Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts.

TH Bethke, T Eschenhagen, A Klimkiewicz… - Arzneimittel …, 1992 - europepmc.org
TH Bethke, T Eschenhagen, A Klimkiewicz, C Kohl, H Von Der Leyen, H Mehl, U Mende…
Arzneimittel-forschung, 1992europepmc.org
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 …
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)
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