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

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L-Cysteine or hydrogen sulfide (H2 S) donors induce a biphasic effect on pre-contracted isolated vessels. The contractile effect is displayed within a concentration range of 10nM-3μM followed by vasodilatation at 30-100μM. Here, we have investigated the signalling involved in H2 S-induced contraction.Vascular response to NaHS or L-cysteine is evaluated on isolated pre-contracted 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 by using UPLC-MS/MS analysis. The involvement of sGC, phosphodiesterase (PDE) 4A and PDE5 are also evaluated.CSE-derived H2 S-induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. H2 S contractile effect involves a transient increase of cGMP and cAMP metabolism operated by PDE5 and PDE4A, thus unmasking cIMP contracting action. The stable cell-permeable analogue of cIMP elicits concentration dependent contraction on phenylephrine stable tone. The lack of cIMP, coupled to the hypo-contractility displayed by vessels harvested from CSE-/- mice, confirms that H2 S-induced contraction involves cIMP.The endothelium dynamically regulates the vessel homeostasis also by modulating the contractile tone. This mechanism also involves CSE-derived H2 S that explicates its action through cIMP.

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Authors: E Mitidieri, V Vellecco, V Brancaleone, D Vanacore, O L Manzo, E Martin, I Sharina, Y Krutsenko, M C Monti, E Morretta, A Papapetropoulos, G Caliendo, F Frecentese, G Cirino, R Sorrentino, R d’Emmanuele di Villa Bianca, M Bucci