Abstract for Paper VIII

Biochemical Kinetic Calculations of Dual Ca²⁺ Site Activation of Cardiac Muscle Contraction; The mechanisms of effectors

Using published kinetic and binding constants and the two-site model of Ca²⁺ activation, a kinetic Scheme for the control of muscle contraction is constructed that allows calculation of cross-bridge recruitment as a function of [Ca²⁺] and hence ATPase activity. A simple Hookean approach with a novel relationship of cross-bridge number to rigidity is then used to calculate the force developed under static or transient [Ca²⁺] conditions. This allows the comparison of the forces developed and, most importantly, the relaxation rates when particular kinetic constants are used. The results of changes in conditions and the use of effectors on the actomyosin ATPase can then be interpreted in simple chemical kinetic terms. The differing participation of Ca²⁺ and ATP in the separate processes of thick- and thin-filament activation, i.e. recruitment and procession of cross-bridges, is apparent in their respective cooperativities. Three effectors of muscle contraction, each acting via the troponin complex, are then considered in the light of the kinetic Scheme proposed. These calculations demonstrate the greatly improved understanding derived from the kinetic model. As well as the molecular basis of the Frank–Starling Law the model explains both the anomalous decrease in Ca²⁺ sensitivity of the myofibrils that accompanies adrenergic stimulation and how Levosimendan, an activating drug, is paradoxically an inhibitor of Ca²⁺ binding to troponin-C. Isoprenaline and Levosimendan both increase the muscle relaxation rate. A striking conclusion is the suggestion that a combination of an inhibitor of cardiac function (a Ca²⁺ channel blocker) and stimulation (adrenergic or induced by Levosimendan) may be beneficial in cases of diastolic failure.