine],
and the direct sGC-stimulant [3-(5'-hydroxymethyl-2'furyl)-1-benzyl
indazole] YC-1 but did not affect relaxations induced by papaverine
and atriopeptin II. Moreover, the rightward shift of the CRCs to
Angeli's salt, peroxynitrite, and linsidomine was similar to that of
NO. These results suggested that ODQ is specific for sGC. Furthermore,
they indicate that NO can cause vasorelaxation independent of cGMP.
Three interesting exceptions were observed to the otherwise rather
uniform inhibitory effect of ODQ: the responses to acetylcholine,
glycerol trinitrate, and sodium nitroprusside. The latter two agents
are known to require metabolic activation, possibly by cytochrome
P-450-type proteins. The 3- to 5-log-order rightward shift of their
CRCs suggests that, in addition to sGC, ODQ may interfere with heme
proteins involved in the bioactivation of these NO donors and the
mechanism of vasorelaxation mediated by acetylcholine. In support of
this notion, ODQ inhibited hepatic microsomal NO production from both
glycerol trinitrate and sodium nitroprusside as well as NO synthase
activity in aortic homogenates. The latter effect seemed to require
biotransformation of ODQ. Collectively, these data reveal that ODQ
interferes with various heme protein-dependent processes in vascular
and hepatic tissue and lacks specificity for sGC.
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