Role of the soluble guanylyl cyclase α1/α2 subunits in the relaxant effect of CO and CORM-2 in murine gastric fundus

Carbon monoxide (CO) has been shown to cause enteric smooth muscle relaxation by activating soluble guanylyl cyclase (sGC). In gastric fundus, the sGC alpha(1)beta(1) heterodimer is believed to be the most important isoform. The aim of our study was to investigate the role of the sGC alpha(1)/alpha(2) subunits in the relaxant effect of CO and CORM-2 in murine gastric fundus using wild-type (WT) and sGC alpha(1) knock-out (KO) mice. In WT mice, CO (bolus)-induced relaxations were abolished by the sGC inhibitor 1H-[1,2,4]oxadiazolo-[4,3-a]quinoxalin-1-one (ODQ), while CORM-2- and CO (infusion)-induced relaxations were only partially inhibited by ODQ. In sGC alpha(1) KO mice, relaxant responses to CO and CORM-2 were significantly reduced when compared with WT mice, but ODQ still had an inhibitory effect. The sGC sensitizer 1-benzyl-3-(5'-hydroxymethyl-2'-furyl-)-indazol (YC-1) was able to potentiate CO- and CORM-2-induced relaxations in WT mice but lost this potentiating effect in sGC alpha(1) KO mice. Both in WT and sGC alpha(1) KO mice, CO-evoked relaxations were associated with a significant cGMP increase; however, basal and CO-elicited cGMP levels were markedly lower in sGC alpha(1) KO mice. These data indicate that besides the predominant sGC alpha(1)beta(1) isoform, also the less abundantly expressed sGC alpha(2)beta(1) isoform plays an important role in the relaxant effect of CO in murine gastric fundus; however, the sGC stimulator YC-1 loses its potentiating effect towards CO in sGC alpha(1) KO mice. Prolonged administration of CO-either by the addition of CORM-2 or by continuous infusion of CO-mediates gastric fundus relaxation in both a sGC-dependent and sGC-independent manner.