The carbon monoxide prodrug oCOm‐21 increases Ca2+ sensitivity of the cardiac myofilament.

Patients undergoing cardiopulmonary bypass procedures require inotropic support to improve hemodynamic function and cardiac output. Current inotropes such as dobutamine, can promote arrhythmias, prompting a demand for improved inotropes with little effect on intracellular Ca2+ flux. Low‐dose carbon monoxide (CO) induces inotropic effects in perfused hearts. Using the CO‐releasing pro‐drug, oCOm‐21, we investigated if this inotropic effect results from an increase in myofilament Ca2+ sensitivity. Male Sprague Dawley rat left ventricular cardiomyocytes were permeabilized, and myofilament force was measured as a function of ‐log [Ca2+] (pCa) in the range of 9.0–4.5 under five conditions: vehicle, oCOm‐21, the oCOm‐21 control BP‐21, and levosimendan, (9 cells/group). Ca2+ sensitivity was assessed by the Ca2+ concentration at which 50% of maximal force is produced (pCa50). oCOm‐21, but not BP‐21 significantly increased pCa50 compared to vehicle, respectively (pCa50 5.52 vs. 5.47 vs. 5.44; p < 0.05). No change in myofilament phosphorylation was seen after oCOm‐21 treatment. Pretreatment of cardiomyocytes with the heme scavenger hemopexin, abolished the Ca2+ sensitizing effect of oCOm‐21. These results support the hypothesis that oCOm‐21‐derived CO increases myofilament Ca2+ sensitivity through a heme‐dependent mechanism but not by phosphorylation. Further analyses will confirm if this Ca2+ sensitizing effect occurs in an intact heart. [ABSTRACT FROM AUTHOR]