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

• Published in: European journal of pharmacology Vol. 572; no. 2; pp. 197 - 206
• Main Authors: De Backer, Ole, Lefebvre, Romain A.
• Format: Journal Article
• Language: English
• Published: Amsterdam Elsevier B.V 31-10-2007; Elsevier
• Subjects: Animals; Biological and medical sciences; Carbon monoxide; Carbon Monoxide - pharmacology; Carbon monoxide-releasing molecule-2; Gastric fundus; Gastric Fundus - drug effects; Gastric Fundus - physiology; In Vitro Techniques; Interstitial cells of Cajal; Isometric Contraction; Jejunum; Jejunum - drug effects; Jejunum - physiology; K Ca channels; Male; Medical sciences; Mice; Mouse; Muscle Relaxation; Muscle, Smooth, Vascular - drug effects; Muscle, Smooth, Vascular - physiology; Organometallic Compounds - pharmacology; Pharmacology. Drug treatments; Potassium Channel Blockers - pharmacology; Relaxation; Soluble guanylyl cyclase; Vasodilator Agents - pharmacology; Relaxation; Carbon monoxide-releasing molecule-2; Jejunum; Mouse; K Ca channels; Soluble guanylyl cyclase; Gastric fundus; Carbon monoxide; Interstitial cells of Cajal; Stomach; Digestive system; Enzyme; Rodentia; Phosphorus-oxygen lyases; Lyases; KCa channels; Guanylate cyclase; Small intestine; Interstitial cell; Vertebrata; Mammalia; Animal; Mechanism of action
• ISSN: 0014-2999; 1879-0712
• DOI: 10.1016/j.ejphar.2007.06.005

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 μM) were associated with a significant increase in cGMP levels, whereas for CORM-2 (300 μM) 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 Ca
2+-activated K
+ (IK
Ca-BK
Ca) channel blocker charybdotoxin significantly reduced CO- and CORM-2-induced relaxations in jejunal tissue; this same effect was observed with the BK
Ca 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 K
Ca channels, and a nitric oxide (NO)-mediated amplification of CO signaling in jejunum is suggested.