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)

We investigated, at first in low-flow global ischemia and then with ischemic preconditioning, the effects of a compound, (4-isopropyl-3-methylsulphonylbenzoyl)guanidine hydrochloride (HOE 642), known to inhibit the Na+/H+ exchange in rat cardiomyocytes. In rat isolated hearts, perfused on a Langendorff apparatus with Krebs-Henseleit carbonate buffer, the action potentials and the contractile function were measured during a 25-min period of global low-flow ischemia (coronary flow, 0.3 mL.min-1) followed by a 30-min reperfusion. In hearts previously preconditioned, two intermittent periods of total ischemia for 5 min each, separated by 5 min reflow, were performed before low-flow ischemia. Treated hearts received HOE 642 (3.0 x 10(-8) mol.min-1) exclusively during low-flow ischemia. Treatment with HOE 642 during low-flow ischemia improves cardiac performance and lowers the rise in diastolic tension during reperfusion. Concomitantly HOE 642 shortens the action potential, and has striking effects on ventricular arrhythmias during reperfusion as well. These results support the concept that Na+/H+ exchange activation is a contributing factor to low-flow ischemia-reperfusion injuries. HOE 642 exhibited minor effects when combined with the preconditioning protocol, but a lengthening in action potential was observed and ventricular arrhythmias were mostly affected. Preconditioned hearts demonstrated marked glycogen depletion compared with controls. These results support the hypothesis that preconditioning could decrease glycogenolysis and therefore subsequently limit acidification during low-flow ischemia.
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PMID:Electrophysiological approach of the role of Na+/H+ exchange in low-flow global ischemia and in ischemic preconditioning. 911 33

The inhibition of the Na+/H+ exchanger during cardiac ischemia and reperfusion has been shown to be beneficial for the preservation of the cellular integrity and functional performance. The aim of the present investigation was to come up with potent and selective benzoylguanidines as NHE inhibitors for their use as an adjunctive therapy in the treatment of acute myocardial infarction. During the course of our investigations it became clear that the substitution ortho to the acylguanidine was of crucial importance for the potency of the compounds. 4-Chloro- and 4-fluoro-2-methylbenzoic acids 6 and 7 were prepared using the directed ortho metalation technique with the carboxylic acid as the directing group. With the LDA/methyl iodide system the 2-methyl group could be extended to an ethyl group. 4-Alkyl groups were inserted by the palladium-catalyzed cross-coupling reaction into the 4-bromo-2-methylbenzoic acid methyl ester (20). Starting with benzoic acids 6-19, the methylsulfonyl group was introduced by a sequence of standard reactions (sulfochlorination, reduction, and methylation). 4-Aryl derivatives 68-75 were synthesized by the palladium-catalyzed Suzuki reaction. A large number of nucleophilic displacement reactions in the 4-position were carried out with S-, O-, and N-nucleophiles as well as with the cyano and trifluoromethyl group. Using the ester method, acid chlorides, or Mukaiyama's procedure, the 5-(methylsulfonyl)benzoic acid derivatives were finally converted to the (5-(methylsulfonyl)benzoyl)guanidines 165-267 with excessive guanidine. In some cases nucleophilic substitutions with pyridinols and piperidine derivatives were carried out at the end of the reaction sequence with the 4-halo-N-(diaminomethylene)-5-(methylsulfonyl)-benzamides. Variations in the 4-position were most reasonable, but the volume of the substituents was of crucial importance. Substitution in the 3- and particularly in the 6-position led to considerable worsening of the inhibitory effects of the Na+/H+ exchanger. The 2-methyl compounds, however, showed without exception higher in vitro activities than their respective demethyl counterparts as they are exemplified by the reference compounds 266 and 267, obviously caused by a conformational restriction of the acylguanidine chain. The development compound (2-methyl-5-(methylsulfonyl)-4-pyrrolobenzoyl)guanidine, methanesulfonate (246) is a NHE-1 subtype specific NHE inhibitor, being 27-fold more potent toward the NHE-1 than the NHE-2 isoform. 246 was found to act cardioprotectively not only when given before an experimentally induced ischemia, but also curatively after the onset of symptoms of acute myocardial infarction when given prior to the induction of reperfusion.
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PMID:(2-Methyl-5-(methylsulfonyl)benzoyl)guanidine Na+/H+ antiporter inhibitors. 920 43

