Effects of amrinone and enoximone on the subclasses of cyclic AMP phosphodiesterase from human heart and kidney.
We observed the intracellular localization of low-Km cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDEIII) subclasses in human heart in comparison to that in human kidney by using comparable potencies of specific inhibitors. PDEIII was observed in not only soluble fraction but particulate fraction in human heart and kidney. Both soluble and particulate PDEIII from human heart selectively hydrolyzed cAMP with similar Km values of 0.36 and 0.40 microM, respectively. They were potently inhibited by amrinone, enoximone, and cyclic guanosine monophosphate (cGMP), but were weakly inhibited by rolipram with much the same IC50 values. Although several animals having soluble and particulate PDEIII possess two pharmacologically distinct subclasses of PDEIII, human heart has only one form, cGMP-sensitive PDEIII. In contrast to cardiac PDEIII, both soluble and particulate PDEIII from human kidney were not readily inhibited by amrinone, enoximone, and cGMP, but rather strongly inhibited by rolipram. Human kidney contains only cGMP-less sensitive form of PDEIII in soluble and particulate fractions. These results suggest that the intracellular distribution of PDEIII subclasses in human hearts are significantly different from those in the hearts of other animal species, and subclasses of PDEIII in humans hearts could not be distinguished by intracellular localization but by organ specificity.
Department of Internal Medicine, Mie University School of Medicine, Japan.
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H
Masuoka
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Ito
T
T
Nakano
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Naka
T
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Tanaka
D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000302:isolation & purification; D000293:Adolescent; D000328:Adult; D000368:Aged; D000676:Amrinone / Q000494:pharmacology*; D002316:Cardiotonic Agents / Q000494:pharmacology*; D002848:Chromatography, DEAE-Cellulose; D017335:Enoximone; D005260:Female; D006321:Heart / Q000187:drug effects; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007668:Kidney / Q000187:drug effects / Q000201:enzymology*; D007700:Kinetics; D008297:Male; D009206:Myocardium / Q000201:enzymology* / Q000648:ultrastructure; D013347:Subcellular Fractions / Q000187:drug effects / Q000201:enzymology
D002316:Cardiotonic Agents; D007093:Imidazoles; D017335:Enoximone; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D000676:Amrinone