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

Endothelial driving factors pathophysiologically affect the regulation of coronary circulation. To investigate the regulation of vascular function by endothelium-derived relaxing factor (EDRF) and endothelial cells, endothelium-dependent relaxation impairment was studied in acute ischemia-reperfusion injury in large coronary artery and coronary microvasculature. EDRF (NO) production and release were inhibited due to ischemia-reperfusion injury to the endothelium of large coronary arteries. There was an increased sensitivity selective to ET-1 in large coronary arteries exposed to ischemia and reperfusion. Reduced endothelium-dependent relaxation and augmented ET-1 sensitivity in large coronary arteries suggest the existence of spasmogeneity in reperfused blood vessels. Ischemia and reperfusion also brought about various morphological and functional changes in the reperfused coronary microvasculature. Edema of perivascular interstitium and endothelial cells was the main observation and caused a decrease in the ability of the microvascular bed to dilate because of extravascular compression. To examine the long-term suppression of NO synthesis accompanying endothelial dysfunction, the long-term reactions of coronary arteries and myocardium due to chronic inhibition of NO synthesis by continuously infused L-NAME was investigated. Endothelial cell impairment, proliferation and disarrangement of medial smooth muscle cells, microvascular injury due to platelet thrombi and increased perivascular fibrous tissue were found in rat coronary arteries. Myocardial fibrosis due to coronary microvascular injury was observed. These changes in coronary arterial and myocardial structure were suppressed by ACE inhibitors. Therefore, ACE inhibitors are useful in the treatment of coronary microvascular impairments.
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PMID:Regulation and failure of coronary circulation. 897 73

The present study was designed to investigate if TAK-044, a novel endothelin (ET) ETA/ETB receptor antagonist, inhibits ischemia-reperfusion liver injury. The initial study showed the presence of both ETA and ETB receptors in canine hepatic membrane fractions using the specific binding assay of labeled ET-1 with ET isomers and TAK-044. The nonselective ETA/ETB receptor antagonist TAK-044 inhibited the specific binding of ET-1 to the receptors in a concentration-dependent manner. In subsequent studies using a canine 70% partial liver ischemic model (60 minutes), we found that an intravenous injection of TAK-044 (3 mg/kg) before ischemia significantly inhibited the release of serum liver enzymes (aspartate transaminase, alanine transaminase, mitochondrial glutamic oxaloacetic transaminase, and an increase of indocyanine green retention rate after reperfusion, compared with the control group. Elevation of the portal venous pressure was also suppressed significantly during the portal triad occlusion, and a rapid restoration of oxygen pressure in the liver tissue after reperfusion was observed in the TAK-044-treated group. Morphometric analysis revealed that the hepatocyte swelling and sinusoidal contraction 1 hour after reperfusion were significantly less severe in the treated group than in the control group. The sludging of erythrocytes in the sinusoidal lumens was also minimal in the treated group. In conclusion, the significant suppression of hepatic microcirculatory disturbance and tissue injury after ischemia-reperfusion were shown in the TAK-044-treated group. This finding indicates that the pretreatment of TAK-044 is useful as a hepatoprotective agent against ischemia-reperfusion injury, which is otherwise produced by a pathway involving ET-1.
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PMID:Hepatoprotective effect of the endothelin receptor antagonist TAK-044 against ischemia-reperfusion injury in the canine liver. 909 1

Excessive release of glutamate, from glial cells as well as neurons, is thought to be a major cause of neuronal death in ischemia. To investigate glutamate release from glial cells, we measured glutamate efflux from cultures of rat astrocytes preloaded with L-[3H]glutamate. Glutamate efflux was induced by either 60 mM KCI or Na+-free medium, suggesting that the efflux is due to the reversed operation of a Na+- and K+-coupled glutamate uptake machinery. While investigating various neuropeptides and neurotransmitters, we found that endothelin (ET) specifically induced efflux of glutamate. Northern blot analysis and binding study showed that the ET type B receptor (ET(B)-R) subtype was expressed two to three times more densely than the ET type A receptor (ET(A)-R) in astrocytes. The ET(B)-R antagonist IRL 2500 partially inhibited efflux of glutamate induced by 1 nM ET-1 in a concentration-dependent manner, causing a maximal inhibition of 60% at 1 microM. However, the ET(A)-R antagonist BQ-123 did not cause significant inhibition even at 10 microM. Combination of both antagonists completely inhibited the ET-1-induced efflux. These results indicate that both receptor subtypes are involved in efflux of glutamate with a major contribution from the ET(B)-R. Our findings suggest that ET, which is known to be released in ischemia, may exacerbate neurodegeneration by stimulating efflux of glutamate.
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PMID:Endothelin evokes efflux of glutamate in cultures of rat astrocytes. 910 48

