Two isoforms of cGMP-inhibited cyclic nucleotide phosphodiesterases in human tissues distinguished by their responses to vesnarinone, a new cardiotonic agent.
We examined the inhibitory effects of vesnarinone, a new cardiotonic agent, on human cyclic nucleotide phosphodiesterase (PDE). Vesnarinone selectively inhibited the activity of human cardiac cGMP-inhibited PDE with a Ki value of 8.5 microM. The inhibition of human cardiac cGMP-inhibited PDE by vesnarinone was not competitive but was of the mixed type with respect to cAMP. Although the activities of the cGMP-inhibited PDE from human heart, aorta, platelets, and kidney were inhibited to the same extent by cGMP, enoximone, and cilostazole, vesnarinone inhibited the activities of cardiac and kidney cGMP-inhibited PDE with 10 times greater potency than those of platelet and aorta cGMP-inhibited PDE. These results suggest that there exist, in human tissues, two isoforms of cGMP-inhibited PDE that can be distinguished by reference to the inhibitory effects of vesnarinone.
First Department of Internal Medicine, Mie University School of Medicine, Japan.
H
H
Masuoka
M
M
Ito
M
M
Sugioka
H
H
Kozeki
T
T
Konishi
T
T
Tanaka
T
T
Nakano
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors / Q000378:metabolism; D001011:Aorta / Q000201:enzymology; D001792:Blood Platelets / Q000201:enzymology; D002118:Calcium / Q000494:pharmacology; D002147:Calmodulin / Q000494:pharmacology; D002316:Cardiotonic Agents / Q000494:pharmacology*; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism; D006152:Cyclic GMP / Q000494:pharmacology*; D017335:Enoximone / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D007668:Kidney / Q000201:enzymology; D009206:Myocardium / Q000201:enzymology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D011719:Pyrazines; D011804:Quinolines / Q000494:pharmacology*; D013777:Tetrazoles / Q000494:pharmacology
D002147:Calmodulin; D002316:Cardiotonic Agents; D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011719:Pyrazines; D011804:Quinolines; D013777:Tetrazoles; C041667:vesnarinone; D017335:Enoximone; D000242:Cyclic AMP; D010727:Phosphoric Diester Hydrolases; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D006152:Cyclic GMP; D000077407:Cilostazol; D002118:Calcium