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Exchanger Inhibitor (exchanger + inhibitor)

Distribution by Scientific Domains

Medical Sciences	83%

Kinds of Exchanger Inhibitor

na+/h+ exchanger inhibitor

Selected Abstracts

Design, Synthesis, and Structure,Activity Relationships of 3,4-Dihydropyridopyrimidin-2(1H)-one Derivatives as a Novel Class of Sodium/Calcium Exchanger Inhibitor.

CHEMINFORM, Issue 12 2006
Hirohiko Hasegawa
Abstract ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract, please click on HTML or PDF. [source]

5-(N -ethyl-N-isopropyl)-amiloride enhances SMN2 exon 7 inclusion and protein expression in spinal muscular atrophy cells

ANNALS OF NEUROLOGY, Issue 1 2008
Chung-Yee Yuo PhD
Objective Spinal muscular atrophy (SMA) is a common inherited neuromuscular disorder caused by homozygous loss of function of the survival motor neuron 1 (SMN1) gene. All SMA patients carry at least one copy of a nearly identical SMN2 gene. However, a critical nucleotide change in SMN2 results in alternative splicing and exclusion of exon 7 in the majority of SMN2 messenger RNA (mRNA), thus producing a low level of functional SMN protein. Increasing SMN protein production by promoting SMN2 exon 7 inclusion could be a therapeutic approach for SMA. It has been shown that cellular pH microenvironment can modulate pre-mRNA alternative splicing in vivo. In this study, we tested whether inhibitors of the Na+/H+ exchanger can modulate the exon 7 splicing of SMN2 mRNA Methods We treated SMA lymphoid cell lines with Na+/H+ exchanger inhibitors and then measured SMN2 exon 7 splicing by reverse transcriptase polymerase chain reaction and SMN protein production by Western blotting and immunofluorescence Results We found that treatment with an Na+/H+ exchanger inhibitor, 5-(N -ethyl-N-isopropyl)-amiloride (EIPA), significantly enhances SMN2 exon 7 inclusion and SMN protein production in SMA cells. In addition, EIPA increases the number of nuclear gems in SMA cells. We further explored the underlying mechanism, and our results suggest that EIPA may promote SMN2 exon 7 inclusion through upregulation of the splicing factor SRp20 in the nucleus Interpretation Our finding that EIPA, an inhibitor of the Na+/H+ exchanger, can increase SMN protein expression in SMA cells provides a new direction for the development of drugs for SMA treatment. However, further translational studies are needed to determine whether this finding is applicable for SMA treatment or just a proof of cellular pH effect on SMN splicing. Ann Neurol 2007 [source]

Dose-dependent pharmacokinetics of a new Na+/H+ exchanger inhibitor KR-33028 in rats

BIOPHARMACEUTICS AND DRUG DISPOSITION, Issue 8 2007
Young Hoon Kim
Abstract The dose-dependency of the pharmacokinetics of a new Na+/H+ exchanger inhibitor, KR-33028 was evaluated in rats after intravenous and oral administration. After intravenous administration of KR-33028 (1, 5, 10 and 20mg/kg doses), the systemic clearance (Cl) was reduced and AUC was nonlinearly increased as a function of dose. The volume of distribution (Vss), however, remained unchanged as the dose was increased, which was consistent with unaltered plasma protein binding in vitro (unbound fraction = 0.09,0.12). Upon oral administration (2, 10 and 20mg/kg doses), KR-33028 was rapidly absorbed, and this was consistent with high Caco-2 Papp values found in vitro. There were nonlinear increases in AUC and Cmax, and the absolute oral bioavailability (F) was significantly increased as the dose was increased (F = 23.3%, 40.7% and 78.2% for 2, 10 and 20mg/kg doses, respectively). The extent of urinary excretion was low for both intravenous (0.5,0.7%) and oral (0.2,0.8%) doses. The reduced systemic clearance and increased oral bioavailability at high doses appears to be due to a saturable first-pass metabolism. Copyright © 2007 John Wiley & Sons, Ltd. [source]

