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

Background and Purpose: L-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 mu M followed by vasodilatation at 30-100 mu M. Here, we have investigated the signalling involved in the H2S-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 gamma-lyase (CSE-/-), soluble guanylyl cyclase (sGC(alpha 1)(-/-)) 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 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 Implications: The endothelium dynamically regulates vessel homeostasis by modulating contractile tone. This also involves CSE-derived H2S that is mediated by cIMP.

Automated summary

The study found that H2S-induced contraction requires an intact eNOS/NO/sGC pathway and involves cIMP as a second messenger. The contraction effect involves a transient increase of cGMP and CAMP metabolism caused by PDE5 and PDE4A, unmasking cIMP contraction. This research provides important insights into vascular regulatory mechanisms.