Phosphodiesterase-inhibiting properties of newer inotropic agents

The positive inotropic effects of the bipyridine derivatives amrinone and milrinone and of the benzimidazole compounds sulmazole, pimobendane, and UD-CG 212 Cl are due at least in part to inhibition of cardiac phosphodiesterase activity and hence to an increase in myocardial cyclic AMP (cAMP) content. Compared with the other agents, the contribution of the cAMP system appears to be relatively small in the case of pimobendane and UD-CG 212 Cl. This reduced effect is probably advantageous because an increase in cAMP leads not only to positive inotropic but also to positive chronotropic effects and possibly to arrhythmogenesis. The latter in particular may limit the usefulness of new cardiotonic agents, although--at least theoretically--a cAMP-dependent arrhythmogenic action might be overcome by additional "antiarrhythmic" properties, e.g., prolongation of the action potential, depression of transient depolarizations, or depression of the fast Na+ inward current. Sulmazole and pimobendane have been shown to have an additional effect on the contractile properties in that they increase the sensitivity of the myofibrils to Ca++.