title: Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts.
abstract: The effects of enoximone (MDL 17043, Perfan, CAS 77671-31-9) on the activities of the phosphodiesterase (PDE) isoenzymes I-IV and on force of contraction were investigated in ventricular preparations isolated from failing (end-stage myocardial failure, NYHA IV) and non-failing human hearts. In both tissues four PDE isoenzymes (PDE I-IV) with similar properties were separated by DEAE-sepharose chromatography. The effects of enoximone on PDE I-IV activities did not differ between non-failing and failing human hearts. As compared to PDE I (IC50 2100 mumol/l) and II (IC50 2900 mumol/l) enoximone is a selective PDE III (cGMP-inhibited PDE, IC50 5.9 mumol/l) and PDE IV (cGMP-insensitive PDE, IC50 21.1 mumol/l) inhibitor. Milrinone, 3-isobutyl-1-methylxanthine (IBMX) and UD-CG 212 Cl, a derivative of pimobendan, were studied in the failing heart for comparison. Milrinone inhibited PDE I-IV activities similar to enoximone, revealing IC50 values for inhibition of PDE III and IV (1.2 and 3.3 mumol/l) which were about two orders of magnitude lower than that of PDE I and II (173 and 306 mumol/l). UD-CG 212 Cl was the most potent (IC50 0.05 mumol/l) and most selective PDE III inhibitor tested (IC50 for PDE I, II and IV were 175, 181 and 40.8 mumol/l, resp.), whereas IBMX inhibited PDE I-IV nonselectively (IC50 15.3, 26.2, 5.6, 5.8 mumol/l, respectively). In trabeculae carneae from nonfailing and failing human hearts enoximone increased force of contraction only marginally by 18.0 +/- 9.1% (n = 8) and 24.5 +/- 8.7% (n = 9) of the predrug value.(ABSTRACT TRUNCATED AT 250 WORDS)
authors.affiliation: Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Fed. Rep. of Germany.
authors.forename: T
authors.initials: T
authors.lastname: Bethke
authors.forename: T
authors.initials: T
authors.lastname: Eschenhagen
authors.forename: A
authors.initials: A
authors.lastname: Klimkiewicz
authors.forename: C
authors.initials: C
authors.lastname: Kohl
authors.forename: H
authors.initials: H
authors.lastname: von der Leyen
authors.forename: H
authors.initials: H
authors.lastname: Mehl
authors.forename: U
authors.initials: U
authors.lastname: Mende
authors.forename: W
authors.initials: W
authors.lastname: Meyer
authors.forename: J
authors.initials: J
authors.lastname: Neumann
authors.forename: S
authors.initials: S
authors.lastname: Rosswag
mesh_terms: D000328:Adult; D009202:Cardiomyopathies / Q000201:enzymology*; D002848:Chromatography, DEAE-Cellulose; D017335:Enoximone; D005260:Female; D006321:Heart / Q000187:drug effects*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000201:enzymology*; D010042:Ouabain / Q000031:analogs & derivatives / Q000494:pharmacology; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*
chemical_list: D007093:Imidazoles; D010726:Phosphodiesterase Inhibitors; C000977:dihydroouabain; D010042:Ouabain; D017335:Enoximone; D007545:Isoproterenol