Role of the Na+–H+ exchanger (NHE1) in heart muscle function during transient acidosis. A study in papillary muscles from rat and guinea pig hearts

2003 ◽  
Vol 81 (10) ◽  
pp. 937-943 ◽  
Author(s):  
Rune Sundset ◽  
Geir Bertelsen ◽  
Kirsti Ytrehus
Keyword(s):  
Hydrogen Exchange ◽  
Contractile Function ◽  
Electrical Conductance ◽  
Papillary Muscles ◽  
Intracellular Acidosis ◽  
Electrophysiological Properties ◽  
Stimulus Response ◽  
Sodium Hydrogen ◽  
Response Interval ◽  
Sodium Hydrogen Exchanger

The sodium–hydrogen exchanger (NHE) helps the cell to recover from intracellular acidosis. In this study, we have investigated the effect of HOE 642 (a specific NHE1 blocker) on papillary muscles from rats and guinea pigs during transient acidosis and PKC activation by recording developed force (DF), action potential characteristics, and electrical conductance (stimulus–response interval). Two protocols were used, with or without HOE 642 (10–5 mol/L): papillary muscle was exposed (i) for 15 min to a glucose-free, nonoxygenated HEPES buffer containing lactate (20 mmol/L) (pH 6.8) followed by 15 min recovery or (ii) to a PKC activator (phorbolmyristate acetate (PMA) (10–9 mol/L)) for 30 min. The DF after acidification remained significantly decreased in the NHE-blocked papillary muscles. During recovery from acidosis, papillary muscles exposed to HOE 642 remained at a higher electrical resistance. The present study shows that post-acidotic continued depression of DF and change in tissue electrophysiological properties might occur as a result of blocking the NHE. During infarct development, the tissue-protecting effect of NHE blockade has been well documented. When acidosis or reduced contractile function is present, however, blocking NHE by HOE 642 might not improve the situation.Key words: sodium–hydrogen exchange (NHE), HOE 642 (cariporide), gap junction, PKC, acidosis.

scholarly journals Mineralocorticoid Action and Sodium-Hydrogen Exchange: Studies in Experimental Cardiac Fibrosis

Endocrinology ◽  
2003 ◽  
Vol 144 (9) ◽  
pp. 3848-3851 ◽  
Author(s):  
Morag Young ◽  
John Funder
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Hydrogen Exchange ◽  
Cardiac Fibrosis ◽  
Inflammatory Cell ◽  
Mineralocorticoid Receptor Antagonist ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Coronary Vasculitis ◽  
Potassium Canrenoate

Abstract There is increasing evidence that the trigger for cardiac fibrosis in response to mineralocorticoid/salt administration is coronary vasculitis and that effects can be seen within days of deoxycorticosterone acetate (DOCA) administration. Furthermore, rapid, nongenomic mineralocorticoid effects on the sodium-hydrogen exchanger (NHE-1) in vascular smooth muscle cells have recently been described. That this mechanism may act as an inflammatory or profibrotic signal was tested by comparing the specific NHE-1 antagonist cariporide and the mineralocorticoid receptor antagonist K canrenoate in the rat model of mineralocorticoid/salt perivascular fibrosis over 8 d of DOCA/salt administration. Interstitial collagen, inflammatory cell infiltration, and inflammatory markers were determined. DOCA elevated blood pressure above control, cariporide +DOCA, or K canrenoate +DOCA rats, without cardiac hypertrophy. At 8 d interstitial collagen was significantly elevated in the DOCA-alone group, with levels in cariporide- and K canrenoate-treated rats not different from control. Expression of osteopontin, cyclooxygenase-2, and ED-1 were elevated by DOCA treatment, blocked by potassium canrenoate, and (for ED-1 and osteopontin) partially reduced by cariporide. These results suggest mineralocorticoid/salt-induced cardiac fibrosis may involve coronary vascular smooth muscle cell NHE-1 activity as a possible contributor to the cascade of transcriptional events that produce the characteristic coronary vasculitis seen with excess mineralocorticoid and salt.

