Inotropic and energetic effects of altering the force-calcium relationship: mechanisms, experimental results, and potential molecular targets.

Conventional positive inotropy with beta-adrenergic agonists or phosphodiesterase inhibitors increases the amplitude of the calcium transient and is associated with increases in myocardial oxygen consumption that may not be desirable when used in heart failure. Alternatively, agents that increase the sensitivity of the contractile apparatus without increasing the amplitude of the calcium transient have been shown to increase contractility without increasing energy consumption. Also, agents that result in negative inotropy while maintaining the amplitude of the calcium transient result in more energy-inefficient negative inotropy in comparison with agents that cause negative inotropy though a decrease in the amplitude of the calcium transient. These experiments suggest that calcium handling is responsible for a large proportion of the total energy expenditure associated with changes in inotropy. Problems that remain with the use of calcium-sensitizing agents include uncertainty regarding the site of action, adverse effects on systemic and coronary vasculature and diastolic function, and concomitant phosphodiesterase-inhibiting activity. One alternative is to use genetically engineered mouse models in which specific mutations selective to the myocyte can be produced. Potential molecular targets include the protein kinase A and C phosphorylation sites on troponin I, which, when phosphorylated, mediate a reduction in calcium sensitivity and a reduction in maximal actomyosin adenosinetriphosphatase activity, respectively. Mutations at these sites, by altering the relationship between force and calcium, may provide significant insights into the molecular mechanisms controlling the energetics of positive inotropy.