Pharmacological profile of SL 59.1227, a novel inhibitor of the sodium/hydrogen exchanger

BRITISH JOURNAL OF PHARMACOLOGY, Issue 6 2000
Janine Lorrain
The NHE1 isoform of the Na+/H+ exchanger plays an important role in the regulation of intracellular pH and in cardiac cell injury caused by ischaemia and reperfusion. SL 59.1227 is a novel imidazolypiperidine Na+/H+ antiport inhibitor which is structurally unrelated to previously described acylguanidine inhibitors such as cariporide. Recovery of pHi following an intracellular acid load was measured in CCL39-derived PS120 variant cells, selectively expressing either NHE1 or NHE2 isoforms of the Na+/H+ exchanger. pHi recovery was potently and selectively slowed by SL 59.1227 in NHE1-expressing cells (IC50 3.3±1.3 nM) versus NHE2-expressing cells (2.3±1.0 ,M). The respective IC50 values for cariporide were 103±28 nM (NHE1) and 73±46 ,M (NHE2). In anaesthetized rats following left coronary artery occlusion (7 min) and reperfusion (10 min) SL 59.1227 (10,100 ,g kg,1 min,1 i.v.) inhibited ischaemia-mediated ventricular tachycardia (71,100%) and reperfusion-induced ventricular fibrillation (75,87%) and prevented mortality. Bolus i.v. administration of SL 59.1227 (1 mg kg,1) produced anti-arrhythmic effects when administered either before or during ischaemia. Cardiac infarct size was determined in anaesthetized rabbits following left coronary artery occlusion (30 min) and reperfusion (120 min). Infarct size measured as a percentage of the area at risk was 36.2±3.4% (control group) versus 15.3±3.9% (SL 59.1227 0.6 mg kg,1 i.v.). SL 59.1227 is the first example of a potent and NHE1-selective non-acylguanidine Na+/H+ exchanger inhibitor. It possesses marked cardioprotective properties. British Journal of Pharmacology (2000) 131, 1188,1194; doi:10.1038/sj.bjp.0703671 [source]

Resuscitation with Na+/H+ exchanger inhibitor in traumatic haemorrhagic shock: Cardiopulmonary performance, oxygen transport and tissue inflammation

CLINICAL AND EXPERIMENTAL PHARMACOLOGY AND PHYSIOLOGY, Issue 3 2010
Dongmei Wu
Summary 1. The aim of the present study was to examine the effects of inhibition of the Na+/H+ exchanger (NHE-1) on cardiopulmonary performance, oxygen carrying capacity and tissue inflammation in a pig model of traumatic haemorrhage,resuscitation. 2. In 12 instrumented anaesthetized pigs, traumatic haemorrhage was modelled by producing tibia fractures, followed by haemorrhage of 25 mL/kg for 20 min, and then a 4 mm hepatic arterial tear with surgical repair after 20 min. Animals then underwent low-volume fluid resuscitation with either Hextend (vehicle; n = 6; Hospira, Lake Forest, IL, USA) or 3 mg/kg BIIB513 (an NHE-1 inhibitor) + Hextend (n = 6). The experiment was terminated 6 h after the beginning of resuscitation. 3. Compared with vehicle-treated controls, the addition of NHE-1 inhibition with BIIB513 significantly improved the left ventricle stroke work index and attenuated increases in pulmonary arterial pressure and pulmonary vascular resistance. Furthermore, BIIB513 treatment significantly increased the oxygenated haemoglobin ratio, blood oxygen content and mixed venous blood oxygen saturation and improved blood oxygen delivery. In addition, BIIB513 treatment reduced lung tissue levels of interleukin-6 by 80%, tumour necrosis factor-, by 37% and myeloperoxidase activity by 38%. Nuclear factor-,B DNA binding activity in the lung was also slightly and significantly attenuated following BIIB513 treatment. 4. In conclusion, the present study shows that NHE-1 inhibition facilitates the response to fluid resuscitation after traumatic haemorrhage by improving cardiac function, pulmonary vascular function and oxygen carrying capacity, which results in reduced tissue inflammatory injury. [source]