Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea-pig hearts.
1. The present study compared the cyclic nucleotide phosphodiesterase (PDE) activities in cardiomyocytes and ventricular cardiac tissue from guinea-pigs. The aim of the study was to determine whether PDE activities in ventricular tissue accurately reflect the isoenzymes present in cardiomyocytes. 2. In homogenates of cardiomyocytes and multicellular ventricular tissue, four distinct soluble PDE activities could be separated by DEAE-sepharose chromatography. 3. In multicellular cardiac tissue as well as in cardiomyocyte preparations, adenosine 3':5'-cyclic monophosphate (cyclic AMP) PDE isoenzymes I-IV were comparable in terms of substrate affinities, and inhibition or stimulation by guanosine 3':5'-cyclic monophosphate (cyclic GMP). However, in cardiomyocytes the Vmax values of PDE I-IV were lower by a factor of about 2 to 7 and the basal activities were lower by a factor of about 3 to 5 as compared to multicellular cardiac tissue. 4. To investigate whether the PDE I-IV activities were similarly inhibited by PDE inhibitors in both preparations, we studied the effects of 3-isobutyl-1-methylxanthine (IBMX), UD-CG 212 Cl (2-(4-hydroxy-phenyl)-5-(5-methyl-3-oxo-4, 5-dihydro-2H-6-pyridazinyl)benzimidazole HCl) and rolipram. UD-CG 212 Cl was a selective PDE III inhibitor in cardiomyocytes (IC50 0.3 mumol l-1) and in ventricular tissue (IC50 value 0.1 mumol l-1). Rolipram selectively inhibited PDE IV in cardiomyocytes (IC50 1.4 mumol ml-1) and in ventricular tissue (IC50 1.1 mumol l-1) whereas IBMX was a nonselective PDE inhibitor in both preparations.5. It is concluded that the PDE isoenzymes I-IV from multicellular ventricular tissue can be used as a representative system for investigating PDE inhibiting properties of PDE inhibitors in the myocardium since comparable PDE isoenzymes I-IV exist in guinea-pig ventricular cardiomyocytes and multicellular ventricular tissue.
Bethke
T
T
Abteilung Allgemeine Pharmakologie, Universitäts-Krankenhaus Eppendorf, Universität Hamburg, Germany.
Meyer
W
W
Schmitz
W
W
Scholz
H
H
Stein
B
B
Thomas
K
K
Wenzlaff
H
H
D015056:1-Methyl-3-isobutylxanthine / Q000494:pharmacology; D015105:3',5'-Cyclic-AMP Phosphodiesterases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000818:Animals; D002852:Chromatography, Ion Exchange; D000242:Cyclic AMP / Q000378:metabolism; D006168:Guinea Pigs; D006321:Heart / Q000187:drug effects; D006352:Heart Ventricles / Q000187:drug effects / Q000201:enzymology; D066298:In Vitro Techniques; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D009206:Myocardium / Q000166:cytology / Q000201:enzymology*; D010726:Phosphodiesterase Inhibitors / Q000494:pharmacology*; D011724:Pyridazines / Q000494:pharmacology; D011760:Pyrrolidinones / Q000494:pharmacology; D020889:Rolipram
D007527:Isoenzymes; D010726:Phosphodiesterase Inhibitors; D011724:Pyridazines; D011760:Pyrrolidinones; C047936:UD CG 212 Cl; D000242:Cyclic AMP; D015105:3',5'-Cyclic-AMP Phosphodiesterases; D020889:Rolipram; D015056:1-Methyl-3-isobutylxanthine