The aim of the study was to evaluate the cardioprotective and antiarrhythmic effects of intravenous Na+/H+ blockers (cariporide and SM-20550) in a rat model of ischemia and a long period reperfusion (14 days). This model allowed study of the role of Na+/H+ exchanger against late myocardial infarct expansion and left ventricular dysfunction. Each compound was administered 5 min before ischemia. Cariporide (from 0.16 mg/kg) and SM-20550 (from 0.04 mg/kg) significantly and dose-dependently reduced the number of ventricular premature beats during ischemia. The duration of ventricular tachycardia was importantly shortened in the presence of cariporide (0.63 mg/kg) and SM-20550 (0.16 mg/kg). Furthermore, cariporide (0.63 mg/kg) and SM-20550 (from 0.04 mg/kg) significantly reduced the infarct expansion: 43 +/- 2% in the cariporide group and 42 +/- 2% at 0.16 mg/kg SM-20550 versus 48 +/- 1% in the vehicle group. Cariporide and SM-20550 significantly prevented the left ventricular free wall thinning associated with the thickness ratio, suggesting a significant reduction of the ventricular dilation. Cariporide and SM-20550 significantly improved the negative dP/dtmax, suggesting a partial restoration of the cardiac relaxation. Collectively, Na+/H+ blockers administered before ischemia reduced arrhythmias and also prevented the remodeling process of the heart during postinfarction.

01 Jun 2003·European Journal of Medicinal ChemistryQ1 · MEDICINE

An overview of inhibitors of Na+/H+ exchanger

Q1 · MEDICINE

Review

Author: L Pochet ; D Laeckmann ; B Masereel

The Na(+)/H(+) exchanger (NHE) is involved in intracellular pH homeostasis of many mammalian cell types. To date seven NHE isoforms (NHE1-NHE7) have been identified. NHE1 is the most predominant isoform expressed in heart where it contributes to cardiomyocyte pH homeostasis. Although the NHE activation is essential for the restoration of physiological pH, hyperactivation of NHE1 during ischemia-reperfusion episodes disrupts the intracellular ion balance, leading to cardiac dysfunction and damage. Beside its ability to inhibit a conductive Na(+) channel and the Na(+)/Ca(++) exchanger, amiloride was the first drug described as NHE inhibitor. Double substitution of the nitrogen of the 5-amino group of amiloride gave DMA, EIPA, MIBA and HMA. Later, several acylguanidines were prepared to selectively inhibit NHE1. The replacement of the pyrazine ring of amiloride by a pyridine ring or by a phenyl increased the potency and the NHE selectivity. The simultaneous replacement of the pyrazine ring by a phenyl, of the 6-chloro by a sulfomethyl led to drugs such as HOE-694, cariporide, eniporide and BIIB-513 which also selectively inhibited NHE1. In the last decade several bicyclic guanidines were prepared: zoniporide, MS-31038, SM-20220, SM-20550, SMP-300, KB-R9032, BMS-284640, T-162559, TY-12533, S-3226 or SL-591227. Extensive pre-clinical studies indicated that NHE inhibitors afford substantial protection in different animal models of myocardial ischemia (MI) and reperfusion, but the results of clinical trials involving eniporide and cariporide were mixed.

01 Apr 2002·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Protective Effect of Na+/H+ Exchange Inhibitor, SM-20550, on Impaired Mitochondrial Respiratory Function and Mitochondrial Ca2+ Overload in Ischemic/Reperfused Rat Hearts

Q4 · MEDICINE

Article

Author: Ohashi, Naohito ; Matsui, Kazuki ; Yamamoto, Setsuko

The aim of this study was to investigate whether a selective Na+/H+ exchange inhibitor, SM-20550, can modulate the mitochondrial respiratory function and mitochondrial Ca2+ content in isolated rat hearts subjected to 40 min of ischemia and 20 min of reperfusion. SM-20550 (10, 100 nM) was administered for 5 min prior to ischemia and for 20 min during the reperfusion period. At 20 min after reperfusion, treatment with SM-20550 (10, 100 nM) improved the recovery of left ventricular developed pressure and suppressed the rise in left ventricular end-diastolic pressure. Mitochondrial function, assessed by the state 3 oxygen respiration rate, respiratory control index, and oxidative phosphorylation rate, was significantly impaired after ischemia/reperfusion. Administration with SM-20550 (10, 100 nM) attenuated the impaired mitochondrial function, improving the state 3 respiration rate, respiratory control index, and oxidative phosphorylation rate. The mitochondrial Ca2+ content was significantly increased after ischemia/reperfusion but was suppressed by treatment with SM-20550 (10, 100 nM). A significant linear correlation was observed between the respiratory control index and mitochondrial Ca2+ content in the ischemic/reperfused hearts. In conclusion, SM-20550 improved the postischemic recovery of left ventricular function and concurrently protected mitochondrial function mediated by preventing mitochondrial Ca2+ overload.

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Indication	Highest Phase	Country/Location	Organization	Date
Myocardial Reperfusion Injury	Preclinical	JP	Gunma University	01 Jun 1999
Myocardial Reperfusion Injury	Preclinical	JP	Sumitomo Pharma Co., Ltd.	01 Jun 1999
Arrhythmias, Cardiac	Preclinical	JP	Sumitomo Pharmaceuticals Co., Ltd.	-
Myocardial Ischemia	Preclinical	JP	Sumitomo Pharmaceuticals Co., Ltd.	-

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