Mechanisms regulating the vascular smooth muscle Na/H exchanger (NHE-1) in diabetes

1998 ◽  
Vol 76 (5) ◽  
pp. 751-759 ◽  
Author(s):  
Katherine M Hannan ◽  
Peter J Little
Keyword(s):  
Smooth Muscle ◽  
Vascular Smooth Muscle ◽  
Smooth Muscle Cells ◽  
Vascular Smooth Muscle Cells ◽  
Hydrogen Exchange ◽  
Muscle Cells ◽  
Cell Types ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Multiple Cell

Vascular disease is a major component of the complications associated with diabetes. The pathology involves hypertrophy and proliferation of vascular smooth muscle cells and the production and modification of extracellular matrix. The sodium/hydrogen exchanger has been widely implicated in the growth of multiple cell types, including vascular smooth muscle. Increases in sodium/hydrogen exchange activity serve as an effector or at least as an indicator of vascular activation. This article is concerned with the role of the biochemical abnormalities of diabetes exerting their pathological effects on vascular smooth muscle cells via altering sodium/hydrogen exchange activity.Key words: diabetes, sodium/hydrogen exchanger, vascular smooth muscle, complications.

A Novel Role Of Tescalcin-Sodium/Hydrogen Exchange Axis Underlying Sorafenib Resistance In FLT3-ITD+ AML

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3848-3848
Author(s):  
Cheuk Him Man ◽  
Anskar Y.H. Leung ◽  
Stephen Sze Yuen Lam ◽  
Murphy Ka Hei Sun ◽  
Howard Chun Hung Chow ◽  
...  
Keyword(s):  
Hydrogen Exchange ◽  
Conflicts Of Interest ◽  
Resistant Cell ◽  
Gene Encoding ◽  
Sorafenib Treatment ◽  
Sodium Hydrogen ◽  
Sodium Hydrogen Exchanger ◽  
Induced Apoptosis

Abstract Internal tandem duplication (ITD) of FLT3 (fms-like tyrosine kinase 3) in acute myeloid leukemia (AML) is associated with inferior clinical outcome. Sorafenib is effective in targeting chemo-refractory FLT3-ITD+ AML. However, leukemia progresses invariably. Mechanisms of drug resistance are not completely understood. We hypothesized that a gene encoding tescalcin (TESC), which activate a sodium/hydrogen exchanger 1 (NHE1) and known to be up-regulated at leukemia progression during continuous sorafenib treatment, may underlie TKI resistance. TESC was over-expressed in FLT3-ITD+ AML lines MOLM-13 and MV4-11. Knocking down TESC by siRNA lowered intracellular pH and induced apoptosis. The results were recapitulated by treatment with a NHE1 inhibitor, 5-(N,N-Hexamethylene) amiloride (HMA). Sorafenib resistant MOLM-13 cell line (M13-RE) was generated by long term culture of sorafenib. M13-RE significantly increased its sensitivity to HMA. HMA also enhanced suppression of FLT3 signaling by sorafenib in otherwise resistant cell lines. Treating MOLM-13, MV4-11 and primary FLT3-ITD+ AML cells with HMA significantly reduced leukemia initiation in NOD/SCID mouse xenotransplantation. These observations provided novel information about the pathogenetic role of the TESC-NHE1-pHi axis in mediating sorafenib resistance in AML. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Screening of 5- and 6-Substituted Amiloride Libraries Identifies Dual-uPA/NHE1 Active and Single Target-Selective Inhibitors

2021 ◽  
Vol 22 (6) ◽  
pp. 2999
Author(s):  
Benjamin J. Buckley ◽  
Ashna Kumar ◽  
Ashraf Aboelela ◽  
Richard S. Bujaroski ◽  
Xiuju Li ◽  
...  
Keyword(s):  
Selectivity Ratio ◽  
Dual Targeting ◽  
Sodium Hydrogen ◽  
Type Plasminogen Activator ◽  
Single Target ◽  
Urokinase Type Plasminogen Activator ◽  
Anti Cancer ◽  
Sodium Hydrogen Exchanger ◽  
A Cell ◽  
Cell Invasiveness

