New mechanisms for positive inotropic agents: Focus on the discovery and development of imazodan

Abstract

Intense efforts during the last decade to identify a useful positive inotropic agent to replace digitalis for the treatment of congestive heart failure have led to the discovery of several dozen potential substitutes, of which a number are currently undergoing clinical trials. In addition to producing a variety of new therapeutic entities, research in this area has also yielded valuable new information regarding the fundamental events that regulate calcium homeostasis and contractile function in the cardiac cell. For example, several of these new inotropic agents, including the calcium-channel stimulator BAY-k 8644, the sodium-channel stimulator DPI-201-186, and the sodium-calcium exchange inhibitor dichlorobenzamil, have provided considerable insight into the role of sodium and calcium in regulating contractility and the molecular events that mediate potential-dependent ion channels. Likewise, the discovery and development of agents like imazodan, amrinone, enoximone, and other selective type III phosphodiesterase inhibitors have provided new information regarding multiple molecular forms of cyclic nucleotide phosphodiesterase, compartmentation of cyclic AMP, and the importance of soluble vs. membrane-bound phosphodiesterases.

Electrophysiological effects of amrinone on the automaticity and membrane current system of the rabbit sinoatrial node cells

“…Second, even PDE III, per se, appears to have several subclasses. In canine ventricular muscle, for instance, part of the PDE III is bound to the membrane whereas the rest is contained in the intracellular space in a soluble form, and their different distribution in different fiber types could result in dissimilar responses to a given inhibitor [26]. Third, the fact that even the same selective PDE III inhibitor may show a positive inotropic action in the rabbit myocardium but not in the rat [24] suggests that, depending on the animal species, an increase in intracellular cyclic AMP level caused by PDE inhibition could be subject to different degrees of modulation in the process involving cyclic GMP [25].…”