In Vitro Investigations on a New Positive Inotropic and Vasodilating Agent (BM 14.478) That Increases Myocardial Cyclic AMP Content and Myofibrillar Calcium Sensitivity

BM 14.478 (7,7-dimethyl-2-(4-pyridyl)-6,7-dihydro-3H,5H pyrrolo[2,3-f]benz-imidazol-6-one) was investigated in several in vitro experiments to elucidate its positive inotropic and vasodilating efficacy and its mode of action. A direct positive inotropic action was achieved in papillary muscles (10(-6) to 5 X 10(-4) M) and electrically driven atria (10(-8) to 5 X 10(-4) M) from guinea pig hearts. The effect was not affected by propranolol, cimetidine, or tetrodotoxin, but diminished by carbachol. The effect of isoprenaline was amplified by threshold concentrations of BM 14.478 (10(-6) M). There was only a slight intrinsic chronotropic activity in spontaneously beating guinea pig atria. Atrial cyclic AMP (cAMP) was increased from 1.46 +/- 0.06 to 1.97 +/- 0.03 pmol/mg wet wt, at 3 X 10(-6) M. This might be due to an inhibition of cardiac phosphodiesterase(s) (PDE). IC50 of bovine PDE was 7.2 X 10(-5) M (5.4 X 10(-5) M to 9.7 X 10(-5) M). BM 14.478 shortened the duration of transmembrane action potential (90% repol.) by 8% and increased the Vmax of slow action potentials by 32% at 3 X 10(-4) M. In skinned porcine heart muscle fibers an increase in calcium-activated force up to 43 +/- 7% was observed (10(-7) to 10(-4) M). Rat aortas were relaxed by about 75% maximally (10(-7) to 10(-4) M). It is concluded that BM 14.478 is a potent inotropic drug which acts via an increase in myocardial cAMP content and in calcium sensitivity of contractile proteins.