A new concept for the mechanism of Ca+(+)-regulation of muscle contraction. Implications for physiological and pharmacological approaches to modulate contractile function of myocardium

Abstract

Recent development of an experimental protocol to determine kinetics of active cross-bridge turnover is muscle allows analysis of possible Ca+(+)-effects on cross-bridge turnover kinetics. This analysis enabled us to distinguish the two main hypotheses about the mechanism of regulation of muscle contraction. In the first hypothesis, the number of actively turning over cross-bridges is changed, while cross-bridge turnover kinetics are unaffected by Ca++ (regulation by "cross-bridge recruitment"). In the other hypotheses, cross-bridge turnover kinetics are controlled by Ca++, while the number of actively turning over cross-bridges is essentially unaffected (regulation by "rate modulation"). It is found that the major mechanism of regulation of muscle contraction is by a change in the rate constant (fapp) that determines the transition of a cross-bridge from the weak-binding (non-force generating) configuration to its strong-binding (force generating) configuration. It is demonstrated that the concept of "rate modulation" requires reinterpretation of force-pCa relations and of the mechanisms of physiological and pharmacological modulation of force-pCa relations. On this basis, an additional mechanism for positive inotropic interventions is demonstrated which may have advantages over the previously established mechanisms.