A phosphodiesterase inhibitor is a drug that blocks one or more of the five subtypes of the enzyme phosphodiesterase (PDE), thereby preventing the inactivation of the intracellular second messengers, cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) by the respective PDE subtype(s). The ubiquitous presence of this enzyme means that non-specific inhibitors have a wide range of actions, the actions in the heart, and lungs being some of the first to find a therapeutic use. History The different forms or subtypes of phosphodiesterase were initially isolated from rat brains in the early 1970s and were soon afterward shown to be selectively inhibited in the brain and in other tissues by a variety of drugs. The potential for selective phosphodiesterase inhibitors as therapeutic agents was predicted as early as 1977 by Weiss and Hait. This prediction meanwhile has proved to be true in a variety of fields. Classification Nonselective PDE inhibitors Methylated xanthines and derivatives: caffeine, a minor stimulant aminophylline IBMX (3-isobutyl-1-methylxanthine), used as investigative tool in pharmacological research paraxanthine pentoxifylline, a drug that has the potential to enhance circulation and may have applicability in treatment of diabetes, fibrotic disorders, peripheral nerve damage, and microvascular injuries theobromine theophylline, a bronchodilator Methylated xanthines act as both competitive nonselective phosphodiesterase inhibitors, which raise intracellular cAMP, activate PKA, inhibit TNF-alpha and leukotriene synthesis, and reduce inflammation and innate immunity and nonselective adenosine receptor antagonists But different analogues show varying potency at the numerous subtypes, and a wide range of synthetic xanthine derivatives (some nonmethylated) have been developed in the search for compounds with greater selectivity for phosphodiesterase enzyme or adenosine receptor subtypes. PDE2 selective inhibitors EHNA (erythro-9-(2-hydroxy-3-n)adenine) BAY 60-7550 (2-[(3,4-dimethoxyphenyl)methyl]-7-[(1R)-1-hydroxyethyl]-4-phenylbutyl]-5-methyl-imidazo[5,1-f][1,2,4]triazin-4(1H)-one) Oxindole PDP (9-(6-Phenyl-2-oxohex-3-yl)-2-(3,4-dimethoxybenzyl)-purin-6-one) PDE3 selective inhibitors Amrinone, milrinone and enoximone are used clinically for short-term treatment of cardiac failure. These drugs mimic sympathetic stimulation and increase cardiac output. Anagrelide Cilostazol is used in the treatment of intermittent claudication. Pimobendan is FDA approved for veterinary use in the treatment of heart failure in animals. PDE3 is sometimes referred to as cGMP-inhibited phosphodiesterase. PDE4 selective inhibitors Mesembrenone, an alkaloid from the herb Sceletium tortuosum Rolipram, used as investigative tool in pharmacological research Ibudilast, a neuroprotective and bronchodilator drug used mainly in the treatment of asthma and stroke. It inhibits PDE4 to the greatest extent, but also shows significant inhibition of other PDE subtypes, and so acts as a selective PDE4 inhibitor or a non-selective phosphodiesterase