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SM-20550, a new Na+/H+ exchange inhibitor and its cardioprotective effect in ischemic/reperfused isolated rat hearts by preventing Ca2+-overload.

Abstract
We investigated the effect of a newly synthesized compound, SM-20550 [N-(aminoiminomethyl)-1,4-dimethyl-1H-indole-2-carboxamide methanesulfonic acid] on Na+/H+ or Na+/Ca2+ exchange activity in rat cardiomyocytes, and on radioligand binding with several channels or receptors in membrane preparations, and ischemia/reperfusion injury in isolated perfused rat hearts. In myocytes, SM-20550 concentration-dependently inhibited the recovery from acidosis induced by an NH4Cl prepulse in HCO3(-)-free solution. Its IC50 was 10(-8) M, which was 10 times lower than that of ethylisopropyl amiloride (EIPA). SM-20550 (10(-6) M) did not affect the Na+-dependent Ca2+ influx (Na+/Ca2+ exchange activity) in cardiomyocytes. In the radioligand binding assay, SM-20550 did not have affinity for K+ channel, beta-adrenoceptor, adenosine, angiotensin, or endothelin receptors, and had low affinity for Na+ and Ca2+ channels and alpha-adrenoceptors, only at the concentrations of 10(-6)-10(-5) M. In perfused hearts exposed to 40 min of global ischemia and 20 min of reperfusion, SM-20550 (10(-8)-10(-7) M) significantly reduced the elevation of left ventricular end-diastolic pressure during reperfusion, improved the postischemic recovery of developed pressure, and prevented coronary perfusion pressure increase after reperfusion. Furthermore, SM-20550 reduced creatine phosphokinase release during reperfusion and prevented the abnormal gain of tissue Na+ and Ca2+ at the end of reperfusion. These results suggest that SM-20550 is a potent, highly specific Na+/H+ exchange inhibitor, which exerts a protective effect against myocardial ischemia/reperfusion injury. In addition, our data strongly support the hypothesis that Na+/H+ exchange plays an important role in the development of postischemic cardiac dysfunction, most likely by inducing Na+ and Ca2+ overload.
AuthorsS Yamamoto, K Matsui, M Kitano, N Ohashi
JournalJournal of cardiovascular pharmacology (J Cardiovasc Pharmacol) Vol. 35 Issue 6 Pg. 855-62 (Jun 2000) ISSN: 0160-2446 [Print] United States
PMID10836718 (Publication Type: Journal Article)
Chemical References
  • Amidines
  • Calcium Channels
  • Indoles
  • Receptors, Adrenergic
  • SM 20550
  • Sodium-Hydrogen Exchangers
  • Calcium
Topics
  • Amidines (pharmacology)
  • Animals
  • Binding, Competitive (drug effects)
  • Calcium (metabolism)
  • Calcium Channels (metabolism)
  • Dose-Response Relationship, Drug
  • Heart (drug effects)
  • In Vitro Techniques
  • Indoles (pharmacology)
  • Male
  • Myocardial Ischemia
  • Myocardial Reperfusion Injury (physiopathology)
  • Myocardium (cytology, metabolism)
  • Rats
  • Rats, Sprague-Dawley
  • Rats, Wistar
  • Receptors, Adrenergic (metabolism)
  • Sodium-Hydrogen Exchangers (antagonists & inhibitors, metabolism)
  • Time Factors

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