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 (H2 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 H2 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 (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 RESULTS: 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 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 H2 S-induced contraction involves cIMP. CONCLUSION AND IMPLICATIONS: The endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE-derived H2 S that is mediated by cIMP.