Fumio Kurogouchi, Yasuyuki Furukawa*, Ding Zhao, Masamichi Hirose,
Koichi Nakajima, Masato Tsuboi and Shigetoshi Chiba
Department of Pharmacology, Shinshu University School of Medicine, Matsumoto
390-8621, Japan
*ﾊTo whom correspondence should be addressed.
Abstract: 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 (0.03-3ﾊmmol)
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 (17ﾊnmol) 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.
Keywords: KB-R7943 (2-[2-[4-(4-nitrobenzyloxy)phenyl]ethyl]isothiourea
methanesulfonate),
Na+/Ca2+ exchanger, Inotropism, Chronotropism, Heart