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

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.