EFFECTS OF CALCIUM SENSITIZERS ON INTRACELLULAR CALCIUM HANDLING AND MYOCARDIAL ENERGETICS

Calcium sensitizers may influence myocardial energetics by their actio n on calcium turnover and on crossbridge behavior. Using a myothermal method, the effects of the Ca2+ sensitizer EMD-53998 on calcium cyclin g, crossbridge behavior, and myocardial energy turnover were compared with the effects of an increase in extracellular calcium from 1.25 to 7.5 mM and with the effects of the catecholamine isoproterenol. All th ree inotropic interventions increased isometric force development in r ight ventricular rabbit papillary muscles. Relaxation time was decreas ed with isoproterenol, unchanged with high calcium, and increased with EMD 53998. Calcium cycling-related energy consumption, as measured by tension-independent heat, increased by 234% with high calcium, by 439 % with isoproterenol, and by 77% with EMD 53998. In contrast to high c alcium and isoproterenol, EMD 53998 increased economy of crossbridge c ycling by increasing the force-time integral of the individual crossbr idge cycle. The data indicate that EMD 53998 acts by phosphodiesterase inhibition and myofilament calcium sensitization. The latter effect i s in part mediated by alteration of crossbridge behavior. Because of i ts effects on calcium cycling and crossbridge function myocardial ener gy turnover was reduced significantly with EMD 53998, whereas energy t urnover was unchanged with high calcium and was increased with isoprot erenol. The new calcium sensitizer levosimendan was investigated in is olated failing human myocardium. Levosimendan dose-dependently increas ed isometric tension. The inotropic effect was associated with increas ed rate of relaxation and reduced relaxation time. Measurements of int racellular calcium using the photoprotein aequorin suggest that levosi mendan acts by increasing myofilament calcium sensitivity and by incre asing cAMP due to phosphodiesterase inhibition. However, the contribut ion of the cAMP system to the action of levosimendan appears to be rat her small. Therefore, the finding of a positive lusitropic effect of l evosimendan may be consistent with the notion that levosimendan binds to troponin-C and increases calcium sensitivity only at high (systolic ) intracellular calcium concentrations.