Calcium-sensitivity modulation of cardiac myofibrillar proteins

Myocardial contractile force may be altered not only by changing intracellular free Ca2+ but also by increasing or decreasing the calcium responsiveness of the myofilaments. The latter effect may be due to interventions that decrease the calcium affinity of troponin C, such as intracellular acidosis or factors that act "downstream" of the calcium-troponin-C interaction in the process of muscle activation. These include inorganic phosphate, which accumulates under hypoxic conditions. Conversely, calcium responsiveness may be increased by drugs that probably increase the calcium affinity of troponin C, such as sulmazole, adibendan, pimobendan, and isomazole. These and related drugs also increase the force development of skinned trabeculae that are submaximally activated by Ca2+ stimulation in ATP salt solution. Thus, we confirmed earlier studies showing that adibendan increased submaximal Ca2+-activated force of pig-heart trabecula skinned by 0.5% lubrol-WX. Qualitatively similar results were obtained with pimobendan. However, calcium responsiveness may not only be modulated by factors influencing troponin, but also by modulation of crossbridge rate constants as well as by other factors that act downstream of troponin C. These include peptides derived from thin-filament proteins and subfragment S1 of myosin.