Mechanisms of the vasorelaxing effects of CORM-3, a water-soluble carbon monoxide-releasing molecule: interactions with eNOS

Abstract

The purpose of the present work was to elucidate the mechanisms underlying the endothelium-dependent and endothelium-independent components of the vascular relaxation induced by a water-soluble and ruthenium-based carbon monoxide (CO)-releasing agent, tricarbonylchloro(glycinato)ruthenium(II) (CORM-3). Changes in isometric tension and cyclic guanosine monophosphate (cGMP) production were measured in isolated aortic rings from normotensive Wistar-Kyoto rats. Nitric oxide (NO) generation was assessed in cultured human umbilical vein endothelial cells (HUVEC) by electron spin resonance. In rat aortic rings, CORM-3, but not the inactivated compound, iCORM, induced relaxations. In rings with but not in those without endothelium relaxations were partially inhibited by L-nitro-arginine (L-NA), 1H-(1,2,4)-oxadiazolo(4,2-a)quinoxalin-1-one (ODQ), or hydroxocobalamin, inhibitors of NO-synthase, soluble guanylyl cyclase, and scavenger of NO, respectively. In rings with and without endothelium, deoxyhemoglobin abolished the relaxations. A combination of potassium channel blockers (barium, glibenclamide, and iberiotoxin) blunted the relaxation in rings without endothelium. CORM-3 produced an endothelium-dependent generation of cGMP that was inhibited by L-NA. CORM-3, but not iCORM, inhibited the endothelium-dependent relaxation to acetylcholine without affecting the response to sodium nitroprusside. In HUVEC, CORM-3 produced a concentration-dependent release of NO. Therefore, CORM-3-induced relaxations involve the soluble guanylyl cyclase-independent activation of smooth muscle potassium channels. Additionally, CO can produce concomitantly activation and inhibition of NO synthase, the former being responsible for the endothelium- and cGMP-dependent effect of CORM-3, the latter for the inhibition of acetylcholine-induced endothelium-dependent relaxations.

CORM‐401 induces calcium signalling, NO increase and activation of pentose phosphate pathway in endothelial cells

“…In the present work we clearly demonstrate that CO liberated from CORM‐401 induces NO production in endothelial cells. Similar effects have been described for other CO‐RMs or CO gas in different cell types or vascular tissue preparations . Various mechanisms responsible for NO increase following CO treatment were proposed previously; they include displacement of NO from a cellular storage pool or activation of NO synthase via calcium or phosphatidylinositol 3‐kinase/Akt pathways .…”

The influence of ruthenium on vascular tone

“…This study is the first to demonstrate a strong vasorelaxant effect of RuCl 3 . Only one study reported a vasoactive effect of RuCl 3 , namely a limited contractile effect on rat aortic rings [17]. This divergence could be due to species differences as already shown for CO and CORM‐2,[12] but this is rather unlikely.…”

“…Hence, scavenging of the already low NO levels by ruthenium‐based drugs would seriously counteract their beneficial effect. It was already demonstrated that CORM‐2 attenuates NO donor‐induced relaxations, and that the water‐soluble ruthenium‐based CO‐releasing molecule RuCl(CO) 3 ‐glycinate (=CORM‐3) inhibits endothelium‐ and NO‐dependent relaxations [16,17]. However, the influence of ruthenium itself on NO‐mediated signalling is not completely explored.…”

A modern literature review of carbon monoxide poisoning theories, therapies, and potential targets for therapy advancement.

“…This causes a rapid rise in free nitric oxide levels both intracellularly and extracellularly. At the same time, CO has also been shown to be capable of activating certain forms of nitric oxide synthase, resulting in an overall increased production of nitric oxide (Alshehri et al, 2013;Thom et al, 1997b). This dysregulation of NO homeostasis can lead to profound hypotension that is resistant to catecholamines (Fischer and Levin, 2010;Ketteler et al, 1998).…”