Tissue specificity of cAMP‐phosphodiesterase inhibitors: Rolipram, amrinone, milrinone, enoximone, piroximone, and imazodan

Abstract

AbstractThe effects of nine cAMP‐phosphodiesterase inhibitors, including amrinone, milrinone, enoximone, piroximone, imazodan (Cl‐914), CK‐2438 (4,5‐dihydro‐6‐[pyridin‐4‐yl]‐3‐[2H]pyridazinone), rolipram, ZK‐73433 4[(3,4‐dimethoxy‐phenyl)methyl]‐2‐pyrolidinone), and IBMX (3‐isobutyl‐1‐methylxanthine) were determined on crude enzyme fractions prepared from heart, brain, and thoracic aorta of dogs. Inhibitors, such as amrinone, milrinone, enoximone, piroximone, imazodan, and CK‐2438, were found to be specific for the enzyme from the heart, but not that from the brain and thoracic aorta. On the other hand, rolipram and ZK‐73433 were potent inhibitors of the brain enzyme, but not of enzymes from the heart and thoracic aorta. None of these compounds effectively depressed cGMP‐phosphodiesterase from the thoracic aorta. Conversely, IBMX was nonspecific because it was equally active on the cAMP‐phosphodiesterases from all three tissues and the cGMP‐phosphodiesterase from the thoracic aorta. The abilities of these compounds to inhibit the cAMP‐phosphodiesterase from the three tisses were not a function of their different lipid solubilities. It is concluded that most inhibitors exhibited tissue specificity on the cAMP‐phosphodiesterases from various organs of one animal species. These data also suggest the existence of isoforms of cAMP‐phosphodiesterase (PDE‐III) in different tissues.