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(Circulation Research. 2002;90:e17.)
© 2002 American Heart Association, Inc.

UltraRapid Communications

Carbon Monoxide-Releasing Molecules

Characterization of Biochemical and Vascular Activities

Roberto Motterlini, James E. Clark, Roberta Foresti, Padmini Sarathchandra, Brian E. Mann, Colin J. Green

From the Vascular Biology Unit (R.M., J.E.C., R.F., P.S., C.J.G.), Department of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex, UK; and the Department of Chemistry (B.E.M.), University of Sheffield, Sheffield, UK.

Correspondence to R. Motterlini, Vascular Biology Unit, Dept of Surgical Research, Northwick Park Institute for Medical Research, Harrow, Middlesex HA1 3UJ, UK. E-mail r.motterlini{at}ic.ac.uk

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.

Key Words: carbon monoxide • transition metal carbonyls • heme oxygenase-1 • vascular function • gene expression

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