DIFFERENTIAL-EFFECTS OF PHOSPHODIESTERASE INHIBITORS ON ACCUMULATION OF CYCLIC-AMP IN ISOLATED VENTRICULAR CARDIOMYOCYTES

The intracellular actions of phosphodiesterase (PDE) inhibitors on the accumulation of cyclic nucleotides were studied in isolated ventricul ar cardiomyocytes from adult Sprague-Dawley rats. Elevated levels of c yclic AMP, due to the effects of selective PDE inhibitors, were detect ed only when the levels of cyclic nucleotide were enhanced with forsko lin (10 mu M). The time course for the elevation of cyclic AMP levels was similar for all the PDE inhibitors tested, following the pattern o f an initial rise in the first 2-4 min, proceeded by a steady state at 67 +/- 6% of the maximum stimulation. HN-10200 hylsulfinyl-2-thienyl] -1H-imidazo-[4,5-c]-pyridine hydrochloride), a new imidazopyridine der ivative, had a similar concentration-dependent profile to the structur ally related compound, sulmazole (AR-L 115 BS, -[2-methoxy-4-methylsul finyl)phenyl]-1H-pyridine). Both the non-selective inhibitor, 3-isobut yl-1-methylxanthine (IBMX), and the selective PDE IV inhibitor, Ro 20- 1724 butoxy-4-methoxyphenyl)methyl]-2-imidazolidinone), potentiated th e forskolin-stimulated levels of cyclic AMP with a much greater effica cy than sulmazole or HN-10200. The concentrations of forskolin require d by IBMX, sulmazole and HN-10200 (10(-3) M) to increase levels of cyc lic AMP by 4 pmol/mg protein were 3.2 x 10(-6) M, 1.32 x 10(-5) M and 1.46 x 10(-5) M, respectively. Enoximone failed to cause an increase i n the levels of cyclic AMP, even when stimulated with maximal concentr ations of forskolin. Furthermore, in the presence of forskolin, enoxim one attenuated the response of Ro 20-1724 and IBMX in a concentration- dependent manner. Enoximone, similarly to HN-10200, sulmazole, Ro 20-1 724 and IBMX did not produce any significant effect on levels of cycli c GMP under elevated conditions in the presence of sodium nitroprussid e. The combined action of Ro 20-1724, with either HN-10200, sulmazole, or IBMX (10(-4) M), on intracellular levels of cyclic AMP, was not gr eater than the response to Ro 20-1724 alone. These data demonstrate th e differential actions of PDE III and PDE IV inhibitors in rat ventric ular cardiomyocytes. It is suggested that enoximone has a high selecti vity for the PDE III isoenzyme so that hydrolysis of cyclic AMP by the PDE IV isoenzyme is not inhibited, in accordance with the lack of inc rease in cyclic AMP by enoximone in rat cardiomyocytes. HN-10200 and s ulmazole, producing small increases in intracellular levels of cyclic AMP, are less selective PDE III inhibitors than enoximone. In contrast , the non-selective PDE inhibitor, IBMX, and the PDE IV inhibitor, Ro 20-1724, produced large increases in intracellular levels of cyclic AM P and it is likely, therefore, that Ro 20-1724 has effects on both the PDE III and PDE IV isoforms in rat cardiomyocytes.