Inhibition of cystathionine‐gamma lyase dampens vasoconstriction in mouse and human intracerebral arterioles

Abstract

AbstractAimIn extracerebral vascular beds cystathionine‐gamma lyase (CSE) activity plays a vasodilatory role but the role of this hydrogen sulfide (H2S) producing enzyme in the intracerebral arterioles remain poorly understood. We hypothesized a similar function in the intracerebral arterioles.MethodsIntracerebral arterioles were isolated from wild type C57BL/6J mouse (9–12 months old) brains and from human brain biopsies. The function (contractility and secondary dilatation) of the intracerebral arterioles was tested ex vivo by pressure myography using a perfusion set‐up. Reverse transcription polymerase chain reaction was used for detecting CSE expression.ResultsCSE is expressed in human and mouse intracerebral arterioles. CSE inhibition with L‐propargylglycine (PAG) significantly dampened the K+‐induced vasoconstriction in intracerebral arterioles of both species (% of maximum contraction: in human control: 45.4 ± 2.7 versus PAG: 27 ± 5.2 and in mouse control: 50 ± 1.5 versus PAG: 33 ± 5.2) but did not affect the secondary dilatation. This effect of PAG was significantly reversed by the H2S donor sodium hydrosulfide (NaSH) in human (PAG + NaSH: 38.8 ± 7.2) and mouse (PAG + NaSH: 41.7 ± 3.1) arterioles, respectively. The endothelial NO synthase (eNOS) inhibitor, Nω‐Nitro‐l‐arginine methyl ester (L‐NAME), and the inhibitor of soluble guanylate cyclase (sGC), 1H‐[1,2,4]oxadiazolo[4,3‐a]quinoxalin‐1‐one (ODQ) reversed the effect of PAG on the K+‐induced vasoconstriction in the mouse arterioles and attenuated the K+‐induced secondary dilatation significantly.ConclusionCSE contributes to the K+‐induced vasoconstriction via a mechanism involving H2S, eNOS, and sGC whereas the secondary dilatation is regulated by eNOS and sGC but not by CSE.