An NHE-1 inhibitor
Description:
IC50: 0.05, 3 and 1000 μM for NHE1, NHE3 and NHE2, respectively
Na–H exchange (NHE) represents an important mechanism for mediating such injury. NHE represents an important mechanism for the development of myocardial ischemic and reperfusion injury and inhibitors have been consistently shown to protect the ischemic and reperfused heart by correcting the ionic imbalance associated with this form of pathological insult. Cariporide is a potent NHE inhibitor.
In vitro: Cariporide concentration dependently inhibited the amiloride sensitive sodium influx in rabbit erythrocytes, reduced the swelling of human platelets caused by intracellular acidification, and delayed pH recovery in rat cardiomyocytes [1].
In vivo: In anaesthetised rats undergoing coronary artery ligation intravenous and oral pretreatment with Cariporide caused a dose dependent reduction or a complete prevention of ventricular premature beats, ventricular fibrillation, and ventricular tachycardia. The compound was well tolerated and neutral to circulatory variables [1].
Clinical trial: Cariporide has been evaluated in a large dose-finding Phase II/Phase III clinical trial to assess the efficacy in patients with acute coronary syndromes. Overall results failed to demonstrate protection but sub-group analysis revealed significant risk reductions with the highest cariporide dose especially in high risk patients undergoing coronary artery bypass surgery [2].
Reference:
[1] Scholz W, Albus U, Counillon L, G?gelein H, Lang HJ, Linz W, Weichert A, Sch?lkens BA.? Protective effects of HOE642, a selective sodium-hydrogen exchange subtype 1 inhibitor, on cardiac ischaemia and reperfusion. Cardiovasc Res. 1995 Feb;29(2):260-8.
[2] Karmazyn M.? Pharmacology and clinical assessment of cariporide for the treatment coronary artery diseases. Expert Opin Investig Drugs. 2000 May;9(5):1099-108.
Cell experiment: | Neonatal rat cardiomyocytes are randomly separated into groups: (1) control group, (2) incubation with 100 μM hydrogen peroxide, or (3) pretreatment with 10 μM cariporide for 20 minutes followed by 100 μM hydrogen peroxide. Caspase-3 activity is measured by detection of the cleavage of a colorimetric caspase-3 substrate, N-acetyl-Asp-Glu-Val-Asp-p-nitroaniline, using an assay kit[1]. |
Animal experiment: | Rats: Cariporide and/or bumetanide are administered intravenously (15 or 30?mg/kg in 2 to 4 doses, respectively, of 7.5?mg/kg) starting at 20?minutes before initiation of pMCAO. For neurologic outcome experiments, some rats are given cariporide and/or bumetanide by a single intraperitoneal injection[4]. |
参考文献: [1]. Teshima Y, et al. Cariporide (HOE642), a selective Na+-H+ exchange inhibitor, inhibits the mitochondrial death pathway. Circulation. 2003 Nov 4;108(18):2275-81. | |
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