A novel cyclic GMP-lowering agent, LY83583, blocks carbachol-induced cyclic GMP elevation in rabbit atrial strips without blocking the negative inotropic effects of carbachol

A novel cyclic GMP-lowering agent, LY83583(6-anilino-5,8-quinolinedione), was used to investigate the possibility that increases in myocardial cyclic GMP levels are responsible for the negative inotropic effects of cholinergic agonists. Concentrations of carbachol from 0.3 to 3 microM elevated cyclic GMP levels in electrically paced rabbit atrial strips by 75 to 200% and decreased contractile force in the strips by 30 to 60%. Pretreatment of the muscles for 10 min with 10 microM LY83583 significantly lowered resting cyclic GMP levels and completely blocked the elevation of cyclic GMP by these concentrations of carbachol. However, the negative inotropic effects of carbachol were not blocked by the LY83583. These results indicate that the negative inotropic effects of carbachol in rabbit atrium are not mediated by increases in tissue levels of cyclic GMP.