Involvement of 3',5'-cyclic inosine monophosphate in cystathionine γ-lyase-dependent regulation of the vascular tone.

Abstract

Background and Purposel‐cysteine or hydrogen sulfide (H2S) donors induce a biphasic effect on precontracted isolated vessels. The contractile effect occurs within a concentration range of 10 nM to 3 μM followed by vasodilatation at 30–100 μM. Here, we have investigated the signalling involved in the H2S‐induced contraction.Experimental ApproachVascular response to NaHS or l‐cysteine is evaluated on isolated precontracted with phenylephrine vessel rings harvested from wild type, cystathionine γ‐lyase (CSE−/−), soluble guanylyl cyclase (sGCα1 −/−) and endothelial nitric oxide synthase (eNOS−/−) knock‐out mice. The cAMP, cGMP and inosine 3′,5′‐cyclic monophosphate (cIMP) levels are simultaneously quantified using ultra‐performance liquid chromatography–tandem mass spectrometry (UPLC‐MS/MS) analysis. The involvement of sGC, phosphodiesterase (PDE) 4A and PDE5 are also evaluated.Key ResultsCSE‐derived H2S‐induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. H2S contractile effect involves a transient increase of cGMP and cAMP metabolism caused by PDE5 and PDE4A, thus unmasking cIMP contracting action. The stable cell‐permeable analogue of cIMP elicits concentration‐dependent contraction on a stable background tone induced by phenylephrine. The lack of cIMP, coupled to the hypocontractility displayed by vessels harvested from CSE−/− mice, confirms that H2S‐induced contraction involves cIMP.Conclusion and ImplicationsThe endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE‐derived H2S that is mediated by cIMP.