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)

The effects of endothelin 1 (ET-1; 300 pmol/rat intracarotid) on somatosensory evoked potential were investigated in rats. ET-1 led to an amplitude reduction, peak latency prolongations and waveform disturbances. There was a large interindividual variability. The late cortical components were more affected than the earlier potentials at a thalamic or cortical level. ET-1-induced SEP changes developed quickly after the drug injection and persisted for at least 30 min. It is assumed that the observed effects probably reflect the occurrence of a progressively developing ischemia subsequent to ET-1 administration. Moreover, the pattern of ET-1-induced changes suggests a greater sensitivity of the synaptic transmission to the ischemic influence than the axonal conduction.
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PMID:Effect of endothelin on somatosensory evoked potentials in rats. 147 35

Endothelin (ET) is a potent vasoconstrictor peptide that may have pathophysiological roles in the microcirculation of the peripheral nervous system. We examined the local action of epineurial ET-1 on sciatic endoneurial blood flow using serial hydrogen clearance measurements in anesthetized, paralyzed, and ventilated Sprague-Dawley rats. In separate rats, we made serial measurements of sciatic motor multifiber conduction before and then after application of epineurial ET (saline on contralateral nerve) 2 and 24 h and 4 and 7 days later. Epineurial bathing solutions of ET increased microvascular resistance and reduced local endoneurial blood flow in a dose-responsive fashion with a half-maximum effective concentration of 10(-8) M. Maximum vasoconstriction at 10(-6) M ET was associated with a fall in endoneurial blood flow from 18.7 (pre-ET) to 7.2 ml x 100 g-1 x min-1. Epineurial norepinephrine (10(-7) to 10(-10) M) also resulted in vasoconstriction, but of lesser degree. Pretreatment with intraperitoneal nimodipine, a dihydropyridine Ca2+ channel antagonist, but not phentolamine, prevented the vasoconstrictive action of ET. Three of eight animals developed temporary but complete axonal conduction block at the site of ET administration (10(-5) M) and four others had partial conduction block. Contralateral saline-treated sciatic fibers were unaffected. Local ET action on extrinsic epineurial microvessels results in reversible ischemia of the underlying endoneurium that may be associated with conduction block. ET's action is more potent than norepinephrine and appears dependent on L-type voltage-gated Ca2+ channels.
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PMID:Acute endoneurial ischemia induced by epineurial endothelin in the rat sciatic nerve. 148 4

To determine the organ distribution of production of the three endothelin (ET) isopeptides, we have developed three ribonuclease protection assays specific for the messenger RNAs (mRNAs) of rat ETs 1, 2, and 3.12 organs from adult Sprague-Dawley rats were examined: heart, lung, liver, spleen, kidney, stomach, small intestine, large intestine, testis, muscle, salivary gland, and brain. The mRNA for ET1 was five times more abundant in the lung than in any other organ studied, moderate expression was seen in the large intestine, and lower levels of mRNA were detected in each of the other organs examined. ET2 was expressed at high level in both large and small intestine and at low level in stomach, muscle, and heart, but ET2 mRNA could not be detected elsewhere. ET3 mRNA was found in all organs, particularly in small intestine, lung, kidney, and large intestine. Because of reports suggesting that ETs might be involved in the hypoperfusion and hypofiltration observed in postischemic kidneys, we have also studied levels of mRNA in kidneys that had previously been subjected to 25 or 45 min of clamping of the renal pedicle. At 6 h after 45 min of ischemia, ET1 mRNA increased to a peak of 421 +/- 69% (mean +/- SEM, n = 3) of that in a standard renal RNA preparation. By contrast, ET3 mRNA decreased in the postischemic organ, falling to a value of 19 +/- 2% of standard at the same time point. The effects of ischemia on ET1 and ET3 mRNAs were long-lasting, with elevation of ET1 and depression of ET3 persisting for days. ET2 mRNA remained undetectable throughout. These findings (a) support a role for ET1 in postischemic renal vascular phenomena and (b) demonstrate a situation in which the expression of ET isoforms is clearly subject to differential regulation.
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PMID:Organ distribution of the three rat endothelin messenger RNAs and the effects of ischemia on renal gene expression. 152 10

