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

Abstract

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.

Keywords: calcium sensitivity; carbon monoxide; heme; myofilament.