The K+-sparing diuretic amiloride shows off-target anti-cancer effects in multiple rodent models. These effects arise from the inhibition of two distinct cancer targets: the trypsin-like serine protease urokinase-type plasminogen activator (uPA), a cell-surface mediator of matrix degradation and tumor cell invasiveness, and the sodium-hydrogen exchanger isoform-1 (NHE1), a central regulator of transmembrane pH that supports carcinogenic progression. In this study, we co‑screened our library of 5- and 6-substituted amilorides against these two targets, aiming to identify single-target selective and dual-targeting inhibitors for use as complementary pharmacological probes. Closely related analogs substituted at the 6-position with pyrimidines were identified as dual-targeting (pyrimidine 24 uPA IC50 = 175 nM, NHE1 IC50 = 266 nM, uPA selectivity ratio = 1.5) and uPA-selective (methoxypyrimidine 26 uPA IC50 = 86 nM, NHE1 IC50 = 12,290 nM, uPA selectivity ratio = 143) inhibitors, while high NHE1 potency and selectivity was seen with 5-morpholino (29 NHE1 IC50 = 129 nM, uPA IC50 = 10,949 nM; NHE1 selectivity ratio = 85) and 5-(1,4-oxazepine) (30 NHE1 IC50 = 85 nM, uPA IC50 = 5,715 nM; NHE1 selectivity ratio = 67) analogs. Together, these amilorides comprise a new toolkit of chemotype-matched, non-cytotoxic probes for dissecting the pharmacological effects of selective uPA and NHE1 inhibition versus dual-uPA/NHE1 inhibition.

scholarly journals Phosphoproteomic Analysis of Two Contrasting Maize Inbred Lines Provides Insights into the Mechanism of Salt-Stress Tolerance

2019 ◽  
Vol 20 (8) ◽  
pp. 1886 ◽  
Author(s):  
Xiaoyun Zhao ◽  
Xue Bai ◽  
Caifu Jiang ◽  
Zhen Li
Keyword(s):  
Salt Stress ◽  
Inbred Line ◽  
Carbon Metabolism ◽  
Phosphoenolpyruvate Carboxykinase ◽  
Glutathione Metabolism ◽  
Label Free ◽  
Plasma Membrane Intrinsic Protein ◽  
Sodium Hydrogen ◽  
Salt Response ◽  
Sodium Hydrogen Exchanger

Salinity is a major abiotic stress that limits maize yield and quality throughout the world. We investigated phosphoproteomics differences between a salt-tolerant inbred line (Zheng58) and a salt-sensitive inbred line (Chang7-2) in response to short-term salt stress using label-free quantitation. A total of 9448 unique phosphorylation sites from 4116 phosphoproteins in roots and shoots of Zheng58 and Chang7-2 were identified. A total of 209 and 243 differentially regulated phosphoproteins (DRPPs) in response to NaCl treatment were detected in roots and shoots, respectively. Functional analysis of these DRPPs showed that they were involved in carbon metabolism, glutathione metabolism, transport, and signal transduction. Among these phosphoproteins, the expression of 6-phosphogluconate dehydrogenase 2, pyruvate dehydrogenase, phosphoenolpyruvate carboxykinase, glutamate decarboxylase, glutamate synthase, l-gulonolactone oxidase-like, potassium channel AKT1, high-affinity potassium transporter, sodium/hydrogen exchanger, and calcium/proton exchanger CAX1-like protein were significantly regulated in roots, while phosphoenolpyruvate carboxylase 1, phosphoenolpyruvate carboxykinase, sodium/hydrogen exchanger, plasma membrane intrinsic protein 2, glutathione transferases, and abscisic acid-insensitive 5-like protein were significantly regulated in shoots. Zheng58 may activate carbon metabolism, glutathione and ascorbic acid metabolism, potassium and sodium transportation, and the accumulation of glutamate to enhance its salt tolerance. Our results help to elucidate the mechanisms of salt response in maize seedlings. They also provide a basis for further study of the mechanism underlying salt response and tolerance in maize and other crops.

scholarly journals A unique sodium-hydrogen exchange isoform (NHE-4) of the inner medulla of the rat kidney is induced by hyperosmolarity.

1994 ◽  
Vol 269 (47) ◽  
pp. 29704-29709
Author(s):  
C Bookstein ◽  
M W Musch ◽  
A DePaoli ◽  
Y Xie ◽  
M Villereal ◽  
...  
Keyword(s):  
Hydrogen Exchange ◽  
Rat Kidney ◽  
Sodium Hydrogen
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