Studies in different preparations have suggested that Na+/H+ exchange is one mechanism causally involved in cell death in myocardial ischemia and reperfusion. The time delay of cell death by pretreatment with the Na+/H+-exchange inhibitor HOE642, cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate), was investigated in regionally ischemic, reperfused porcine hearts. HOE642 (1 mg/kg) was injected intravenously in 14 thoracotomized pigs 10 min before occlusion of the left anterior descending coronary artery (45 min of ischemia, six pigs; 70 min of ischemia, six pigs; 90 min of ischemia, two pigs). Ischemia was followed by 24 h of reperfusion. Six animals (45 min of ischemia) served as controls. Infarct size was determined as a ratio of infarcted (tetrazolium stain, histology) to ischemic myocardium (dye technique), and regional myocardial function was assessed by sonomicrometry. HOE642 did not affect global hemodynamic parameters. In the pretreated group with 45 min of ischemia, HOE642 significantly decreased histochemical infarct size from 51.2 +/- 12.6% (control group) to 13.2 +/- 12% (p < 0.005) and histologic infarct size from 44.5 +/- 9% to 17.1 +/- 7% (p < 0.005). Recovery of regional systolic shortening after 24 h of reperfusion was improved from 2 +/- 6% (control group) to 12 +/- 7% (p = 0.02). In addition, myocardial contracture and increase in heart rate during early reperfusion were attenuated. When ischemia was prolonged to 70 min after pretreatment with HOE642, infarct size, recovery of systolic shortening, myocardial contracture, and increase in heart rate did not differ from those of the control group. Pretreatment with HOE642 increased the tolerance to ischemia/reperfusion by approximately 20-25 min. Inhibition of Na+/H+ exchange appears to be very promising in the clinical treatment of acute myocardial ischemia and reperfusion.
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PMID:Time delay of cell death by Na+/H+-exchange inhibition in regionally ischemic, reperfused porcine hearts. 926 52

The protective effect of T-593 ((+/-)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3'-[2-[[[5-(methylamino) methyl-2-furyl]methyl]thio]ethyl]-2"-(methylsulfonyl)guanidine, CAS 140695-21-2), a new histamine H2-receptor antagonist, was investigated in rats with acute gastric mucosal injury. An ischemic injury followed by reperfusion was produced by applying a small vascular clamp to the celiac artery for 30 min and then removing it for 60 min. T-593 significantly reduced the area of the lesion in the stomach in a dose-dependent manner, and doses of 0.3 and 3.0 mg/kg inhibited the increase of lipid peroxides in the gastric mucosa after ischemia-reperfusion. A spin-trapping method using 5,5-dimethyl-1-pyrroline-N-oxide showed that T-593 scavenged hydroxyl radicals generated by the hydrogen peroxide-ferrous iron sulfate system. T-593 also significantly inhibited the increase of lipid peroxides induced by free-radical initiators in gastric mucosal homogenates. Thus, the protective effect of T-593 against acute gastric mucosal injury induced by ischemia and followed by reperfusion may result, in part, from its antioxidant properties.
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PMID:Effect of the histamine H2-receptor antagonist (+/-)-(E)-1-[2-hydroxy-2-(4-hydroxyphenyl)ethyl]-3'-[2-[[[5-methylamino ) methyl-2-furyl] methyl]thio]ethyl]-2"-(methylsulfonyl)guanidine on acute gastric mucosal injury in rats and its free-radical scavenging activities. 927 43

