title: Carbon monoxide-releasing molecules: characterization of biochemical and vascular activities.
abstract: Carbon monoxide (CO) is generated in living organisms during the degradation of heme by the enzyme heme oxygenase, which exists in constitutive (HO-2 and HO-3) and inducible (HO-1) isoforms. Carbon monoxide gas is known to dilate blood vessels in a manner similar to nitric oxide and has been recently shown to possess antiinflammatory and antiapoptotic properties. We report that a series of transition metal carbonyls, termed here carbon monoxide-releasing molecules (CO-RMs), liberate CO to elicit direct biological activities. Specifically, spectrophotometric and NMR analysis revealed that dimanganese decacarbonyl and tricarbonyldichlororuthenium (II) dimer release CO in a concentration-dependent manner. Moreover, CO-RMs caused sustained vasodilation in precontracted rat aortic rings, attenuated coronary vasoconstriction in hearts ex vivo, and significantly reduced acute hypertension in vivo. These vascular effects were mimicked by induction of HO-1 after treatment of animals with hemin, which increases endogenously generated CO. Thus, we have identified a novel class of compounds that are useful as prototypes for studying the bioactivity of CO. In the long term, transition metal carbonyls could be utilized for the therapeutic delivery of CO to alleviate vascular- and immuno-related dysfunctions. The full text of this article is available at http://www.circresaha.org.
authors.affiliation: Vascular Biology Unit, Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK. r.motterlini@ic.ac.uk
authors.forename: Roberto
authors.initials: R
authors.lastname: Motterlini
authors.forename: James E
authors.initials: JE
authors.lastname: Clark
authors.forename: Roberta
authors.initials: R
authors.lastname: Foresti
authors.forename: Padmini
authors.initials: P
authors.lastname: Sarathchandra
authors.forename: Brian E
authors.initials: BE
authors.lastname: Mann
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Green
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects* / Q000502:physiology; D002248:Carbon Monoxide / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D002417:Cattle; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects* / Q000502:physiology; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors; D006427:Hemin / Q000494:pharmacology; D066298:In Vitro Techniques; D054354:Iron Carbonyl Compounds; D046911:Macromolecular Substances; D009682:Magnetic Resonance Spectroscopy; D008297:Male; D008665:Metalloporphyrins / Q000494:pharmacology; D009131:Muscle, Smooth, Vascular / Q000187:drug effects* / Q000378:metabolism; D009942:Organometallic Compounds / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011524:Protoporphyrins / Q000494:pharmacology; D051381:Rats; D028561:Transition Elements / Q000737:chemistry; D014665:Vasodilator Agents / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D014666:Vasomotor System / Q000187:drug effects* / Q000378:metabolism
chemical_list: D004791:Enzyme Inhibitors; D046911:Macromolecular Substances; D008665:Metalloporphyrins; D009942:Organometallic Compounds; D011524:Protoporphyrins; D028561:Transition Elements; D014665:Vasodilator Agents; C447082:tricarbonyldichlororuthenium (II) dimer; D054354:Iron Carbonyl Compounds; D006427:Hemin; D002248:Carbon Monoxide; C032628:tin protoporphyrin IX; D006419:Heme Oxygenase (Decyclizing)