The acute effect of cyclosporine A (CSA) on myocardial function after ischemia and reperfusion and the mechanism of action was investigated in isolated working guinea-pig hearts. Myocardial function was experimentally infringed by imposing short-term global ischemia and reperfusion (15 min each). External heart work (EHW), determined before and after ischemia, served as the criterion for quantitation of recovery. Control hearts were perfused with modified Krebs-Henseleit buffer, other hearts received buffer supplemented with CsA +/- an endothelin receptor antagonist or exogenous endothelin +/- an inhibitor of nitric oxide (NO) synthesis. To assess the importance of endothelial production of mediators directly, NO release in coronary effluent (continuously measured with an amperometric sensor) and release of 6-keto-prostaglandin F1, (6-keto-PGFb), a stable metabolite of prostacyclin (PGI2), were determined in non-working. Langendorff hearts. Oxidative stress during reperfusion was assessed by measuring glutathione release in coronary venous effluent. Cyclosporine A (0.8 microM) improved post-ischemic function significantly (59% recovery of EHW nu 31% for controls). At 0.08 microM. CsA was without beneficial effect (30% recovery). The endothelin (ET)A- and ETB-receptor antagonist bosentan inhibited the protective action of 0.8 microM CsA (32% recovery). Exogenous ET-1 (80 pM) improved recovery to 53%, an effect which was blocked by the inhibitor of NO-synthase, NG-nitro-L-arginine (NOLAG. 1 microM. 31% recovery. In the control group, post-ischemic NO release in coronary effluent recovered from zero to about 100% of the pre-ischemic value by 10 min. but then decreased rapidly during the subsequent 15 min of reperfusion. In hearts treated with 0.8 microM CsA, NO release stayed at 100% of the pre-ischemic value throughout reperfusion, the difference between controls and CsA-treated hearts being significant after 20 min of reperfusion. On the other hand, coronary venous release of 6-keto-PGF1a was not different between the groups. Release of glutathione during early reperfusion first 5 min) was significantly lowered (P < 0.05) to about 50% in CsA (0.8 microMI- and ET-I-treated compared with controls (8.8 nmol/min). Cyclosporine A acts as a cardioprotective agent in our model of ischemia and reperfusion, presumably by elevating the level of endogenous nitric oxide and thereby reducing oxidative stress.
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PMID:Cardioprotection by cyclosporine A in experimental ischemia and reperfusion--evidence for a nitric oxide-dependent mechanism mediated by endothelin. 914 Aug 13

This study was designed to investigate whether or not a novel nonselective endothelin A/B (ETA/ETB) receptor antagonist (TAK-044) provides hepatoprotection during porcine liver transplantation. The grafts were stored in chilled Euro-Collins solution and recirculated following reflush with lactated Ringer's with (TAK group) or without (control group) TAK-044 (10 mg/kg). Intracellular (cytoplasma, mitochondria, and nucleus) calcium (Ca) concentrations were measured in the hepatic biopsy materials obtained serially at varying time point from donor laparotomy to recipient closure using an electron probe X-ray microanalyzer. Liver function tests also were determined. The cold and warm ischemia times of the grafts were comparable between the two groups. The peak endothelin-1 T-1) concentration after recirculation was significantly higher in the TAK group than in the control group (129 +/- 30 pg/ml vs 26 +/- 6.5 pg/ml). However, release of liver enzymes, increases in total bile acid, and deterioration of indocyanine green retention rate were significantly suppressed in the TAK group. In the control group, the intracellular Ca concentrations, especially in the mitochondrial fraction, were elevated markedly following recirculation of the hepatic arterial flow. In the TAK group, this effect was suppressed. Thus, the supplementary use of the nonselective ETA/ETB receptor antagonist TAK-044 via a rinse route may alleviate an early postreperfusion microcirculatory disturbance of the liver grafts without adverse effects by the increased ET-1 on the systemic circulation.
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PMID:Hepatoprotective effect of a nonselective endothelin receptor antagonist (TAK-044) in the transplanted liver. 924 65

