Inhibition by bertosamil of cardiac responses to pinacidil or Bay k 8644 in isolated dog atria and ventricles

Abstract

We investigated the effects of a novel bradycardic agent, bertosamil (3-isobutyl-7-isopropyl-9,9-pentamethylene-3,7-diazabicyclo[3.3.1]nonane sesquihydrogenfumarate), on the sinus rate and atrial contractile force and the left ventricular contractile force in isolated, blood-perfused dog hearts and the blocking effects of bertosamil on the chronotropic and inotropic responses to pinacidil and Bay k 8644 (methyl-1,4-dihydro-2,6-dimethyl-3-nitro-4-(2-trifluoromethylphenyl)-piridine-5-carboxylate). Bertosamil (0.1–100 nmol) caused transient positive, followed by continuous negative, chronotropic responses and positive inotropic responses in atria, and increased the left ventricular contractile force. Neither propranolol nor atropine affected the cardiac responses to bertosamil. Bertosamil (3–100 nmol) dose dependently attenuated the negative chronotropic and inotropic responses to pinacidil but not to acetylcholine. Bertosamil at a high dose attenuated the positive cardiac responses to Bay k 8644, norepinephrine and isoproterenol. These results suggest that bertosamil inhibits negative cardiac responses mediated by an ATP-sensitive K + channel but not an acetylcholine muscarinic receptor and, at a high dose, attenuates the L-type Ca 2+ channel-mediated positive cardiac responses in isolated dog hearts.