title: Na(+)/H(+) exchanger in the regulation of platelet activation and paradoxical effects of cariporide.
abstract: Platelets are anucleated cell fragments derived from mature megakaryocytes and function in hemostasis when the endothelium is injured. Hemostasis involving platelets can be divided into four phases: adhesion, activation, secretion, and aggregation. Platelet activation requires a rise in intracellular Ca(2+) concentrations and results in both a morphological change and the secretion of platelet granule contents. Na(+)/H(+) exchanger isoform 1 (NHE1) regulates the intracellular pH (pHi) and the volume of platelets. In addition, NHE1 plays a large role in platelet activation. Thrombus generation involves NHE1 activation and an increase in [Ca(2+)]i, which results from NHE1-mediated Na(+) overload and the reversal of the Na(+)/Ca(2+) exchanger. Cariporide (HOE-642), a potent NHE1 inhibitor, has inhibitory effects on the degranulation of human platelets, the formation of platelet-leukocyte-aggregates, and the activation of the GPIIb/IIIa receptor (PAC-1). However, despite the demonstrated protection against myocardial infarction as mediated by cariporide in patients undergoing coronary artery bypass graft surgery, the EXPEDITION clinical trial revealed that cariporide treatment increased mortality due to thromboembolic stroke. These findings suggest that a better understanding of NHE1 and its effect on platelet function and procoagulant factor regulation is warranted in order to develop therapies using NHE inhibitors.
authors.affiliation: Department of Neurology, University of Pittsburgh, USA.
authors.forename: He Benny
authors.initials: HB
authors.lastname: Chang
authors.affiliation: Department of Neurology, University of Pittsburgh, USA; Dept. of Neurological Surgery, The Second Affiliated Hospital of the Harbin Medical University, Harbin 150086, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Gao
authors.affiliation: Department of Neurology, University of Pittsburgh, USA.
authors.forename: Rachel
authors.initials: R
authors.lastname: Nepomuceno
authors.affiliation: Dept. of Neurological Surgery, The Second Affiliated Hospital of the Harbin Medical University, Harbin 150086, China.
authors.forename: Shaoshan
authors.initials: S
authors.lastname: Hu
authors.affiliation: Department of Neurology, University of Pittsburgh, USA; Veterans Affairs Pittsburgh Health Care System, Geriatric Research, Educational and Clinical Center, Pittsburgh, PA 15213, USA. Electronic address: sund@upmc.edu.
authors.forename: Dandan
authors.initials: D
authors.lastname: Sun
mesh_terms: D000818:Animals; D000889:Anti-Arrhythmia Agents / Q000494:pharmacology*; D001792:Blood Platelets / Q000187:drug effects / Q000378:metabolism; D002561:Cerebrovascular Disorders / Q000188:drug therapy; D002986:Clinical Trials as Topic; D006146:Guanidines / Q000494:pharmacology*; D006801:Humans; D015539:Platelet Activation / Q000187:drug effects* / Q000502:physiology*; D017923:Sodium-Hydrogen Exchangers / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013450:Sulfones / Q000494:pharmacology*
chemical_list: D000889:Anti-Arrhythmia Agents; D006146:Guanidines; D017923:Sodium-Hydrogen Exchangers; D013450:Sulfones; C093373:cariporide
keywords: Cariporide; EXPEDITION trial; HOE 642; Ischemia reperfusion; NHE1; Platelet aggregation