Contrasting effects of isoproterenol and phosphodiesterase III inhibitor on intracellular calcium transients in cardiac myocytes from failing hearts.

1. Effects of a newly developed phosphodiesterase (PDE) III inhibitor, E-1020, on intracellular calcium transients were compared with those of isoproterenol (ISO) in isolated single myocytes from failing hearts secondary to pulmonary hypertension induced by monocrotaline injection. Myocytes were isolated by enzyme digestion using a Langendorff apparatus. Changes in intracellular calcium concentrations ([Ca2+]i) were recorded using a fura-2 fluorescence microscopic technique. Cyclic AMP contents of the hearts were measured by radio-immunoassay. 2. Myocytes from failing hearts showed Ca2+ transients with a low peak (low amplitude) and delayed decline of Ca2+ transients. Both ISO and E-1020 increased peak [Ca2+]i, max + d[Ca2+]i/dt, and max - d[Ca2+]i/dt in a concentration-dependent manner while both agents decreased T80L (time to 80% decline of amplitude from peak light). The concentrations which increased peak [Ca2+]i by 50% were 1.6 x 10(-9) mol/L of ISO and 2 x 10(-6) mol/L of E-1020. These concentrations increased cAMP in the heart to the same levels. Analysis of the effects of both agents on peak [Ca2+]i versus max - d[Ca2+]i/dt showed that ISO is much more effective on peak [Ca2+]i while E-1020 is more effective on max - d[Ca2+]i/dt. 3. These results showed that the effects of ISO and E-1020 on the parameters of intracellular Ca2+ transients of single myocytes from failing hearts are slightly different, and suggest that E-1020 may improve diastolic function as well as systolic function in failing hearts.