The effects of a novel piperazine derivative, INO 2628, on the negative inotropic and chronotropic responses to intracardiac parasympathetic nerve stimulation and carbachol, to adenosine and to the K+ channel openers, pinacidil and nicorandil, were investigated in isolated, blood-perfused dog heart preparations. INO 2628 (0.1-10 mumol) injected into the sinus node artery of the isolated atrium induced negative chronotropic and small positive inotropic responses in a dose-dependent manner. INO 2628 antagonized the negative chronotropic and inotropic responses to intracardiac vagus stimulation and carbachol in a dose-dependent manner, whereas INO 2628 did not antagonize the negative cardiac responses to adenosine. Pinacidil and nicorandil caused dose-dependent negative inotropic and small negative chronotropic responses in isolated atria and ventricles, suggesting that pinacidil-related K+ channels are much sparser in SA nodal pacemaker cells than in cardiac muscle cells. INO 2628 dose dependently antagonized the negative inotropic responses to pinacidil and nicorandil, but it did not modify the nicardipine-, pentobarbital- or G-strophanthin-induced cardiac responses. These results suggest that INO 2628 inhibits the negative cardiac effects of acetylcholine at muscarinic receptors and directly inhibits K+ channels in the isolated dog heart.
