Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sodium/proton antiporters or exchangers (NHE) are integral membrane proteins present in most, if not all, living organisms. In mammals, these transporters chiefly catalyze the electroneutral exchange of Na(+) and H(+) down their respective concentration gradients and are crucial for numerous physiological processes, ranging from the fine control of intracellular pH and cell volume to systemic electrolyte, acid-base and fluid volume homeostasis. NHE activity also facilitates the progression of other cellular events such as adhesion, migration, and proliferation. Thus far, eight distinct NHE genes (NHE1/SLC9A1-NHE8/SLC9A8) and several pseudogenes have been identified in the human genome. The functional genes encode proteins of varying primary sequence identity (25-70%), but share a common predicted secondary structure comprising 12 conserved membrane-spanning segments at the amino-terminus and a more divergent, cytoplasmically-oriented, carboxy-terminus. They show considerable heterogeneity in their patterns of tissue/cell expression and membrane localization. Functional studies have revealed further differences in their kinetic properties, sensitivity to pharmacological antagonists, and regulation by diverse hormonal and mechanical stimuli. Altered NHE activity has been linked to the pathogenesis of several diseases, including essential hypertension, congenital secretory diarrhea, diabetes, and tissue damage caused by ischemia/reperfusion. Further characterization of their functional properties should lead to a better understanding of their unique contributions to human health and disease.
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PMID:Diversity of the mammalian sodium/proton exchanger SLC9 gene family. 1284 33

The first part of this report on the Australian Health and Medical Research Congress, held November 25-29, 2002, in Melbourne, Australia, considers some of the symposia and three plenary lectures: Neurosteroids: Nature's Valium, G-Protein-Coupled Receptors and the Mike Rand Memorial Lecture. In the new era in relaxin research symposium, we learned that relaxin is a general antifibrotic agent rather than just a hormone of pregnancy. The drugs discussed in the drug discovery symposium included drugs from natural products, allosteric modulators, antibodies to cytokines and AM-336, an N-type Ca(2+) channel blocker. In the matrix proteases symposium, we learned of the importance of these enzymes in bone, endometrial remodeling and cardiovascular disease. The emphasis of the cytokine antagonist symposium was the involvement of cytokines in rheumatoid arthritis and how these effects could be inhibited with cytokine antagonists. The second part of this report is on the cardiovascular components of the meeting. One of the major strengths of Australian research is the cardiovascular area. Thus, it was not surprising that there were three major symposia with a cardiovascular theme this congress. Although the clinical trials of the NHE1 inhibitors in ischemia and reperfusion have been disappointing to date, evidence was presented in the sodium-hydrogen exchanger symposium that these agents might be beneficial in hypertrophy and heart failure. The discussion in the vessel wall biology in diabetes symposium ranged from molecular aspects to clinical trials. In this, and the NAD(P)H oxidases symposium, many new potential drug targets were discussed. The plenary lecture of the High Blood Pressure Research Council concerned the pathophysiology and management of obesity hypertension, and included a discussion of the drugs for weight reduction.
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PMID:Health and medical research down under in 2002. 1294 54

The ubiquitously expressed Na(+)/H(+) exchanger isoform 1 (NHE1) functions as a major intracellular pH (pH(i)) regulatory mechanism in many cell types, and in some tissues its activity may contribute to ischemic injury. In the present study, cortical astrocyte cultures from wild-type (NHE1(+/+)) and NHE1-deficient (NHE1(-/-)) mice were used to investigate the role of NHE1 in pH(i) recovery and ischemic injury in astrocytes. In the absence of HCO(3)(-), the mean resting pH(i) levels were 6.86 +/- 0.03 in NHE1(+/+) astrocytes and 6.53 +/- 0.04 in NHE1(-/-) astrocytes. Removal of extracellular Na(+) or blocking of NHE1 activity by the potent NHE1 inhibitor HOE-642 significantly reduced the resting level of pH(i) in NHE1(+/+) astrocytes. NHE1(+/+) astrocytes exhibited a rapid pH(i) recovery (0.33 +/- 0.08 pH unit/min) after NH(4)Cl prepulse acid load. The pH(i) recovery in NHE1(+/+) astrocytes was reversibly inhibited by HOE-642 or removal of extracellular Na(+). In NHE1(-/-) astrocytes, the pH(i) recovery after acidification was impaired and not affected by either Na(+)-free conditions or HOE-642. Furthermore, 2 h of oxygen and glucose deprivation (OGD) led to an approximately 80% increase in pH(i) recovery rate in NHE1(+/+) astrocytes. OGD induced a 5-fold rise in intracellular [Na(+)] and 26% swelling in NHE1(+/+) astrocytes. HOE-642 or genetic ablation of NHE1 significantly reduced the Na(+) rise and swelling after OGD. These results suggest that NHE1 is the major pH(i) regulatory mechanism in cortical astrocytes and that ablation of NHE1 in astrocytes attenuates ischemia-induced disruption of ionic regulation and swelling.
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PMID:Increased tolerance to oxygen and glucose deprivation in astrocytes from Na(+)/H(+) exchanger isoform 1 null mice. 1501 53