Endothelin (ET)-1 is a potent vasoactive peptide elaborated by the vascular endothelial cells. In the present study we examined the effects of ischemia-hypoxia (I/H) on ET-1 release from isolated perfused guinea pig lungs and heart. Guinea pig lungs subjected to 15 min I/H followed by reperfusion and reventilation significantly (P less than .05) augmented ET-1 release from 14.1 +/- 2.7 to 30.4 +/- 5.6, 27.3 +/- 4.0 and 28.0 +/- 5.0 pg/g of dry weight of lung at 15, 30 and 45 min after I/H, respectively. Pretreatment of guinea pigs with phosphoramidon (10 mg/kg i.v.), an ET converting enzyme inhibitor, 10 min before the removal of lungs abrogated the I/H-induced increases in ET-1 release without affecting the base-line values of ET-1. Phosphoramidon also attenuated the elevations in pulmonary insufflation pressure (PIP) produced by I/H. Moreover, infusion of big ET-1 (BET-1; 30 micrograms/over 15 min) into isolated perfused guinea pig lungs enhanced PIP that was abolished by phosphoramidon. Isolated guinea pig hearts subjected to 15 or 30 min of global ischemia exhibited no disturbances in ET-1 release or mechanical activity. In addition, the increases in perfusion pressure elicited by BET-1 infusion (12 micrograms/over 30 min) into isolated guinea pig hearts was unaffected by phosphoramidon. In a separate study in anesthetized guinea pigs, phosphoramidon significantly attenuated the increases in blood pressure and PIP elicited by BET-1 (10 micrograms/kg i.v.); the pressor and PIP responses to ET-1 (4 micrograms/kg i.v.) were not affected.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Phosphoramidon abolishes the increases in endothelin-1 release induced by ischemia-hypoxia in isolated perfused guinea pig lungs. 152 13

The effect of aerobic perfusion, of up to 90 min global ischemia, and of reperfusion on 125I-labeled porcine endothelin (125I-ET-1) binding site density (Bmax), affinity (KD), and selectivity was investigated using cardiac membranes harvested from adult Sprague-Dawley rats. Membranes from nonperfused hearts bound 125I-ET-1 with a Bmax of 117.0 +/- 8.8 fmol/mg protein, a KD of 0.076 +/- 0.005 nM, and a Hill coefficient approaching unity. Neither aerobic perfusion nor 10 min of normothermic ischemia and subsequent reperfusion altered these binding parameters. The extension of the ischemic episode increased Bmax (23, 32, 62, and 60% increase after 20, 30, 60, and 90 min ischemia, respectively). Reperfusion further increased Bmax (P less than 0.01 at 15 min reperfusion after 20 and 30 min ischemia, and after 30 min reperfusion following 60 min ischemia) without changing selectivity. Affinity was reduced after 60 (P less than 0.05) and 90 (P less than 0.01) min ischemia. Ischemia at 22 degrees C had no effect on the density or affinity of these binding sites.
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PMID:Ischemia and reperfusion increase 125I-labeled endothelin-1 binding in rat cardiac membranes. 218 Mar 23

To study the involvement of endogenous endothelin (ET) in the development of cerebral ischemia, we measured by radioimmunoassay brain tissue content of immunoreactive (ir)-ET-1 in a model of focal cerebral ischemia in the rat. Permanent occlusion of the middle cerebral artery (OMCA) was accompanied after 24 h by a progressive but marked elevation of ir-ET-1 in the ipsilateral compared with the contralateral hemisphere (119% after 24 h; 184% after 48 h and 459% after 72 h). The pial vessels and the arteries of the circle of Willis did not respond with ir-ET-1 production. The increase in ir-ET-1 content in tissues was first observed in the caudate nucleus (after 24 h) and later in the cortex (after 48 h), which was more variably injured. Transient ischemia followed by recirculation led to a slight increase of ir-ET-1, which also appeared after 24 h of recirculation. This study demonstrates that during permanent OMCA, the tissue content of ir-ET-1 markedly and progressively increases, whereas less severe ischemia (transient) is accompanied by a modest elevation of ir-ET-1 levels. These results suggest that endogenous ir-ET-1 production is involved in the development and the severity of ischemic injury.
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PMID:Elevated tissue endothelin content during focal cerebral ischemia in the rat. 750 72

The effect of nitro-L-arginine (NLA), inhibitor of NO synthase, on ET-1 content in cerebrospinal fluid (CSF) and on the vascular system was investigated in global ischemia/reperfusion of Mongolian gerbils. The results indicate that NLA induced a prolonged (2-3-fold) increase of ET-1 concentration above that seen in the CSF of untreated animals during ischemia/reperfusion. Both the transient and prolonged rise of ET-1 content observed in the CSF coincided with the reduction in the cerebral blood flow seen in untreated and NLA-treated gerbils, respectively, at the time of reperfusion.
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PMID:Nitro-L-arginine augments the endothelin-1 content of cerebrospinal fluid induced by cerebral ischemia. 758 11