An increased release of the potent vasoconstrictor endothelin (ET) may play a role in the development of myocardial stunning. We, therefore, hypothesized that blockade of ET with either monoclonal antibodies against ET-1 and ET-3 (a-ET1/3-ab) or with the ET(A) receptor antagonist BQ123 would improve the reduction in myocardial blood flow (MBF; H2 clearance) and fractional wall thickening (FT; pulsed Doppler) after repetitive ischemia/reperfusion in an in situ perfused rat model. Under baseline conditions, ET-1 dose dependently decreased MBF and increased mean arterial blood pressure. FT and heart rate were unaltered. Pretreatment with both a-ET1/3-ab or BQ123 effectively blocked the effects of ET. Following repetitive ischemia, MBF was significantly reduced from 3.5 +/- 0.4 to 2.1 +/- 0.3 ml x min-1 x g-1 (p < 0.05) and FT from 16.2 +/- 1.7 to 9.4 +/- 1.1% in the control group (p < 0.05). Pretreatment with either antibodies did not significantly improve the attenuation in MBF and FT at the end of the ischemic protocol. These results indicate that inhibition of ET-1 by monoclonal antibodies or by ET(A) receptor blockade does not influence the decrease in MBF and FT in repetitive ischemia/reperfusion. We, therefore, propose that ET is not a major determinant in the development of myocardial stunning.
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PMID:Endothelin does not contribute to the attenuation in myocardial function and blood flow after repetitive ischemia in the rat heart. 942 97

Renal endothelin-1 (ET-1 ) production is increased by hypoxia and has been implicated in ischemia-induced renal hypoperfusion. Because the inner medullary collecting duct (IMCD) is a major source of ET- 1 in the kidney, and because ET- 1--in the setting of ischemic renal failure-may alter medullary perfusion, we sought to determine whether hypoxia modulated ET-1 production by IMCD cells. Primary cultures of rat IMCD cells were exposed to 21%, 3%, or 0%O2. IMCD ET-1 secretion significantly increased after exposure of cultures to 3% O2 (114.1% +/- 4.7% increase over control value) and 0%O2 (171.7% +/- 7.9% increase). ET-1 mRNA levels, as determined by reverse transcription-polymerase chain reaction, also increased 2.5-fold after 24-hour exposure to 0% O2. We speculate that a hypoxia-induced increase in IMCD ET-1 production plays a role in modulating renal medullary perfusion during ischemic renal failure.
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PMID:Hypoxia regulates endothelin-1 production by the inner medullary collecting duct. 945 26

Hepatic ischemia-reperfusion (IR) injury caused by portal vein clamping is a common problem in hepatobiliary surgery. Endothelin (ET) is a potent vasoconstrictor and is associated with IR injury. This study evaluated the effect of ET on liver cell injury and hepatic regeneration after hepatectomy with IR. The portal veins of rats were clamped for 20 min, then unclamped and a 70% partial hepatectomy was performed. TAK-044 (TAK), the nonselective ETA/ETB receptor antagonist, was administered s.c. 30 min before laparotomy [TAK(+)]. Portal blood ET-1, GOT levels, hepatic blood flow, histologic change, DNA synthesis of hepatocytes, and the relationship of Ito cells and perisinusoidal cells were evaluated. ET-1 concentration increased after IR and was significantly higher in the TAK(+) group owing to the blockade of ET receptors. Increased GOT levels and sinusoidal congestion were reduced, but DNA synthesis of hepatocytes and hepatic blood flow did not change in the TAK(+) group. Changes in desmin staining showed that Ito cells might be related to IR injury. In conclusion, ET-1 was associated with IR injury and TAK-044 reduced but did not affect hepatocyte DNA synthesis after partial hepatectomy.
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PMID:Endothelin in liver cell injury and regeneration after 70% hepatectomy with portal ischemia. 959 18

