Cariporide (HOE-642) is a Na+/H+ exchanger 1 (NHE1) inhibitor. Cariporide reduces intracellular Na+ and Ca2+ overload, alleviates cellular alkalinization and swelling, and attenuates ischemia-reperfusion injury and inflammation by inhibiting cardiomyocyte apoptosis and neutrophil infiltration. Cariporide can be used for studies on myocardial infarction, stroke, and myocardial ischemia-reperfusion injury[1-4].
In vitro, treatment of H-2452AcT cells with 160µM Cariporide for 72h down-regulated p-AKT, up-regulated p53, accumulated ROS, depolarized mitochondrial membrane potential, increased DNA damage, and induced apoptosis[5]. Treatment of N1S1 cells with 200µM Cariporide for 6h decreased intracellular pH, increased extracellular pH, and induced cell death[6]. Treatment of MCF-7/ADR cells with 6µg/ml Cariporide for 48h decreased NHE1, MDR1, and NF-κB p65 expression, increased cleaved caspase-3 and cleaved caspase-9, and decreased Bcl-2[7].
In vivo, oral administration of 600mg/kg Cariporide in chow to SGLT2 knockout mice with heart failure for 8 days prevented diastolic and systolic dysfunction, ventricular and atrial hypertrophy, lung and liver edema, decreased NCX protein expression, 4-HNE, and 3-NT, and increased SOD1[8]. Oral administration of 7.2mg/kg/day Cariporide via drinking water to FVB/N-Tg(MMTVneu)202Mul/J mice for 5 weeks increased serum glucose[9]. A single intraperitoneal injection of 20mg/kg Cariporide combined with 25µg LPS to pregnant C57BL/6J mice at 16.5 days of gestation alleviated LPS-enhanced uterine contraction, inhibited myometrial NHE1 protein expression, and up-regulated myometrial TREK1 protein expression[10].
References:[1] Chin B, Lip GY. Cariporide Aventis. Curr Opin Investig Drugs. 2000 Nov;1(3):340-6.
[2] Laudi S, Vu Tran Z, Steudel W. Cariporide in cardiac resuscitation--Does it really make a difference? Crit Care Med. 2005 Nov;33(11):2707-8.
[3] Karmazyn M. Pharmacology and clinical assessment of cariporide for the treatment coronary artery diseases. Expert Opin Investig Drugs. 2000 May;9(5):1099-108.
[4] Petho Z, Najder K, Beel S, et al. Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer. JCI Insight. 2023 Oct 9;8(19):e170928.
[5] Lee Y, Bae J, Kim S, et al. Cariporide Enhances the DNA Damage and Apoptosis in Acid-tolerable Malignant Mesothelioma H-2452 Cells. Mol Cells. 2017 Aug;40(8):567-576.
[6] Yang W, Wang C, Yu C, et al. pH-regulating Lipiodol Pickering emulsions enhance transarterial embolization therapy via inducing ferroptosis and activating antitumor immunity. Cell Rep Med. 2026 Mar 17;7:102662.
[7] Chen Q, Liu Y, Zhu X, et al. Increased NHE1 expression is targeted by specific inhibitor cariporide to sensitize resistant breast cancer cells to doxorubicin in vitro and in vivo. BMC Cancer. 2019;19:211.
[8] Chen S, Wang Q, Bakker D, et al. Empagliflozin prevents heart failure through inhibition of the NHE1-NO pathway, independent of SGLT2. Basic Research in Cardiology. 2024;119(6):751-772.
[9] Aaen P, Kristensen K, Antony A, et al. Na+/H+-exchange inhibition by cariporide is compensated via Na+,HCO3−-cotransport and has no net growth consequences for ErbB2-driven breast carcinomas. BBA Mol Basis Dis. 2024;1870:167450.
[10] Yu H, Wang X, Tian R, et al. Myometrium infection decreases TREK1 through NHE1 and increases contraction in pregnant mice. Am J Physiol Cell Physiol. 2024;326(4):C1106-C1119.