Effects of OR-1896, an Active Metabolite of Levosimendan, on Contractile Force and Aequorin Light Transients in Intact Rabbit Ventricular Myocardium

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Abstract
We performed experiments in rabbit ventricular papillary muscles loaded with aequorin to elucidate the mechanism of positive inotropic effect (PIE) of OR-1896, an active metabolite of levosimendan. The concentration-response curve (CRC) for OR-1896 was biphasic: PIE of OR-1896 reached a plateau at 10−5M (first phase), and the CRC became steeper at 10−3M and higher (second phase). Maximal response of the first phase was 11% of the maximal response to isoproterenol (ISOmax) and associated with an increase in Ca2+ transients of 5% of ISOmax. For a given degree of PIE, the increase in Ca2+ transients by OR-1896 was lower than that induced by elevation of [Ca2+]o. The PIE of OR-1896 was not associated with impairment of relaxation, and it was abolished by carbachol. In conclusion, OR-1896 has a PIE partly due to an increase in myofibrillar Ca2+ sensitivity that is exerted through crosstalk with signal transduction mediated by cyclic adenosine monophosphate (cAMP).