Levosimendan increased calcium sensitivity and induced a positive inotropic effect without increasing myosin ATPase activity or changing relaxation time in guinea pig papillary muscle.
Does levosimendan improve inotropy without impairing relaxation or increasing energy consumption in guinea pig papillary muscle models?
Levosimendan acts as a positive inotrope by increasing the calcium sensitivity of troponin C without the negative effects of increased energy consumption or impaired relaxation seen with other agents.
Levosimendan is a novel positive inotropic drug targeted to increase contraction force of the heart through its calcium-dependent binding to troponin C (cTnC). We investigated the calcium-sensitizing effect of levosimendan on contractile proteins as well as its positive inotropic and lusitropic effects in paced guinea pig papillary muscle. We also studied the effect on energy consumption of myosin-actin crossbridges in a myosin ATPase assay. The calcium sensitization induced by levosimendan in fibers skinned with saponin was dependent on the perforation velocity of cell membranes. Levosimendan was almost ineffective in slowly perforated fibers, but was the most potent calcium sensitizer in fibers with rapidly perforated cells. The perforation-dependent calcium sensitization was probably due to changes in phosphorylation state of contractile proteins during the slow dissection of fibers. It is noteworthy that the calcium-sensitizing effect of levosimendan was not affected by acidic pH. Levosimendan at therapeutically relevant (0.3-10 microM) concentrations markedly increased calcium sensitivity both at pH 6.7 and 7.0, being more potent than EMD 53998, pimobendan, and MCI-154. The lack of effect of levosimendan on maximum tension supports the hypothesis that levosimendan increases calcium sensitivity through its action on cTnC. Unlike EMD 53998, levosimendan did not increase myosin ATPase activity, indicating that it did not increase the cycling rate of myosinactin crossbridges. In paced papillary muscles, levosimendan induced positive inotropic effect without changing relaxation time. Thus, levosimendan was devoid of the main negative factors described for calcium sensitizers.
Haikala et al. (1995) studied this question. Levosimendan vs. EMD 53998, pimobendan, and MCI-154 was evaluated on Calcium sensitization, myosin ATPase activity, and inotropic/lusitropic effects. Levosimendan increased calcium sensitivity and induced a positive inotropic effect without increasing myosin ATPase activity or changing relaxation time in guinea pig papillary muscle.