The signaling pathways involved in ischemic heart disease are not well characterized. In this study, the roles of Ras-GTPase, tyrosine kinases (TKs) and Ca2+/calmodulin-dependent protein kinase II (CaMKII) in global ischemia and reperfusion (I/R) in a perfused rat heart model were investigated and compared to beneficial effects produced by preconditioning (PC). A 40 min episode of global ischemia followed by a 30 min reperfusion in perfused rat hearts produced significantly impaired cardiac function, measured as left ventricular developed pressure (Pmax) and left ventricular end-diastolic pressure (LVEDP), and impaired coronary hemodynamics, measured as coronary flow (CF) and coronary vascular resistance (CVR). Hearts from male Wistar rats pre-treated with the tyrosine kinase inhibitor, genistein (1 mg/kg/day for 6 days), or the CaMKII inhibitor, KN-93 (578 ng/min for 6 days), produced detrimental effects on recovery of cardiac function and coronary hemodynamics. In contrast, pre-treatment with Ras-GTPase inhibitor FPT III (232 ng/min for 6 days) significantly enhanced cardiac recovery in terms of left ventricular contractility and coronary vascular hemodynamics. Treatment with FPT III also significantly reduced expression of the sodium-hydrogen exchanger-1 (NHE-1) which was elevated during I/R as detected by Western blotting. These data suggest that TKs and CaMKII are involved in signaling pathways leading to recovery from cardiac ischemia, whereas activation of Ras-GTPase signaling pathways are critical in the development of cardiac dysfunction due to I/R.
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PMID:Inhibition of Ras-GTPase, but not tyrosine kinases or Ca2+/calmodulin-dependent protein kinase II, improves recovery of cardiac function in the globally ischemic heart. 1512 5

Despite many studies into the pathophysiology of cardiac ischemia-reperfusion injury, a number of key details are as yet undisclosed. These include the timing and magnitude of the changes in both Na(+)/H(+) exchange (NHE-1) and Na(+) -- HCO(3)(-) -cotransport (NBC) transport rates. We fluorimetrically measured H(i)(+) fluxes (J(NHE-1) and J(NBC)) and Na(i)(+) fluxes in single contracting rabbit ventricular myocytes subjected to metabolic inhibition, pseudo-ischemia (i.e. metabolic inhibition and extracellular acidosis of 6.4), and pseudo-reperfusion. Metabolic inhibition and pseudo-ischemia inhibited NHE-1 by 43 +/- 3.1% and 91 +/- 3.6%, and NBC by 66 +/- 5.4% and 100%, respectively. Inhibition was due to both an acidic shift of the pH(i) at which NHE-1 and NBC become quiescent (set-point pH(i)) and a reduction of the steepness of the pH(i) -- H(i)(+) flux profiles. NHE-1 and NBC did not contribute to Na(i)(+) loading during metabolic inhibition (Na(i)(+) 18 +/- 1.7 mM) or pseudo-ischemia (Na(i)(+) 21 +/- 1.7 mM), because pH(i) acidified less than set-point pH(i)'s. Upon pseudo-reperfusion NBC recovered to 54 +/- 7.3% but NHE-1 to 193 +/- 11% of aerobic control flux, and set-point pH(i)'s returned to near neutral values. Metabolic inhibition and reperfusion caused an acid load of 18 +/- 3.2 mM H(+) 94% of which were extruded by the hyperactive NHE-1. At pseudo-reperfusion Na(i)(+) rose sharply to 31 +/- 5.8 mM within 1.5 min and that coincided with hypercontracture. Cariporide not only prevented the Na(i)(+) transient, but also inhibited pH(i) recovery and prevented hypercontracture. Our results are consistent with the view that NHE-1 is active during metabolic inhibition if, like in whole hearts, pH(i) is driven more acidic than NHE-1 set-point pH(i). Furthermore, either an acidic pH(i) or absence of additional Na(i)(+) loading during reperfusion, or both, limit ischemia-reperfusion injury.
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PMID:NHE-1 and NBC during pseudo-ischemia/reperfusion in rabbit ventricular myocytes. 1527 26

