Mechanism of vasorelaxation and role of endogenous hydrogen sulfide production in mouse aorta

Mohammad Al-Magableh, Joanne Hart

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Abstract

This study aimed to elucidate the molecular mechanism of H(2)S-induced vasorelaxation. Vasorelaxation responses to the H(2)S donor NaHS and the H(2)S precursor L: -cysteine were examined by measuring isometric tone of mouse aortic rings in a small vessel myograph. H(2)S concentrations in Krebs solution were determined with a polarographic sensor. H(2)S expression was examined by Western blot, and H(2)S production from CSE was assayed using a spectroscopic method. In pre-constricted mouse aorta, NaHS (1 muM-3 mM) elicited vasorelaxation of 95 +/- 7 , EC(50) 189 +/- 69 muM. This response was unaffected by removal of the endothelium. Maximum vasorelaxation was significantly attenuated by global blockade of K(+) channels (50 mM K(+)) and the K(ATP) channel blocker glibenclamide (10 muM) alone (P <0.01, ANOVA). Specific inhibition of K(Ca), K(IR), or K(V) channels elicited a significant shift to the right in the concentration-response curve to NaHS (P <0.01, ANOVA) without affecting maximum relaxation. NaHS-mediated vasorelaxation was inhibited by the Cl(-) channel inhibitor DIDS (1 mM, P <0.05, t test), and NaHS caused a significant concentration-dependent inhibition of voltage-gated Ca(2+) channels (P <0.001, two-way ANOVA). The H(2)S-producing enzyme cystathionine-gamma-lyase (CSE) was expressed in mouse aorta and had activity of 7 +/- 3 mumol H(2)S/g/min. L: -cysteine (1 muM-3 mM) elicited a CSE-dependent vasorelaxation of mouse aorta with intact endothelium (20 +/- 7 ), but not when the endothelium was removed. CSE inhibitors DL: -propargylglycine (20 mM) and beta-cyanoalanine (1 mM) caused concentration-dependent contraction of mouse aorta. In mouse aorta, H(2)S elicits endothelium-independent vasorelaxation involving several different ion channels and seems to converge at the vascular smooth muscle cell voltage-gated Ca(2+) channel. The L: -cysteine-CSE-H(2)S pathway contributes to vasorelaxation and appears to modulate basal vessel tone.
Original languageEnglish
Pages (from-to)403 - 413
Number of pages11
JournalNaunyn-Schmiedeberg's Archives of Pharmacology
Volume383
Issue number4
DOIs
Publication statusPublished - 2011

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