Effect of SMP-300, a new Na+/H+ exchange inhibitor, on myocardial ischemia and experimental angina models in rats.

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 nM. In comparison, its IC50s for Na+/Ca2+ exchange and for the Na+ channel were >1000 nM, and those for other channels or receptors tested were >10,000 nM. In rat isolated perfused hearts, SMP-300 (10(-8)-10(-7) M), administered only at preischemia and not during reperfusion, significantly improved the postischemic recovery of cardiac function. SMP-300 (0.03-0.3 mg/kg, i.v.) or 5-(N-ethyl-N-isopropyl)-amiloride (1 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 mg/kg, i.v.) and 5-(N-ethyl-N-isopropyl)-amiloride (1 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.

• Authors: S Yamamoto, K Matsui, M Sasabe, M Kitano, N Ohashi
• Journal: Japanese journal of pharmacology (Jpn J Pharmacol) Vol. 84 Issue 2 Pg. 196-205 (Oct 2000) ISSN: 0021-5198 [Print] Japan
• PMID: 11128043 (Publication Type: Journal Article)

Chemical References

• Azocines
• Neuroprotective Agents
• Pyrroles
• SMP-300
• Sodium-Hydrogen Exchangers
• Vasopressins
• Amiloride
• Isoproterenol
• ethylisopropylamiloride

Topics

• Amiloride (analogs & derivatives, therapeutic use)
• Angina Pectoris (chemically induced, prevention & control)
• Animals
• Azocines (pharmacology, therapeutic use)
• Blood Pressure (drug effects)
• Disease Models, Animal
• Electrocardiography (drug effects)
• Heart (drug effects)
• Heart Rate (drug effects)
• Isoproterenol
• Male
• Myocardial Ischemia (prevention & control)
• Myocardium (metabolism)
• Neuroprotective Agents (pharmacology, therapeutic use)
• Pyrroles (pharmacology, therapeutic use)
• Rats
• Rats, Sprague-Dawley
• Sodium-Hydrogen Exchangers (antagonists & inhibitors, metabolism)
• Vasopressins