title: 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.
authors.affiliation: Institut Recherches Servier, Suresnes, France.
authors.forename: Ali
authors.initials: A
authors.lastname: Alshehri
authors.forename: Marie-Pierre
authors.initials: MP
authors.lastname: Bourguignon
authors.forename: Nicolas
authors.initials: N
authors.lastname: Clavreul
authors.forename: Cécile
authors.initials: C
authors.lastname: Badier-Commander
authors.forename: Willy
authors.initials: W
authors.lastname: Gosgnach
authors.forename: Serge
authors.initials: S
authors.lastname: Simonet
authors.forename: Christine
authors.initials: C
authors.lastname: Vayssettes-Courchay
authors.forename: Alex
authors.initials: A
authors.lastname: Cordi
authors.forename: Jean-Noël
authors.initials: JN
authors.lastname: Fabiani
authors.forename: Tony J
authors.initials: TJ
authors.lastname: Verbeuren
authors.forename: Michel
authors.initials: M
authors.lastname: Félétou
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D002248:Carbon Monoxide / Q000737:chemistry / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology*; D015221:Potassium Channels / Q000378:metabolism; D011485:Protein Binding; D051381:Rats; D011921:Rats, Inbred WKY; D012995:Solubility; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D009942:Organometallic Compounds; D015221:Potassium Channels; D014665:Vasodilator Agents; C476530:tricarbonylchloro(glycinato)ruthenium(II); D009569:Nitric Oxide; D002248:Carbon Monoxide; D052250:Nitric Oxide Synthase Type III