Inhibitory Actions of Endothelin-1 on Pain Processing
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Endothelin-1 (ET-1) in the central nervous system has been suggested to produce suppressive effects on pain transmission. We investigated the manner by which ET-1 exerts this action. ET-1 administered intracerebroventricularly produced a dose-dependent antinociceptive effect in a thermal pain test that utilized a spinal reflex to determine nociceptive thresholds. This suggested that the antinociceptive effect of ET-1 involved a descending pain inhibitory system. The antinociceptive effect was blocked by an ETA receptor antagonist but not by an ETB receptor antagonist, indicating that the action was mediated through the ETA receptor. Antagonists of opioid receptors, serotonin receptors, alpha-2 adrenergic receptors, oxytocin receptors, and dopamine receptors did not block the antinociceptive effect of ET-1. Thus, major descending inhibitory systems were probably not involved. The antinociceptive effect was blocked by intracerebroventricular administration of an alpha-1 adrenergic receptor antagonist. This indicated that the antinociceptive effect involved the activation of a supraspinal noradrenergic pathway, which in turn may activate a still unknown descending pain inhibitory system.Raphe nuclei
Endothelin 3
Nucleus raphe magnus
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Abstract Background: Portal hypertensive gastropathy is an abnormal circulatory state in gastric mucosa with vascular dilatation due to portal hypertension. The aim of the present study was to evaluate expression of endothelin receptors and their roles in the portal hypertensive gastric mucosa. Methods: Portal hypertensive rats were generated by staged portal vein occlusion. Expression of endothelin‐A receptor and endothelin‐B receptor mRNA was examined by reverse transcriptase–polymerase chain reaction, and protein were examined by immunohistochemistry. The changes of mucosal microcirculation by endothelin receptor antagonists were measured with in vivo microscope. Results: Expression of endothelin‐A receptor mRNA was increased significantly in portal hypertensive rats in comparison with sham‐operated control rats ( P < 0.05). There was no significant difference between the two groups in endothelin‐B receptor mRNA expression. Vessels of the gastric mucosa were dilated, and intravessel blood flow was increased significantly in the portal hypertensive group ( P < 0.05). Diameters of mucosal vessels and blood flow were increased significantly by endothelin‐A receptor antagonist (BQ‐485) in the portal hypertensive rats. Endothelin‐B receptor antagonist (IRL‐1038) had no significant effect on mucosal microcirculation. Conclusion: These data suggest that increased expression of endothelin‐A receptor in the portal hypertensive gastric mucosa may be related to the regulation of gastric microcirculation.
Portal hypertensive gastropathy
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Previously we have reported that endothelin receptor A and B antagonists elicit differential effects on cerebral blood flow and cellular damage. In summary, endothelin receptor A antagonists restore microcirculation and diminish cellular damage after injury, while endothelin receptor B antagonists had no effect on either parameter. However, what is not known is the effect of either antagonist on behavioral outcome. Therefore, this work was designed to test the effects of endothelin receptor A and B antagonism on behavioral outcome following traumatic brain injury (TBI).A total of 48 male Sprague-Dawley rats (400-450 g) were used in this study. Four groups (n = 12 per group) were generated as follows: sham operation, trauma+vehicle (0·9% saline), trauma+40 nmol BQ-123 (a selective endothelin receptor A antagonist) and trauma +20 nmol BQ-788 (a selective endothelin receptor B antagonist). All treatments were delivered via intracerebroventricular injection. Trauma was induced using a weight acceleration impact device. Twenty-four hours post-injection animals were tested for 21 days on a radial arm maze task to determine cognitive outcome.Our data indicated that endothelin receptor A antagonism significantly reduced the extent of behavioral deficits following TBI while endothelin receptor B and vehicle injection had no effect.The results suggest that endothelin receptor A, but not endothelin receptor B, antagonism improves behavioral outcome following TBI. Furthermore, these data provide a functional correlate to previously published findings in our laboratory showing that endothelin receptor A antagonism improves both blood flow and cellular outcome following TBI. In a broader sense, this work demonstrates that hypoperfusion following TBI likely contributes to poor outcome following head injury.
