Water-soluble carbon monoxide-releasing molecules: helping to elucidate the vascular activity of the 'silent killer'

Carbon monoxide (CO) is formed during the degradation of haeme by haeme oxygenase (HO). As well as being an important signalling molecule and vasodilator, CO also possesses antihypertensive, anti-inflammatory and antiapoptotic qualities and protects against ischaemic tissue injury. Several approaches have been used to investigate the therapeutic potential of CO, ranging from direct administration of CO gas to the use of prodrugs, which generate CO upon metabolism. A novel approach involves the use of specific CO carriers, which will release measurable, controllable and effective amounts of CO into biological systems. Transitional metal carbonyls based around iron, manganese or ruthenium have recently been developed as CO-releasing molecules (CO-RMs) that, under appropriate conditions, will release CO. Such molecules have been shown to provide cardioprotection in both ex vivo and in vivo experiments. To date, CO-RMs have been largely incompatible with biological systems in that they are only soluble in organic solvents or have to be preactivated either by physical or chemical stimuli. However, the recent development of water-soluble CO-RMs has provided new opportunities to investigate the pharmacological and biological features of CO without such confounding influences. CORM-3, a novel water-soluble CO-RM, has recently been used to confirm the cardioprotective actions of CO. In this issue of British Journal of Pharmacology, Foresti and co-workers report that CORM-3 delivers CO, produces aortic vasodilation ex vivo and reduces blood pressure in vivo via modulation of the same cGMP and potassium channels utilised by endogenous and exogenous CO. These findings suggest that CORM-3 has the potential for use as a modulator of vascular function and hypertension. However, the use of water-soluble CO-RMs raises several questions of their own which will need to be addressed if CO-RMs are to be of future use therapeutically.