Inhibitors of phosphodiesterases
Caffeine and theophylline are competitive but nonspecific inhibitors of phosphodiesterases. But there are specific inhibitors of certain types of phosphodiesterases; 11 types have been described. Recent research made it possible to select specific inhibitors of a type of phosphodiesterase.
Type III phosphodiesterases are present primarily in the myocardium. Their inhibition results in an increase of cyclic AMP and a positive inotropic effect. The inhibitors are amrinone, milrinone and enoximone. Long-term treatment of congestive heart failure by these inhibitors has been disappointing. They are only used in intravenous perfusion, during a limited time, to treat acute myocardial failure. Apart from their cardiac effects, they have vasodilator and bronchodilator properties.
Vesnarinone, in addition to inhibition of phosphodiesterases, induces sodium entry into the myocardium and inhibits cytokine production and seemed to have, over the long term, a favorable effect in congestive heart failure, but this result was contradicted by a later study.
Type IV phosphodiesterases are present in various cells implicated in inflammation and immunity. They inactivate cyclic AMP preferentially. The specific inhibitors of type 4 phosphodiesterases being studied for the treatment of asthma and chronic obstructive broncho-pneumonopathies are cilomilast and roflumilast.
Type V phosphodiesterases are present primarily in the corpus cavernosum of the penis where they inactivate cyclic GMP. Inhibition of phosphodiesterases type V by sildenafil slows down the hydrolysis of cyclic GMP which accumulates and elicits a vasodilation and an erection. See NO-mimetic.
Papaverine is a vasodilator and a musculotropic antispasmodic which acts, at least partially, by inhibition of phosphodiesterases and increase intracellular concentration of Cyclic AMP. It was very largely used as vasodilator but it is now replaced by more suitable drugs. It is still employed by certain surgeons to avoid the spasm of a vessel to be grafted and by certain patients by intracavernous route to treat their erectile dysfunction. In this last case they must be informed risk of priapism.
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