| First Author | Mitidieri E | Year | 2021 |
| Journal | Br J Pharmacol | Volume | 178 |
| Issue | 18 | Pages | 3765-3782 |
| PubMed ID | 33931865 | Mgi Jnum | J:360192 |
| Mgi Id | MGI:7660883 | Doi | 10.1111/bph.15516 |
| Citation | Mitidieri E, et al. (2021) Involvement of 3',5'-cyclic inosine monophosphate in cystathionine gamma-lyase-dependent regulation of the vascular tone. Br J Pharmacol 178(18):3765-3782 |
| abstractText | 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 muM followed by vasodilatation at 30-100 muM. 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 gamma-lyase (CSE(-/-) ), soluble guanylyl cyclase (sGC(alpha1)(-/-) ) 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. |