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Endothelin (ET) receptor antagonists may be beneficial for treating several medical conditions. Human trials with various ET receptor antagonists show that these antagonists elevate the plasma immunoreactive endothelin-1 (irET-1) level, and different classes of antagonists seem to affect the plasma ET-1 level differently. In this report, we study effects of ETA-selective, ETB-selective, and nonselective receptor antagonists on the plasma irET-1 level in the rat, and also compare available clinical data. The plasma irET-1 level was increased by five- and ten-fold after rats were treated with A-192621, an ETB-selective antagonist with Ki values for ETA and ETB at 5600 and 8.8 nM, for 3 days at 30 and 100 mg/kg/day via food. The plasma irET-1 level was increased by 1.8 and 2.4-fold when rats were treated with A-216546, an antagonist with Ki values for ETA and ETB at 0.46 and 13 000 nM, at 10 and 50 mg/kg/day via food for 7 days. As a comparison, the plasma irET-1 level was increased by > 24-fold when rats were treated with A-182086, a nonselective antagonist with Ki values for ETA and ETB at 0.2 and 1.2 nM, at 100 mg/kg/day via food for 9 days. In humans, blockade of ETA by ABT-627 did not result in an elevation in irET-1 until after 7 days of treatment. The results are consistent with the hypothesis that the ETB-receptor is the clearance receptor for ET-1. Our data also suggest that the modest effect of ETA antagonists on the plasma irET-1 level is probably a result of the upregulation of the ET-1 gene via a feedback mechanism.
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Aim:To investigate the effects of endothelin(ET) receptor antagonists on the expression of hepatic ET receptor mRNA in carbon tetrachloride(CCl 4) induced cirrhosis rats. Methods:A total of 32 male SD rats were allocated into carbon tetrachloride group,normal group,endothelin A receptor antagonist group(ETRA) and endothelin B receptor antagonist group(ETRB).The posterior 2 groups were injected with BQ 123(12.5 μg/kg) and with BQ 788(15 μg/mg),respectively besides the administration of CCl 4.Hepatic ET receptor mRNA was measured by reverse transcription polymerase chain reaction (RT PCR).Results:Hepatic ETRA mRNA in the latter 2 groups had no significant differences campared with that of control group;Hepatic ETRB mRNA expression had significant difference between the posterior 2 groups. Conclusion: ET receptor antagonists can partly regulate the expression of hepatic ET receptor mRNA in CCl 4 -induced cirrhotic rats.
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Summary: Endothelin (ET) receptor antagonists may be beneficial for treating several medical conditions. Human trials with various ET receptor antagonists show that these antagonists elevate the plasma immunoreactive endothelin-1 (irET-1) level, and different classes of antagonists seem to affect the plasma ET-1 level differently. In this report, we study effects of ETA-selective, ETB-selective, and nonselective receptor antagonists on the plasma irET-1 level in the rat, and also compare available clinical data. The plasma irET-1 level was increased by five- and ten-fold after rats were treated with A-192621, an ETB-selective antagonist with Ki values for ETA and ETB at 5600 and 8.8 nM, for 3 days at 30 and 100 mg/kg/day via food. The plasma irET-1 level was increased by 1.8 and 2.4-fold when rats were treated with A-216546, an antagonist with Ki values for ETA and ETB at 0.46 and 13 000 nM, at 10 and 50 mg/kg/day via food for 7 days. As a comparison, the plasma irET-1 level was increased by > 24-fold when rats were treated with A-182086, a nonselective antagonist with Ki values for ETA and ETB at 0.2 and 1.2 nM, at 100 mg/kg/day via food for 9 days. In humans, blockade of ETA by ABT-627 did not result in an elevation in irET-1 until after 7 days of treatment. The results are consistent with the hypothesis that the ETB-receptor is the clearance receptor for ET-1. Our data also suggest that the modest effect of ETA antagonists on the plasma irET-1 level is probably a result of the upregulation of the ET-1 gene via a feedback mechanism.
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