The syntheses of cariporide mesilate ((4-isopropyl-3-methanesulfonyl-benzoyl) guanidine methanesulfonate, HOE 642, CAS 159138-81-5), currently being clinically investigated as a protective drug in cardiac ischemia and reperfusion states, and of HOE 694 ((3-methanesulfonyl-4-piperidino-benzoyl)guanidine methanesulfonate, CAS 149725-40-6), widely used as a physiological and pharmacological research tool in studies comprising Na+/H+ exchange (NHE) inhibition, are described. Additionally, their selectivity on the different subtypes is disclosed.
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PMID:Synthesis of the highly selective Na+/H+ exchange inhibitors cariporide mesilate and (3-methanesulfonyl-4-piperidino-benzoyl) guanidine methanesulfonate. 942 74

Inhibition of the Na/H exchanger is a promising approach for treating ischemia-reperfusion injury, but no clinical agent is yet available. Recently, we established the structural requirements for potent inhibitors of the Na/H exchanger. In the present work, we designed N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidine 3a as a new lead compound for potent inhibitors with good water-solubility, based on the previous information. During the structural optimization, care was taken to keep the hydrophobicity (clogP) in the range of about 1.5-2.0, which is considered optimum for good bioavailability. Various derivatives of 3a were synthesized and the quantitative structure-activity relationship (QSAR) was studied. The QSAR result indicated that the lengths of the substituents at the 2- and the 4-positions of the 2H-benzo[1,4]oxazine ring are parabolically related to activity. The most potent compounds were (R) and/or (S)-N-(2-ethyl-4-isopropyl(or ethyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidines 3q-t with IC50 values of 0.036-0.073 microM. The water-solubility of the hydrochlorides and methanesulfonates is 3-5 mg/ml, which is sufficient for therapeutic use.
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PMID:Design, synthesis and quantitative structure-activity relationship study of N-(3-oxo-3,4-dihydro-2H-benzo[1,4]oxazine-7-carbonyl)guanidine derivatives as potent Na/H exchange inhibitors. 943 67

Cariporide (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate: HOE642) is a novel Na+-H+ exchange subtype 1 inhibitor and has antiarrhythmic effects on ischemia/reperfusion arrhythmias without apparent cardiovascular effects in dogs and rats when given before coronary occlusion. The aim of this study was to determine the minimum effective dose and to examine the dose related effects of cariporide when it was administered before and during coronary occlusion as well as simultaneously with reperfusion. In the pre-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 140 to 36 (P < 0.01), 59 (P < 0.05) and 23 s (P < 0.01) with 0.03, 0.1 and 1 mg/kg, respectively, and reduced the incidence of reperfusion-induced ventricular tachycardia from 100 to 50 and 58% (P < 0.01), ventricular fibrillation from 83 to 8 and 0% (P < 0.01), and mortality from 75 to 8 and 8% (P < 0.01) with 0.1 and 1 mg/kg, respectively. In the post-treatment group, cariporide dose-dependently reduced the ventricular tachycardia duration from 92 to 37, 40, 42 (P < 0.05) and 24 s (P < 0.01) with 0.03, 0.1, 0.3 and 1 mg/kg, respectively, and the incidence of ventricular tachycardia from 100 to 53% (P < 0.01) by 1 mg/kg, and ventricular fibrillation from 87 to 33, 7 and 7% (P < 0.01), and the mortality from 73 to 27 (P < 0.05), 0 and 7% (P < 0.01) with 0.1, 0.3 and 1 mg/kg, respectively. In the group with simultaneous injection, both doses of cariporide (1 and 3 mg/kg) reduced the incidence of ventricular fibrillation from 83 to 42% (P < 0.05). The heart rate, blood pressure and QT interval did not change after drug treatment.
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PMID:Antiarrhythmic effects of cariporide, a novel Na+-H+ exchange inhibitor, on reperfusion ventricular arrhythmias in rat hearts. 947 25

