Positive inotropic effects of carbon monoxide‐releasing molecules (CO‐RMs) in the isolated perfused rat heart

Background and purpose: Carbon monoxide (CO) generated by the enzyme haeme oxygenase‐1 (HO‐1) during the breakdown of haeme is known to mediate a number of biological effects. Here, we investigated whether CO liberated from two water soluble carbon monoxide‐releasing molecules (CO‐RMs) exerts inotropic effects on the myocardium. Experimental approach: Rat isolated hearts perfused either at constant flow or constant pressure were used to test the effect of CO‐RMs. Key results: CORM‐3, a fast CO releaser, produced a direct positive inotropic effect when cumulative doses (3, 10 and 30 μg min−1) or a single dose (5 μM) were infused at either constant coronary pressure (CCP) or constant coronary flow (CCF). The inotropic effect mediated by CORM‐3 was abolished by blockade of soluble guanylate cyclase or Na+/H+ exchanger, but not by inhibitors of L‐type Ca2+ channels and protein kinase C. CORM‐3 also caused a slight reduction in heart rate but did not alter coronary flow. In contrast, the slow CO releaser CORM‐A1 produced significant coronary vasodilatation when given at the highest concentration (30 μg min−1) but exerted no effect on myocardial contractility or heart rate. Conclusion and implications: A rapid CO release from CORM‐3 exerts a direct positive inotropic effect on rat isolated perfused hearts, whereas CO slowly released by CORM‐A1 had no effect on myocardial contractility but caused significant coronary vasodilatation. Both cGMP and Na+/H+ exchange appear to be involved in this effect but further work is needed to determine the relative contribution of each pathway in CO‐mediated inotropic effect. British Journal of Pharmacology (2006) 149, 1104–1112. doi:10.1038/sj.bjp.0706939