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

Abstract

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 mg min À1 ) or a single dose (5 mM) 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 þ /H þ exchanger, but not by inhibitors of L-type Ca 2 þ 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 mg min À1 ) 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 þ /H þ 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.

Acute myocardial infarction in streptozotocin-induced hyperglycaemic rats: protection by a carbon monoxide-releasing molecule (CORM-3)

“…Several reports have corroborated the protective role that exogenously applied CO plays in many tissues including the cardiac and vascular compartments (Wu and Wang 2005;Kohmoto et al 2006;Musameh et al 2006;Ryter et al 2007;Chora et al 2007;Varadi et al 2007). As a consequence, several experimental systems have tested the possibility that this gaseous molecule, released in small amounts within biological fluids, might serve as a new therapeutic agent (Schober et al 2006;Bani-Hani et al 2006).…”

Improved Myocardial Function After Cold Storage With Preservation Solution Supplemented With a Carbon Monoxide–Releasing Molecule (CORM-3)

“…Functional measurements of control, freshly isolated hearts have been published previously 30 and are included for comparison.…”

“…After cervical dislocation and exsanguination, hearts were perfused on a Langendorff circuit as described previously. 29,30 Measurements were recorded for left ventricular developed pressure (LVDP), its first derivatives (dP/dt max and dP/dt min ), and enddiastolic pressure (EDP) and coronary flow rates. 30 All hearts were based at 300 beats per minute.…”

“…29,30 Measurements were recorded for left ventricular developed pressure (LVDP), its first derivatives (dP/dt max and dP/dt min ), and enddiastolic pressure (EDP) and coronary flow rates. 30 All hearts were based at 300 beats per minute. For the cold preservation solution, St Thomas' Hospital cardioplegic solution-2 (STH-2, pH 7.8) was used.…”

Cardiovascular Effects of Modulators of Soluble Guanylyl Cyclase Activity

“…Musameh et al [237] showed an intersting differential effect of two CO donors on isolated perfused rat hearts, testing both constant coronary flow and constant coronary pressure. CORM-3 showed a direct positive inotropic effect with a slight reduction in heart rate in both settings, but did not affect coronary flow.…”