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Involvement of 3′,5′‐cyclic inosine monophosphate in cystathionine γ‐lyase‐dependent regulation of the vascular tone
Author(s) -
Mitidieri Emma,
Vellecco Valentina,
Brancaleone Vincenzo,
Vanacore Domenico,
Manzo Onorina L.,
Martin Emil,
Sharina Iraida,
Krutsenko Yekaterina,
Monti Maria Chiara,
Morretta Elva,
Papapetropoulos Andreas,
Caliendo Giuseppe,
Frecentese Francesco,
Cirino Giuseppe,
Sorrentino Raffaella,
d'Emmanuele di Villa Bianca Roberta,
Bucci Mariarosaria
Publication year - 2021
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.15516
Subject(s) - vasodilation , phenylephrine , cyclic guanosine monophosphate , chemistry , cystathionine beta synthase , inosine , guanosine , contraction (grammar) , nitric oxide , adenosine , enos , inosine monophosphate , cysteine , biochemistry , pharmacology , medicine , endocrinology , nitric oxide synthase , enzyme , biology , nucleotide , organic chemistry , gene , blood pressure
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.