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

BACKGROUND AND PURPOSE: l‐cysteine or hydrogen sulfide (H(2)S) 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 H(2)S‐induced contraction. EXPERIMENTAL APPROACH: Vascular 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 (sGC(α1) (−/−)) 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 RESULTS: CSE‐derived H(2)S‐induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. H(2)S 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 H(2)S‐induced contraction involves cIMP. CONCLUSION AND IMPLICATIONS: The endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE‐derived H(2)S that is mediated by cIMP.