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 μM followed by vasodilatation at 30–100 μM. 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 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 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.

Involvement of 3′,5′-cyclic inosine monophosphate in cystathionine γ-lyase-dependent regulation of the vascular tone / Mitidieri, E.; Vellecco, V.; Brancaleone, V.; Vanacore, D.; Manzo, O. L.; Martin, E.; Sharina, I.; Krutsenko, Y.; Monti, M. C.; Morretta, E.; Papapetropoulos, A.; Caliendo, G.; Frecentese, F.; Cirino, G.; Sorrentino, R.; d'Emmanuele di Villa Bianca, R.; Bucci, M.. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - 178:18(2021), pp. 3765-3782. [10.1111/bph.15516]

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

Mitidieri E.;Vellecco V.;Brancaleone V.;Vanacore D.;Manzo O. L.;Monti M. C.;Caliendo G.;Frecentese F.;Cirino G.
;
Sorrentino R.;d'Emmanuele di Villa Bianca R.;Bucci M.
2021

Abstract

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 μM followed by vasodilatation at 30–100 μM. 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 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 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.
2021
Involvement of 3′,5′-cyclic inosine monophosphate in cystathionine γ-lyase-dependent regulation of the vascular tone / Mitidieri, E.; Vellecco, V.; Brancaleone, V.; Vanacore, D.; Manzo, O. L.; Martin, E.; Sharina, I.; Krutsenko, Y.; Monti, M. C.; Morretta, E.; Papapetropoulos, A.; Caliendo, G.; Frecentese, F.; Cirino, G.; Sorrentino, R.; d'Emmanuele di Villa Bianca, R.; Bucci, M.. - In: BRITISH JOURNAL OF PHARMACOLOGY. - ISSN 0007-1188. - 178:18(2021), pp. 3765-3782. [10.1111/bph.15516]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11588/875602
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