Vasoactive properties of CORM‐3, a novel water‐soluble carbon monoxide‐releasing molecule

Abstract

1 Carbon monoxide (CO), one of the end products of heme catabolism by heme oxygenase, possesses antihypertensive and vasodilatory characteristics. We have recently discovered that certain transition metal carbonyls are capable of releasing CO in biological fluids and modulate physiological functions via the delivery of CO. Because the initial compounds identified were not water soluble, we have synthesized new CO-releasing molecules that are chemically modified to allow solubility in water. The aim of this study was to assess the vasoactive properties of tricarbonylchloro(glycinato)ruthenium(II) (CORM-3) in vitro and in vivo. 2 CORM-3 produced a concentration-dependent relaxation in vessels precontracted with phenylephrine, exerting significant vasodilatation starting at concentrations of 25-50 mM. Inactive CORM-3, which does not release CO, did not affect vascular tone. 3 Blockers of ATP-dependent potassium channels (glibenclamide) or guanylate cyclase activity (ODQ) considerably reduced CORM-3-dependent relaxation, confirming that potassium channels activation and cGMP partly mediate the vasoactive properties of CO. In fact, increased levels of cGMP were detected in aortas following CORM-3 stimulation. 4 The in vitro and in vivo vasorelaxant activities of CORM-3 were further enhanced in the presence of YC-1, a benzylindazole derivative which is known to sensitize guanylate cyclase to activation by CO. Interestingly, inhibiting nitric oxide production or removing the endothelium significantly decreased vasodilatation by CORM-3, suggesting that factors produced by the endothelium influence CORM-3 vascular activities. 5 These results, together with our previous findings on the cardioprotective functions of CORM-3, indicate that this molecule is an excellent prototype of water-soluble CO carriers for studying the pharmacological and biological features of CO.

A carbon monoxide-releasing molecule (CORM-3) uncouples mitochondrial respiration and modulates the production of reactive oxygen species

“…Identical results were obtained with depleted CORM-3 (data not shown), which is unable to release CO to myoglobin [10,29]. Moreover, we found that the increase in mitochondrial state 2 respiration by CORM-3 (20 µM) is blocked by the presence of myoglobin, a potent CO scavenger ( Figure 2A).…”

Analysis of the Bacterial Response to Ru(CO)3Cl(Glycinate) (CORM-3) and the Inactivated Compound Identifies the Role Played by the Ruthenium Compound and Reveals Sulfur-Containing Species as a Major Target of CORM-3 Action

“…Although previous work has shown that iCORM-3 has much less effect than CORM-3 on biological material (8,17,34,37), very little has been done to elucidate bacterial viability with, and specific responses to, iCORM-3. The data presented herein show that iCORM-3 (made via incubation of CORM-3 in PBS) has virtually no effect on the growth of E. coli, whereas at the same concentration, CORM-3 readily inhibits growth (Fig.…”

“…Despite the ambiguity of its chemical structure, the iCORM-3 compound has been used in studies as a non-CO releasing control for CORM-3 (8,17,34,37) to test the reactivity of the Ru-compound when all labile CO has been removed. In all cases, iCORM-3 was shown to be much less reactive than the CO-RM.…”

Chemoreception in the context of the general biology of ROS

“…Thus, an artificial CO-donor produced a dose dependent relaxation of phenylephrine-precontracted aorta rings that was partially prevented by prior treatment with K ATP channels blocker glibenclamide (Foresti et al, 2004).…”