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Query: UMLS:C0022116 (ischemia)
 91,303 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ischemic insults to the brain in stroke or traumatic brain injury produce excessive release of glutamate from depolarized nerve terminals. This excessive glutamate release in turn stimulates massive calcium entry into nerve cells, activating a biochemical cascade that results in cell death. A major pathway of calcium entry into depolarized nerve cells is through voltage-sensitive, high threshold calcium channels. A large fraction of this calcium entry is mediated through "R-type" calcium channels, channels resistant to blockage by dihydropyridine calcium antagonists such as nimodipine. A newly discovered compound derived from spider venom, CNS 2103, antagonizes both R-type channels and dihydropyridine-sensitive ("L-type") calcium channels. This broad spectrum of action, coupled with selectivity for calcium channels over other classes of voltage-sensitive and ligand-gated ion channels, makes CNS 2103 an interesting lead for development of drugs to treat ischemic brain injury. Activation of presynaptic ("N-type") calcium channels in nerve terminals is a primary cause of excessive neurotransmitter release in brain ischemia. Prevention of glutamate release by blockade of N-type channels in glutamatergic nerve terminals may, at an early stage in the pathophysiological cascade, abort the process leading to nerve cell death. Cambridge NeuroScience has developed a novel rapid kinetic approach for monitoring glutamate release from brain nerve terminals in vitro, and this has led to CNS 1145, a substituted guanidine that selectively blocks a kinetic component of calcium-dependent glutamate release mediated by persistent depolarization. Additional evidence suggests that CNS 1145 antagonizes presynaptic N-type calcium channels, and this may account at least in part for its ability to block glutamate release.
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PMID:New CNS-specific calcium antagonists. 131

Various types of radiopharmacons such as 201Tl, 99mTc-pyrophosphate(PYP), 123I-metaiodobenzyl-guanidine(MIBG), 111In-antimyosin Fab (AM) and 123I-beta-methyl iodophenyl pentadecanoic acid (BMIPP) were applied to a patient under successful reperfusion therapy. In the patient, elevated serum enzyme activity region in the subacute phase. Ten months after the ischemic event, AM uptake was noted at the region which maintained contractility. Two years after the ischemic event, depressed BMIPP uptake and delayed washout were noted at the apical region and the basal anteroseptal region. From these findings, the following conclusions were reached. Depressed 201Tl uptake was noted in the salvaged jeopardized myocardium. The lesions noted in the MIBG images showed depressed myocardial norepenephrine activity. This suggested that depressed sympathetic nervous function caused by severe ischemia persisted long after both myocardial perfusion and myocardial contractility had been restored. From abnormal AM uptake in the contractile myocardium myocardial cell damage, which permitted AM uptake, was persistent ten months after the ischemic event. Depressed BMIPP uptake and delayed washout suggested that abnormal fatty acid metabolism caused by severe ischemia was persistent. Severe ischemia caused various types of pathological states in the myocardium and radioisotope image was useful for studying these states.
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PMID:[Interesting PYP, 201Tl, MIBG, AM and BMIPP myocardial SPECT images in a patient under successful reperfusion therapy]. 153 23

Thallium myocardial imaging is a useful technique to evaluate myocardial perfusion and myocardial viability in ischemic heart disease. However, myocardial imaging using single photon emission computed tomography (SPECT) and gamma-emitting radiopharmaceuticals has been recently developed for more precise evaluation of myocardial infarction and ischemia. The present study evaluates animal experiments and the clinical applications of these new myocardial imaging techniques. Areas considered on 1) myocardial necrosis assessed using 111In-antimyosin, 2) myocardial fatty acid metabolism assessed using 123I-beta-methyl-iodophenyl pentadecanoic acid (BMIPP) and 3) myocardial sympathetic neural activity assessed using 123I-metaiodobenzyl guanidine (MIBG). Dual energy SPECT using these new agents and thallium gives precise characterization of the myocardial tissue in the infarcted and ischemic area.
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PMID:Newly developed myocardial imaging by using single photon emission computed tomography (SPECT). 236 19

