Abstract for Paper IV

The Frank–Starling Law of the Heart; Cross-bridge recruitment and Ca²⁺ cooperativity

There are two categories of Ca²⁺ binding involved in cardiac muscle activation; i) The well recognized and understood cardiac troponin-C (Tn-C) Ca²⁺ binding that is not inhibited by Mg²⁺ and is easily measured by ⁴⁵Ca²⁺ binding and ii) a transient Ca²⁺-binding site which is ATP-dependent and competitively inhibited by Mg²⁺. This second Ca²⁺ binding is restricted to initiation, i.e. cross-bridge recruitment, and thus is not measurable by ⁴⁵Ca²⁺ binding. We propose that the structural changes resulting from muscle stretch, particularly with cardiac muscle, obviate the need for the second Ca²⁺ binding for cross-bridge recruitment. This results in the manifestation of the Frank–Starling “Law of the Heart”. From this we conclude that the stretch-induced increase in Ca²⁺ sensitivity is in fact a result of decreased Ca²⁺ cooperativity, contrary to current belief. Predictions are made regarding the interaction of stretch with the substrates or products of the actomyosin-ATPase reaction on the strength of contraction. These predictions have already been observed, although not previously explained. The cross-bridge recruitment control of muscle contraction implies a processive, or walking, movement of the two-headed myosin II along the thin-filaments. Furthermore, these considerations have major implications in muscle relaxation, cardiac Ca²⁺-sensitizing drugs and the relationship of these to diastolic heart failure.