Mechanisms of relaxation by carbon monoxide-releasing molecule-2 in murine gastric fundus and jejunum

Abstract

This study investigated the effects and mechanisms of action of carbon monoxide-releasing molecule-2 (CORM-2), compared to those of carbon monoxide (CO), in murine gastric fundus and jejunal circular smooth muscle. Functional in vitro experiments and cGMP measurements were conducted. In both tissues, CO and CORM-2 induced concentration-dependent relaxations. CO-induced relaxations were abolished by the soluble guanylyl cyclase (sGC) inhibitor ODQ, while CORM-2-evoked inhibitory responses were only partly prevented by ODQ. Relaxations elicited by CO (300 microM) were associated with a significant increase in cGMP levels, whereas for CORM-2 (300 microM) no significant increase in cGMP levels could be measured. The sGC sensitizer YC-1 was able to accelerate and potentiate both CO- and CORM-2-induced relaxations. Furthermore, the intermediate- and large-conductance Ca2+-activated K+ (IKCa-BKCa) channel blocker charybdotoxin significantly reduced CO- and CORM-2-induced relaxations in jejunal tissue; this same effect was observed with the BKCa channel blocker iberiotoxin. The combination of apamin plus charybdotoxin significantly reduced relaxations in gastric fundus and had synergistic inhibitory effects in jejunum. The NOS inhibitor L-NAME had no effect on the induced relaxations in gastric fundus, but significantly reduced CO- and CORM-2-evoked relaxations in jejunum. In conclusion, these results demonstrate that CO and CORM-2 produce relaxation in gastric fundus and jejunum via sGC and activation of KCa channels, and a nitric oxide (NO)-mediated amplification of CO signaling in jejunum is suggested.