The effects of intravenous (i.v.) infusions of exogenous endothelin-1 (ET-1, 0.05 and 0.1 nmol/kg/min) on incidence and severity of ventricular arrhythmias during 30-min period of acute myocardial ischemia were assessed in anesthetized rats. We examined the role of ETA-receptors in the proarrhythmic effects of both exogenous and endogenous ET using the ETA-receptor antagonist, BQ123. Exogenous ET-1 increased the severity and incidence of ischemic arrhythmias dose dependently. Both doses increased the total incidence of ventricular fibrillation (VF: from 30% in controls to 100 and 88% in rats given 0.05 and 0.1 nmol/kg/min ET-1, respectively); the higher dose also increased total arrhythmia count and duration of ventricular tachycardia (VT). BQ123 (10 micrograms/kg/min) completely abolished this proarrhythmic effect of exogenous ET-1. To assess the role of endogenous ET-1 in the genesis of ischemic arrhythmias, we studied the effects of a range of doses of BQ123 (5-100 micrograms/kg/min) on ischemic arrhythmias. Only one dose of BQ123 (10 micrograms/kg/min) attenuated arrhythmias by reducing total ventricular ectopic count (from 1,423 +/- 112 in controls to 677 +/- 159). The highest dose of BQ123 tested (100 micrograms/kg/min) increased arrhythmias by significantly increasing the incidence of irreversible VF (from 25 to 75%). These results suggest that exogenous ET-1 can aggravate ischemia-induced arrhythmias, an effect that is sensitive to ETA-receptor blockade. However, although endogenous ET-1 may make some contribution to the genesis of arrhythmias resulting from coronary occlusion through an action at ETA receptors, the observed proarrhythmic effect of BQ123 at high doses suggests that this may unmask an effect of ET-1 at other receptors.
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PMID:Effects of endothelin-1 and the ETA-receptor antagonist, BQ123, on ischemic arrhythmias in anesthetized rats. 759 33

Circulating endothelin (ET) levels are elevated in conditions such as endotoxemia, hepatic ischemia-reperfusion injury, or orthotopic liver transplantation, and this potent peptide may contribute to hepatic pathophysiology. We measured the surface binding of [125I]ET-1 to rat Kupffer cells in primary culture at 4 degrees C; the dissociation constant (Kd) was 270 pmol/L, and the apparent Bmax was 3,000 receptors/cell. At 37 degrees C, total association (surface binding plus internalization) was much greater than at 4 degrees C, indicating that internalization of the receptor-ligand complex is rapid; the apparent Kd was 30 pmol/L, comparable with other reports for hepatic-derived cells. Studies using [125I]ET-1, [125I]ET-3, and specific ET (ant)agonists showed that Kupffer cells possess predominantly ET(B) type receptors. Prior treatment with 500 pmol/L unlabeled endothelin rapidly ( < 15 minutes) occluded 60% of subsequent [125I]ET association; using 5 nmol/L unlabeled ET, this occlusion occurred within 1 minute. [125I]ET association with Kupffer cells was unaffected by short-term (approximately 1 hour) treatment with cyclic adenosine monophosphate (cAMP), but long-term (20 hour) treatment resulted in a twofold increase in [125I]ET association with no change in the apparent Kd. Stimulation of protein kinase C in Kupffer cells by phorbol 12-myristate acetate had a dual regulatory effect on [125I]ET association. Short-term ( < 1 hour) treatment with phorbol 12-myristate acetate decreased [125I]ET-3 association by 50%, whereas prolonged treatment (20 hour) increased association twofold. In both cases, the apparent Kd for [125I]-endothelin was unaltered.
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PMID:Endothelin association with the cultured rat Kupffer cell: characterization and regulation. 765 98

The effects of diltiazem and phosphoramidon on sudden death induced by endothelin (ET)-1 and by big ET-1 were compared in rodents. Diltiazem (2 mg/kg, i.v.) remarkably diminished the lethal toxicity of ET-1 with a reduction in the extent of the rise in plasma immunoreactive ET-1-like activity (IR-ET-1), tissue IR-ET-1 accumulation in the heart and the rise in plasma potassium concentration. In big ET-1-induced lethality, diltiazem only slightly prolonged the latency and did not reduce the mortality. Although diltiazem moderately inhibited the rise in plasma IR-ET-1 and potassium concentration in these mice, it did not affect the accumulation of IR-ET-1 in the heart, lung or kidney. Phosphoramidon (2 mg/kg, i.v.) decreased the lethality of big ET-1 with the decrement in elevation of IR-ET-1 in the heart, lung and plasma as well as with the decrease in plasma potassium concentration, but it failed to improve any parameters in ET-1-induced lethality. In anesthetized rats, ET-1 (5 nmol/kg, i.v.) elevated ST-segment of electromyocardiograms, and diltiazem (2 mg/kg, i.v.) significantly reversed this change. Big ET-1 (25 nmol/kg, i.v.) also induced the ST-segment elevation, which was significantly inhibited by phosphoramidon but not by diltiazem. These findings suggest that accumulation of ET-1 in the heart, which may lead to lethal cardiac ischemia, is an important factor in the lethality of ET-1, while additional factors (such as hemoconcentration and bronchoconstriction) may be involved in big ET-1-induced lethality.
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PMID:Possible involvement of different mechanisms in sudden death induced by endothelin-1 and big endothelin-1. 773 38


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