Synergistic action of cyclic GMP on catecholamine-induced chloride current in guinea-pig ventricular cells

1. Effects of cyclic GMP on the catecholamine-induced chloride current (ICl) were studied using the whole-cell patch-clamp technique combined with internal perfusion in single ventricular myocytes dispersed from guinea-pig heart. 2. When ICl was activated by submaximal doses of isoprenaline (0.01-0.1 microM), adrenaline (0.5-1 microM) and histamine (0.2-0.5 microM), intracellular dialysis with cyclic GMP (10-100 microM) induced an extra increase of ICl. No further increase of ICl was induced by cyclic GMP when ICl was maximally activated. In the absence of agonists, cyclic GMP failed to induce ICl. 3. The enhancement by cyclic GMP was also observed when ICl was activated by external application of 0.2-1.0 microM-forskolin or by internal dialysis with a pipette solution containing 50-200 microM-cyclic AMP. 4. In contrast to cyclic GMP, 10-1000 microM-dibutyryl cyclic GMP and 8-bromo-cyclic GMP were ineffective in modifying ICl. 5. Milrinone (1-10 microM), a specific inhibitor of a kind of phosphodiesterase which is inhibited by cyclic GMP, also enhanced ICl activated by submaximal doses of isoprenaline. Milrinone itself did not activate ICl. 6. When ICl was enhanced by 5 microM-milrinone, an additional application of cyclic GMP failed to increase ICl. In the presence of cyclic GMP, milrinone failed to enhance ICl. 7. The above findings on ICl are analogous to the enhancement by cyclic GMP of the beta-adrenergic stimulation of the Ca2+ current reported in the same preparation, and support the hypothesis that in mammalian cardiac cells cyclic GMP potentiates elevation of cyclic AMP induced by beta-adrenergic agents, and thereby increases the amplitudes of ionic currents.