Effect of phosphodiesterase inhibitors on heart contractile behaviour, protein kinase activity and cyclic nucleotide levels

María I. Argel, Leticia Vittone, Angela O. Grassi, Liliana E. Chiappe, Gladys E. Chiappe, Horacio E. Cingolani

Research output: Contribution to journalArticle

Abstract

Three cyclic nucleotide phosphodiesterase inhibitors were examined for their effects upon contractility, relaxation, cAMP-dependent protein kinase activity ratio and cyclic nucleotide levels in the perfused rat heart. Theophylline (2 × 10−4m), papaverine (10−5m) and pentoxifylline (10−4m) were infused at constant heart rate and coronary flow. Developed tension (T), its maximal rate of rise (+Ṫ), its maximal rate of fall (−Ṫ) and time to peak tension (TTP) were measured in fast records. No changes in contractility were observed with theophylline and a slightly positive inotropic effect at 1 min of perfusion with papaverine and pentoxifylline was detected. There was no prolongation in the duration of the systole and a small but significant decrease in TTP after 1 min of papaverine administration was found. After 1 min perfusion cAMP increased from control values of 0.503 ± 0.025 pmol/mg wet weight to 0.773 ± 0.062 (theophylline), 0.784 ± 0.077 (papaverine) and 0.604 ± 0.034 (pentoxifylline). After 15 min perfusion from 0.452 ± 0.031 to 0.762 ± 0.064 (papaverine) and 0.645 ± 0.047 (pentoxifylline). At this time of perfusion cAMP-dependent protein kinase activity ratio was also increased from 0.21 ± 0.01 to 0.30 ± 0.03 (theophylline), 0.31 ± 0.03 (papaverine) and 0.32 ± 0.03 (pentoxifylline). cGMP rose from 8.1 ± 1.2 fmol/mg wet weight to 15.0 ± 1.4 (theophylline) and 12.3 ± 1.4 (papaverine) after 1 min perfusion and after 15 min from 8.2 ± 1.2 to 13.2 ± 1.3 (theophylline) and 13.3 ± 1.9 (papaverine). Pentoxifylline did not produce significant changes. It is suggested that increased cGMP levels interfere with cAMP and cAMP-dependent protein kinase in the mechanical effects of cyclic nucleotide phosphodiesterase inhibitors.

Original languageEnglish (US)
Pages (from-to)939-954
Number of pages16
JournalJournal of Molecular and Cellular Cardiology
Volume12
Issue number10
DOIs
StatePublished - Jan 1 1980

Keywords

  • Cardiac mechanics
  • Heart cAMP-dependent protein kinase
  • Papaverine
  • Phosphodiesterase inhibitors
  • Theophylline
  • cAMP
  • cGMP

ASJC Scopus subject areas

  • Molecular Biology
  • Cardiology and Cardiovascular Medicine

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