The effect of creatinol-O-phosphate (N-methyl-N-(beta-hydroxyethyl)guanidine O-phosphate, creatinolfosfate, Aplodan) pretreatment has been studied on the recovery of contractility of rat isolated heart after hypoxia or ischemia. In normoxia creatinol-O-phosphate (100 mumol/l) evoked a positive inotropic effect only when glucose was present in the physiological solution, it also evoked a slight negative chronotropic effect that was independent of glucose. When creatinol-O-phosphate was present during hypoxia, in the physiological solution, the recovery of the contraction after reoxygenation (in the absence of the drug) was improved in a dose-dependent manner. When creatinol-O-phosphate was present in the physiological solution before ischemia, the recovery of the contractility after reperfusion was higher than in controls; the presence of creatinol-O-phosphate during reperfusion after ischemia accelerated the recovery of contractility. The action of creatinol-O-phosphate on the recovery of cardiac contractility after ischemia was also observed in hearts partially protected with a cardioplegic solution. It is suggested that creatinol-O-phosphate could exert its cardioprotective effect by an action on anaerobic glycolysis.
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PMID:Action of creatinol-O-phosphate on the contractility changes evoked by hypoxia and ischemia in rat isolated heart. 654 74

We investigated the effects of a new compound (3-methylsulfonyl-4-piperidinobenzoyl) guanidine hydrochloride (HOE 694) known to inhibit the Na+/H+ exchanger in a porcine model of ischemia/reperfusion. Ischemia was induced by coronary occlusion (twice for 10 min, with a 30-min reperfusion interval) followed by a 4-h reperfusion period. Treated animals (n = 8) received HOE 694 as a bolus (7 mg/kg) 20 min before ischemia and subsequently as a continuous infusion (0.07 mg/kg) throughout the experiment. Control pigs (n = 11) received vehicle. Regional wall function (percentage of segment shortening, % SS) of the treated animals was significantly improved as compared with that of controls after the 4-h reperfusion period (74.1 +/- 2.5 vs. 50.9 +/- 5.4, p < 0.005). Ventricular fibrillation (VF) could be prevented completely in treated pigs but occurred in 9 of 11 control animals (p < 0.001). Ultrastructural changes after ischemia and reperfusion were moderate and slightly abnormal in controls but much milder and completely recovered in the treated group, respectively. The tissue content of high-energy phosphates did not show a significant difference between groups. Inhibition of the sarcolemmal Na+/H+ antiporter with HOC 694 is antiarrhythmic and diminishes myocardial ischemic cell injury by preventing Na+ overload.
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PMID:Effects of a new Na+/H+ antiporter inhibitor on postischemic reperfusion in pig heart. 751 39

Activation of sarcolemmal Na+/H+ exchange has been proposed as a causal factor in reperfusion arrhythmogenesis. To test this hypothesis, we determined the antiarrhythmic efficacy of two structurally distinct but equipotent Na+H+ exchange inhibitors, 5-(N-ethyl-N-isopropyl)amiloride (EIPA) and the novel drug, 3-methylsulfonyl-4-piperidinobenzoyl guanidine (HOE-694), in isolated rat hearts (n = 12/group) subjected to independent dual coronary perfusion. After 15 min of aerobic perfusion of both beds, flow to the left coronary bed (LCB) was terminated for 10 min; this was followed by 5 min of reperfusion. Various concentrations of each drug were selectively infused into the LCB either during the 5-min period preceding ischemia plus during reperfusion or during reperfusion alone. With the former protocol, 0.01, 0.1, 1, and 10 microM EIPA reduced the incidence of reperfusion-induced ventricular fibrillation (VF) from 92% in controls to 83, 83, 50, and 0% (P < 0.05); the number of hearts in sinus rhythm at the end of reperfusion was increased from 17 to 42, 25, 83 (P < 0.05), and 100% (P < 0.05). HOE-694, at the same concentrations, reduced VF incidence from 92% in control to 83, 58, 50, and 8% (P < 0.05); 25, 67, 75 (P < 0.05), and 100% (P < 0.05) of hearts were in sinus rhythm, compared with 17% of controls, at the end of reperfusion. Even when infused during reperfusion alone, both drugs afforded significant protection against reperfusion-induced VF, which did not differ significantly from that observed when the drugs were also given before ischemia. The similar antiarrhythmic efficacy of EIPA and HOE-694 is consistent with an arrhythmogenic role for activation of Na+/H+ exchange during early reperfusion.
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PMID:Na+/H+ exchange and reperfusion arrhythmias: protection by intracoronary infusion of a novel inhibitor. 781 Jul 41