Evidence suggests that 1) ischemia-reperfusion injury is due largely to cytosolic Ca(2+) accumulation resulting from functional coupling of Na(+)/Ca(2+) exchange (NCE) with stimulated Na(+)/H(+) exchange (NHE1) and 2) 17beta-estradiol (E2) stimulates release of NO, which inhibits NHE1. Thus we tested the hypothesis that acute E2 limits myocardial Na(+) and therefore Ca(2+) accumulation, thereby limiting ischemia-reperfusion injury. NMR was used to measure cytosolic pH (pH(i)), Na(+) (Na(i)(+)), and calcium concentration ([Ca(2+)](i)) in Krebs-Henseleit (KH)-perfused hearts from ovariectomized rats (OVX). Left ventricular developed pressure (LVDP) and lactate dehydrogenase (LDH) release were also measured. Control ischemia-reperfusion was 20 min of baseline perfusion, 40 min of global ischemia, and 40 min of reperfusion. The E2 protocol was identical, except that 1 nM E2 was included in the perfusate before ischemia and during reperfusion. E2 significantly limited the changes in pH(i), Na(i)(+), and [Ca(2+)](i) during ischemia (P < 0.05). In control OVX vs. OVX+E2, pH(i) fell from 6.93 +/- 0.03 to 5.98 +/- 0.04 vs. 6.96 +/- 0.04 to 6.68 +/- 0.07; Na(i)(+) rose from 25 +/- 6 to 109 +/- 14 meq/kg dry wt vs. 25 +/- 1 to 76 +/- 3; [Ca(2+)](i) changed from 365 +/- 69 to 1,248 +/- 180 nM vs. 293 +/- 66 to 202 +/- 64 nM. E2 also improved recovery of LVDP and diminished release of LDH during reperfusion. Effects of E2 were diminished by 1 microM N(omega)-nitro-L-arginine methyl ester. Thus the data are consistent with the hypothesis. However, E2 limitation of increases in [Ca(2+)](i) is greater than can be accounted for by the thermodynamic effect of reduced Na(i)(+) accumulation on NCE.
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PMID:Acute effects of 17beta-estradiol on myocardial pH, Na+, and Ca2+ and ischemia-reperfusion injury. 1538 67

The Na+/H+ exchanger (NHE) extrudes intracellular H+ in exchange for Na+ in an electroneutral process. Of the 6 mammalian exchanger isoforms identified to date, the NHE-1 is believed to be the molecular homologue of the sarcolemma Na+/H+ transporter. The exchanger is activated primarily by a reduction in intracellular pH, although such activation is subject to modulation by a variety of endogenous mediators (catecholamines, thrombin, endothelin) through receptor-mediated mechanisms. A large body of animal studies using both in vitro and in vivo models indicates that the inhibition of the sarcolemma NHE-1 attenuates myocardial injury in ischemia and reperfusion. Cardioprotective effects of NHE-1 inhibition involve a reduced susceptibility to severe ventricular arrhythmia, augmentation of contractile function recovery, and limitation of infarction size during reperfusion. Such protection is likely to arise partly from attenuation of "Ca2+ overload" in ischemic cardiomyocytes, which has been causally linked with all these pathologic phenomena. A marked benefit that has been observed with cariporide (HOE-642) and its structurally related congener HOE-694 in patients with acute myocardial infarction and in cardiac surgery demonstrates that selective NHE-1 inhibitors represent a novel and effective class of cardioprotectors.
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PMID:[Na+/H+ exchange inhibitors: a new class of cardioprotectors]. 1555 84