Nephrovasculopathies are an increasing cause of end-stage renal failure. Nephrosclerosis is a common finding in the hypertensive patient. However, genetic factors play a prominent role in its incidence. Nephrosclerosis is a common cause of early renal failure in blacks of African ancestry, as opposed to white Europeans, in whom hypertensive nephrosclerosis rarely and slowly leads to uremia. That primary hypertension is accompanied by arterionephrosclerosis and arteriolonephrosclerosis, by focal and segmental glomerulosclerosis leading to glomerular obsolescence and by interstitial fibrosis has been established for nearly a century. However, renal vascular lesions can be observed in animal models as well as in some humans, especially blacks, in the absence of, or preceding the onset of hypertension. This suggests that nephroangiosclerosis might stem from a genetic defect in the renal vascular bed, a defect closely associated with the hypertensive trait. Atherosclerotic renal artery stenosis is a major, potentially remediable cause of chronic renal failure, especially in whites. Its prevalence in the atherosclerotic population is in the order of 15 percent. This figure has obvious bearing in terms of health cost. Early diagnosis and treatment by angioplasty or surgery can preclude development to end-stage renal disease and maintenance hemodialysis, as renal atrophy due to chronic ischemia resulting from renal artery stenosis can be halted or partially reversed by revascularization before extensive fibrosis sets in. Finally, renal vascular lesions are commonly observed in the course of various nephropathies, even in the absence of hypertension. The relationship between fibrogenesis and these vascular lesions, which develop along with interstitial fibrosis and entail an unfavorable prognosis in various glomerulopathies, remains to be elucidated. This is especially the case for focal-segmental glomerulosclerosis, membranous glomerulopathy and IgA glomerulonephritis. The pathophysiology of renal fibrosis induced by ischemia is centered on increased generation of angiotensin II that is fibrogenic owing to interaction with endothelin 1, PDGF-BB and TGF-beta. These notions open perspectives toward pharmacologic means to retard or even prevent the development of such various ischemic conditions to end-stage renal failure.
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PMID:[Vascular mechanisms of renal fibrosis. Vasculonephropathies and arterial hypertension]. 1037 63

Using in vivo microscopy red blood cell (RBC) velocities, functional capillary density (FCD) and capillary diameters were estimated after inducing acute pancreatitis by intraductal infusion of sodium taurocholate (0.8 ml; 4%) or after topical superfusion of the pancreas with ET-1 (100 pmol). Sodium taurocholate mediated a significant decrease in RBC velocities between 50 and 70%, transient decrease in capillary diameters by 10%, and a sustained decrease in FCD between 60 and 70% paralleled by a dramatic heterogeneity in blood flow. Topical superfusion of the exteriorized pancreas with ET-1 caused a significant decrease in RBC velocities between 65 and 75%, a sustained decrease in capillary diameters by 10%, and a decrease in FCD by 45% accompanied by an increase in flow heterogeneity. Following sodium taurocholate infusion pancreas histology revealed a severe edema and sublobular acinar cell necrosis, while topical ET-1 application displayed a severe edema of the pancreas with focal acinar cell necrosis. Thus, ET-1 mediated a deterioration of the pancreatic microcirculation, which is similar to the microcirculatory failure found in sodium taurocholate-induced experimental pancreatitis and was associated with focal acinar cell necrosis. We are thus inclined to hypothesize that endothelin released by injured endothelial cells during acute biliary pancreatitis promotes microcirculatory failure and ischemia in acute pancreatitis, eventually leading to acinar cell necrosis.
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PMID:ET-1 induces pancreatitis-like microvascular deterioration and acinar cell injury. 1042 33


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