There is controversy over whether the cardioprotective effects of Na+/H+ exchanger inhibitors are exerted primarily during ischemia or during subsequent reperfusion, possibly because of interstudy differences in experimental conditions. We studied the impact of perfusate buffer composition on the relative degree of protection afforded by Na+/H+ exchanger inhibition during ischemia vs. reperfusion. Isolated rat hearts (n = 8/group) were perfused (37 degrees C, 75 mmHg) with bicarbonate- or N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium and subjected to 20 min of global zero-flow ischemia and 45 min of reperfusion. One of two structurally distinct Na+/H+ exchanger inhibitors [5-(N,N-dimethyl)amiloride (DMA) or (3-methylsulfonyl-4-piperidinobenzoyl)guanidine methanesulfonate (HOE-694), 10 mumol/l] was transiently (5 min) infused 1) immediately before ischemia, 2) during initial reperfusion, or 3) during both of these periods. With bicarbonate-buffered medium, neither drug improved the postischemic recovery of left ventricular developed pressure (LVDP) when given only during reperfusion. In contrast, HOE-694 improved the postischemic recovery of LVDP from 39 +/- 5% in control to 66 +/- 6% (P < 0.05) when given before ischemia and from 33 +/- 4% in control to 65 +/- 4% (P < 0.05) when given before ischemia plus during reperfusion. With the latter protocol, the cardioprotective effect of HOE-694 occurred in a dose-dependent manner at 0.1-10 mumol/l. In contrast to the results with bicarbonate-buffered medium, in the presence of N-2-hydroxyethylpiperazine-N'-2-ethanesulfonic acid-buffered medium, DMA and HOE-694 significantly improved recovery of LVDP (from 34 +/- 5% in controls to 56 +/- 3 and 71 +/- 8%, both P < 0.05) when given only during reperfusion. They also provided significant protection when given before ischemia or before ischemia plus during reperfusion; with the latter protocol, HOE-694 produced an almost complete recovery of LVDP (88 +/- 9 vs. 30 +/- 7% in controls, P < 0.05). In conclusion, our results suggest that the influence of Na+/H+ exchanger activity during reperfusion on the extent of functional recovery is modulated significantly by perfusate buffer composition. As a consequence, the cardioprotective efficacy of Na+/H+ exchanger inhibitors may be overestimated under bicarbonate-free conditions.
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PMID:Impact of extracellular buffer composition on cardioprotective efficacy of Na+/H+ exchanger inhibitors. 877 47

We investigated the potential role of the Na+/H+ exchanger (NHE) during global low-flow ischemia. Isolated working rat hearts were subjected to a low-flow ischemic period of 30 or 60 min at 37 degrees C and then reperfused for 30 min. Under those conditions, the effects of two NHE inhibitors 3-methylsulphonyl-4-piperidinobenzoyl guanidine methanesulphonate (HOE-694, 1 microM) and 5-(N-ethyl-N-isopropyl) amiloride (EIPA, 1 microM), were compared. When added to the perfusion fluid 15 min before induction of ischemia, EIPA partially preserved aortic output (AO) during either a 30- or 60-min low-flow period. A lesser effect, which was not statistically significant, was observed with HOE-694. Therefore, after 30-min ischemia, AO was 18.7 +/- 2.7, 31.4 +/- 3.3% (p < 0.05 vs. control group) and 25.8 +/- 3.2% of the preischemic value in control and EIPA- and HOE-694-treated groups, respectively. Similarly, after 60-min low-flow ischemia, AO was 15.7 +/- 1.8, 32.7 +/- 4.2% (p < 0.05 vs. control group) and 23.3 +/- 5.6% in control and EIPA- and HOE-694-treated groups, respectively. When EIPA and HOE-694 were added to the perfusion solution during the 60-min ischemic period, i.e., at 15 min of low-flow ischemia, AO was maintained at 38.9 +/- 4.9 and 30.2 +/- 2.4% (vs. 15.7 +/- 1.8% in the controls) in HOE-694- and EIPA-treated groups, respectively. EIPA but not HOE-694 also significantly (p < 0.05) improved the AO recovery during reperfusion. When administered later during ischemia, EIPA but not HOE-694 caused some recovery of AO during the remainder of the ischemic period but did not aid recovery during reperfusion. Our data suggest that although inhibition of NHE may be of some benefit during low-flow ischemia, additional effects may be necessary to provide a more efficient cardioprotection. An additional action, e.g., inhibition of the Na+/HCO3- cotransporter, could explain the superior effect of EIPA with respect to HOE-694.
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PMID:Protective effect of the sodium/hydrogen exchange inhibitors during global low-flow ischemia. 889 79

