Phosphodiesterase inhibition in ventricular cardiomyocytes from guinea‐pig hearts

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Abstract
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 μmol l−1) and in ventricular tissue (IC50 value 0.1 μmol l−1). Rolipram selectively inhibited PDE IV in cardiomyocytes (IC50 1.4 μmol ml−1) and in ventricular tissue (IC50 1.1 μmol 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.

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