Phosphodiesterase inhibition

The action of cAMP is terminated when it is cleaved to AMP by phosphodiesterase. Thus phosphodiesterase inhibition increases the concentration of cAMP and enhances b-receptor-mediated inotropic activity. Although phosphodiesterase inhibition depends on cAMP, it is independent of the b-receptor and is effective in the presence of b-receptor downregulation. In addition to mediating positive inotropic action in the heart and vasodilation in vascular smooth muscle, phosphodiesterase inhibition increases cAMP in bronchial smooth muscle (bronchodilation), platelets (decreased platelet aggregation), and liver (gluconeogenesis).

There are three major subgroups of phosphodiesterase. Type I cleaves cGMP, type II cleaves both cGMP and cAMP, and type III is specific for cAMP. Non-selective phosphodiesterase inhibitors have a wide spectrum of clinical effects: aminophylline promotes bronchodilation, cardiac inotropy, and vasodilation; dipyridamole enhances platelet aggregation and coronary vasodilation; papaverine induces profound vasodilation. Thus only those phosphodiesterase inhibitors which are specific for phosphodiesterase III are used as cardiac inotropic agents: the bipyridine derivatives amrinone and milrinone, and the imidazole derivatives enoximone and piroximone. The latter two remain investigational agents in the United States.

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