A Na⁺/Ca²⁺ Exchanger Inhibitor, KB-R7943, Caused Negative Inotropic Responses and Negative Followed by Positive Chronotropic Responses in Isolated, Blood-Perfused Dog Heart Preparations

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Effects of a Na⁺/Ca²⁺ exchanger inhibitor, KB-R7943(2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea methanesulfonate), on the sinoatrial nodal pacemaker activity, atrial contractility and ventricular contractility were investigated in the isolated and blood-perfused right atrium and left ventricle of the dog.KB-R7943(0.03-3μmol)induced negative inotropic effects and negative followed by positive chronotropic effects in the right atrium and negative inotropic effects in the left ventricle.Neither atropine nor hexamethonium affected the cardiac responses to KB-R7943.Propranolol attenuated the positive chronotropic response to KB-R7943 but imipramine did not.Tetrodotoxin potentiated the positive chronotropic response to KB-R7943 in 6 of 11 isolated atria.When NaCl infusion increased atrial contractile force and atrial rate, KB-R7943-induced negative inotropic and chronotropic responses were attenuated in a dose-dependent manner.CaCl₂ infusion potentiated the negative chronotropic response to KB-R7943 but did not affect the inotropic response significantly.On the other hand, ouabain(17nmol)attenuated the negative inotropic response, but not chronotropic response, to KB-R7943.These results suggest that KB-R7943-induced cardiac effects relate to the Na⁺ activity, probably mediated through the Na⁺/Ca²⁺ exchanger, and the Na⁺/Ca²⁺ exchanger modifies the pacemaker activity and myocardial contractility in the dog heart.