Lysophophatidylcholine (LysoPC) accumulates rapidly in the ischemic myocardium and is an important mediator of ischemia-induced cell injury. Na(+)-H+ exchange (NHE) inhibition has been demonstrated to protect the ischemic and reperfused myocardium. We determined whether NHE inhibition can also modulate cardiotoxicity produced by LysoPC (3 and 5 mumol/L) in isolated rat hearts. At 3 mumol/L, LysoPC produced a depression in left ventricular developed pressure (LVDP) and elevation in left ventricular end-diastolic pressure (LVEDP), which were 19 +/- 7% and 1290 +/- 205% of pre-LysoPC values, respectively, after 30 minutes of treatment. In the presence of the NHE inhibitor 4-isopropyl-3-methylsulfonylbenzoyl-guanidine methanesulfonate (HOE 642, 5 mumol/L), LVDP was reduced to only 80.8 +/- 8.6%, and LVEDP increased to 270 +/- 32% (P < .05 for both parameters). LysoPC significantly depressed tissue ATP, creatine phosphate, and glycogen contents and increased lactate levels, all of which were significantly attenuated by HOE 642. Moreover, marked LysoPC-induced ultrastructural abnormalities, including mitochondrial and myofibrillar disruption, were totally prevented by HOE 642. This protection was mimicked by another NHE inhibitor, methylisobutylamiloride (5 mumol/L). HOE 642 was also effective against injury produced by 5 mumol/L LysoPC although, generally, the protection was less marked than that observed against 3 mumol/L; LVDP depression after 30 minutes was 10.1 +/- 4.3% and 41.4 +/- 10.4% of pre-LysoPC values in control and HOE 642-treated hearts, respectively (P < .05), whereas corresponding LVEDP elevations were 1629 +/- 393% and 990 +/- 144% (P > .05). In myocytes superfused with bicarbonate-free buffer subjected to acid loading by NH4Cl pulsing, pH recovery (as measured by acid flux) was significantly stimulated by 3 mumol/L LysoPC, indicative of NHE activation. Our study shows that cardiac injury produced by low concentrations of LysoPC can be effectively attenuated by NHE inhibition. The results also suggest that the beneficial effects of NHE inhibitors on the ischemic myocardium may be, at least partially, mediated by inhibiting the deleterious effects of LysoPC.
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PMID:Na(+)-H+ exchange inhibition protects against mechanical, ultrastructural, and biochemical impairment induced by low concentrations of lysophosphatidylcholine in isolated rat hearts. 897 28

HOE642 (4-isopropyl-3-methylsulphonylbenzoyl-guanidine methanesulphonate), a novel Na(+)-H+ exchange subtype 1 inhibitor, was investigated for its possible antiarrhythmic effects on coronary artery ligation/reperfusion and ouabain-induced arrhythmias in the canine heart which may occur after intracellular Ca2+ overload. Also, the effects of HOE642 on coronary artery ligation/reperfusion of the left coronary artery were tested in rat hearts. HOE642 (1 mg/kg) significantly suppressed the occurrence of fatal ventricular fibrillation during coronary artery ligation and after reperfusion in dogs (2 out of 8 dogs in the treated group compared to 7 out of 8 dogs in the control group, P < 0.05), but did not suppress ventricular premature contractions and ventricular tachycardia during ischemia in the canine hearts. HOE642 at the same dose markedly reduced the total duration and the incidence of reperfusion-induced ventricular tachycardia, and the incidence and mortality of reperfusion-induced ventricular fibrillation in rats (ventricular tachycardia duration, 159 +/- 12 s to 21 +/- 8 s, P < 0.01; ventricular tachycardia, 100% to 69%; ventricular fibrillation, 89% to 0%, P < 0.01; mortality, 89% to 11%, P < 0.01). The heart rate, blood pressure, QT interval and ST segment did not change in the canine and rat hearts. HOE642 slightly decreased the arrhythmic ratio of the ouabain-induced arrhythmia only at two time points (28 and 35 min after injection) in the canine hearts. In conclusion, HOE642 has obvious antifibrillatory effects on ischemia/reperfusion arrhythmias and, in addition, has a weak suppressing effect on the ouabain-induced arrhythmia.
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PMID:Antiarrhythmic effects of HOE642, a novel Na(+)-H+ exchange inhibitor, on ventricular arrhythmias in animal hearts. 899 15


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