We report a case of hypertrophic cardiomyopathy (HCM) with apical left ventricular aneurysm, which is difficult to review because cases are so rare. A 54-year-old Japanese man was first found to have an electrocardiographic abnormality (T-wave inversion at rest) 19 years ago, and non-obstructive apical HCM without identifiable cause was diagnosed by echocardiography, left ventriculography, and clinical findings. After 19 years, he was admitted because of repeated episodes of palpitation and chest oppression at rest. Widespread left ventricular hypertrophy from the anteroseptal wall to the apex with an apical left ventricular aneurysm was detected by echocardiography, left ventriculography, and cardiac magnetic resonance imaging. Histologic examination of the hypertrophic apical myocardium surrounding the aneurysm showed that the myocardial tissue had been extensively replaced by fibrous tissue containing hypertrophic myocardial fibers, and uptakes of [123I]-metaiodobenzyl guanidine (MIBG) and [123I-] beta-methyliodophenyl pentadecanoic acid (BMIPP) in single-photon emission photography images were reduced despite high myocardial perfusion. On the other hand, histologic examination of the hypertrophic anterior wall revealed myocardial hypertrophy with disorganization; myocardial perfusion and the uptakes of MIBG and BMIPP were preserved. Abnormalities of myocardial fatty acid metabolism and sympathetic neuron activity with preserved perfusion flow and histologic changes such as fibrosis in the apical wall are indicative of apical myocardial injury or ischemia (infarction) without coronary artery stenosis; apical aneurysm may have occurred in severe apical HCM with cavity obliteration up to the midventricular level.
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PMID:Hypertrophic cardiomyopathy with apical left ventricular aneurysm. 955 32

Administration of inhibitors of the Na+/H+ exchanger (NHE) have been shown to produce cardioprotective effects in a number of animal models of ischemia-reperfusion injury; however, controversy still exists as to the efficacy of these agents when administered just before reperfusion. To address this question, the efficacy of several doses of a new selective NHE-1 isoform inhibitor (IC50 for inhibition of 22Na uptake in NHE-1 expressing mouse fibroblast cells = 10.4 +/- 1.0 nM), EMD 85131 (2-methyl-5-methylsulfonyl-1-(1-pyrrollyl)-benzoyl-guanidine), was tested in a canine infarct model in which the left anterior descending coronary artery was occluded for 60 min followed by 3 hr of reperfusion. EMD 85131 (0.75 or 3.0 mg/kg) was infused for 15 min before left anterior descending occlusion or 15 min before reperfusion. Infarct size was determined by use of the triphenyltetrazolium chloride histochemical stain and was expressed as a percent of the area at risk. EMD 85131 (0.75 or 3.0 mg/kg) administered before left anterior descending occlusion produced a marked (*P < .05) and dose-related reduction in IS/AAR (24.3 +/- 3.6, control; 9.3 +/- 3.4%, EMD 0.75; 6.4 +/- 2.3%, EMD 3.0). These two doses of EMD also produced significant (*P < .05) reductions in infarct size/area at risk (12.2 +/- 2.1%, EMD 0.75; 13.0 +/- 2.9%, EMD 3.0) when administered 15 min before reperfusion. These results suggest that selective NHE-1 inhibitors are able to markedly reduce infarct size when given before or during ischemia and also suggest that these compounds may have clinical utility when administered after the initiation of an ischemic insult.
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PMID:A new sodium/hydrogen exchange inhibitor, EMD 85131, limits infarct size in dogs when administered before or after coronary artery occlusion. 965 58

Diabetic polyneuropathy is a complication, that affects most patients with longstanding diabetes mellitus, deteriorating their quality of life. In the last few years, new therapeutic approaches have been developed that can improve symptoms and neurologic function, and which may prevent and in some cases stop nerve damage, and even, promote nerve fiber regeneration. These treatments are supported by several investigations in animals and humans: a) thigh glycemic control (insulin), b) aldose reductase inhibition (tolrestat), c) prevention of protein glycation (amino-guanidine), d) improvement of nerve ischemia (vaso-dilators, gamma-linolenic acid), and e) administration of neurotrophic factors (gangliosides). Most evidence support the usefulness for glycemic control. Early treatment is suggested, because marked nerve fiber loss is present in advanced neuropathy.
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PMID:[Treatment of diabetic neuropathy]. 965


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