Setsuko Yamamoto*, Kazuki Matsui, Masao Sasabe, Masahumi Kitano and Naohito
Ohashi
Research Center, Sumitomo Pharmaceuticals Co., Ltd., 1-98, Kasugadenaka
3-Chome, Konohana-ku, Osaka 554-0022, Japan
*Corresponding author.ﾊﾊFAX:+81-6-6466-5287
E-mail: setukoy@sumitomopharm.co.jp
Abstract: We evaluated the effects of SMP-300 (N-(aminoiminomethyl)-11-chloro-5,6,7,8-tetrahydro-8-oxo-4H-pyrrolo[3,2,1-kl][1]benzazocine-2-carboxamide
monomethanesulfonate monohydrate), a newly synthesized compound, on Na+/H+
exchange activity in rat cardiomyocytes and on other ion transporters, channels
and receptors. We also investigated the protective effects of SMP-300 in
isolated ischemic rat hearts and rat isoproterenol- or vasopressin-induced
experimental angina models. SMP-300 concentration-dependently inhibited
recovery from acidosis in rat myocytes, and its IC50 for Na+/H+
exchange was 6ﾊnM. In comparison, its IC50s for Na+/Ca2+
exchange and for the Na+ channel were ﾊ>1000ﾊnM,
and those were ﾊ>10,000ﾊnM for other channels
or receptors tested. In rat isolated perfused hearts, SMP-300 (10-8-10-7ﾊM),
administered only at preischemia and not during reperfusion, significantly
improved the postischemic recovery of cardiac function. SMP-300 (0.03-0.3ﾊmg/kg,
i.v.) or 5-(N-ethyl-N-isopropyl)-amiloride (1ﾊmg/kg, i.v.)
prevented the isoproterenol-induced ST-segment depression in the ECG of
anesthetized rats, in a dose-dependent manner. SMP-300 (0.1ﾊmg/kg, i.v.)
and 5-(N-ethyl-N-isopropyl)-amiloride (1ﾊmg/kg, i.v.) also
inhibited the vasopressin-induced ST-segment depression in the ECG of anesthetized
rats. This is the first report presenting the protective effect of Na+/H+
exchange inhibitors on isoproterenol- or vasopressin-induced ECG changes
in rats, providing the future perspective of SMP-300, a potent Na+/H+
exchange inhibitor, as an anti-anginal drug.
Keywords: SMP-300, Na+/H+ exchange, Heart, Ischemia,
Angina
Copyrightｩ The Japanese Pharmacological Society 2000
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