Na(+)/H(+) exchange (NHE) is involved in the myocardial injury that occurs during ischemia and reperfusion. The goal of the present study was to investigate the role of NHE in hypovolemic circulatory shock by using a potent NHE-1 selective inhibitor BIIB513. Acute rapid hemorrhage was induced in 14 pigs by bleeding (30 mL/kg over 30 min). Seven pigs were used as saline control. Seven other pigs received 3 mg/kg BIIB513 at 30 min after hemorrhage. Each experiment consisted of 2 h of hypovolemia followed by 2 h of fluid resuscitation. One control animal died before the experiment was completed. Six other control animals survived the entire experiment. In contrast, all the BIIB513 treated animals survived the entire protocol. Acute rapid blood loss resulted in impaired myocardial performance as well as severe hemodynamic and metabolic alterations. NHE blockade attenuated the hypovolemic hypotension and improved myocardial performance. NHE blockade also attenuated the metabolic acidosis, improved tissue oxygen delivery, and improved cardiac function from resuscitation. The circulating levels of creatine phosphokinase (CPK) and cardiac troponin-I were significantly lower in the BIIB513 treatment group. These results suggest that NHE activation plays an important pathophysiological role in hypovolemic circulatory shock, and NHE-1 blockade is a powerful intervention to improve cardiovascular outcomes of resuscitation from prolonged hypovolemic circulatory shock.
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PMID:Cardiovascular effects of NA+/H+ exchanger inhibition with BIIB513 following hypovolemic circulatory shock. 1571 27

The present study was performed to evaluate the cardioprotective effects of [5-(2-methoxy-5-chloro-5-phenyl)furan-2-ylcarbonyl]guanidine (KR-32570) on ischemia/reperfusion-induced mechanical and metabolic dysfunction in isolated rat hearts. In addition, the effects of KR-32570 on the Na(+)/H(+)-exchanger (NHE) and lipid peroxidation were also evaluated. KR-32570 strongly inhibited the recovery from acidosis induced by an NH(4)Cl prepulse in PS120 fibroblast cells expressing the human NHE-1 isoform (IC(50): 0.05 and 1.16 microM for KR-32570 and cariporide, respectively). In isolated perfused rat hearts subjected to 30-min ischemia/30-min reperfusion, KR-32570 (1-10 microM) significantly and concentration dependently improved cardiac contractile function and severe contracture in conjunction with causing a marked reduction in lactate dehydrogenase release. Additionally, it (1-10 microM) significantly increased the content of ATP, creatine phosphate and glycogen as well as decreased the tissue lactate content in heart homogenates following ischemia and reperfusion. KR-32570 (1-10 microM) significantly decreased the concentration of 8-iso-prostaglandin F(2 alpha), a reliable marker for oxidant stress, in perfusates from rat hearts subjected to ischemia and reperfusion. In separate experiments, KR-32570 significantly lowered the concentration of malondialdehyde in rat liver homogenate and inhibited Cu(2+)-induced peroxidation of low-density lipoprotein. Taken together, these results suggest that KR-32570 possesses potent cardioprotective effects in perfused rat hearts, and its effects may be mediated by inhibition of NHE-1, preservation of high-energy phosphates, and inhibition of lipid peroxidation.
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PMID:Effects of KR-32570, a new Na+/H+ exchanger inhibitor, on functional and metabolic impairments produced by global ischemia and reperfusion in the perfused rat heart. 1579 86

A series of (5-arylfuran-2-ylcarbonyl)guanidines was synthesized and evaluated for the NHE-1 inhibitory activity and cardiprotective efficacy against ischemia-reperfusion injury. Starting with (5-phenylfuran-2-ylcarbonyl)guanidine 47 with a moderate inhibitory effect on NHE-1, the compounds with various substituents at the phenyl ring were investigated with the aim to optimize the potency. In this study, the 2,5-disubstituted compounds appeared to have better activities than the other analogues, and the 2-methoxy-5-chlorophenyl compound 85 was found as a potent inhibitor of NHE-1 (IC(50) = 0.081 microM). Furthermore, 85 showed a marked reduction of infarct size in the rat myocardial infarction model in vivo and significant improvement of cardiac contractile function in the isolated rat heart ischemia model in vitro.
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PMID:(5-Arylfuran-2-ylcarbonyl)guanidines as cardioprotectives through the inhibition of Na+/H+ exchanger isoform-1. 1582 27


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