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Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts.
Arzneimittelforschung. 1992 Apr; 42(4):437-45.A

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+Show Affiliations

Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Fed. Rep. of Germany.No affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info availableNo affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

1386515

Citation

Bethke, T, et al. "Phosphodiesterase Inhibition By Enoximone in Preparations From Nonfailing and Failing Human Hearts." Arzneimittel-Forschung, vol. 42, no. 4, 1992, pp. 437-45.
Bethke T, Eschenhagen T, Klimkiewicz A, et al. Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts. Arzneimittelforschung. 1992;42(4):437-45.
Bethke, T., Eschenhagen, T., Klimkiewicz, A., Kohl, C., von der Leyen, H., Mehl, H., Mende, U., Meyer, W., Neumann, J., & Rosswag, S. (1992). Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts. Arzneimittel-Forschung, 42(4), 437-45.
Bethke T, et al. Phosphodiesterase Inhibition By Enoximone in Preparations From Nonfailing and Failing Human Hearts. Arzneimittelforschung. 1992;42(4):437-45. PubMed PMID: 1386515.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Phosphodiesterase inhibition by enoximone in preparations from nonfailing and failing human hearts. A1 - Bethke,T, AU - Eschenhagen,T, AU - Klimkiewicz,A, AU - Kohl,C, AU - von der Leyen,H, AU - Mehl,H, AU - Mende,U, AU - Meyer,W, AU - Neumann,J, AU - Rosswag,S, PY - 1992/4/1/pubmed PY - 1992/4/1/medline PY - 1992/4/1/entrez SP - 437 EP - 45 JF - Arzneimittel-Forschung JO - Arzneimittelforschung VL - 42 IS - 4 N2 - 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) SN - 0004-4172 UR - https://www.unboundmedicine.com/medline/citation/1386515/Phosphodiesterase_inhibition_by_enoximone_in_preparations_from_nonfailing_and_failing_human_hearts_ DB - PRIME DP - Unbound Medicine ER -