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

Abstract

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 (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 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.

Keywords: cyclic nucleotides; cystathionine γ-lyase; gasotransmitters; inosine 3′,5′-cyclic monophosphate; phosphodiesterases; vascular homeostasis; vasoconstriction.