Effects of Endothelin Receptor Antagonists on the Plasma Immunoreactive Endothelin-1 Level
Terry J. OpgenorthJerry L. WessaleDouglas B. DixonAndrew AdlerSamuel V. CalzadillaRobert J. PadleyJinshyun R. Wu‐Wong
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Abstract:
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.Keywords:
Endothelin receptor antagonist
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Objective To study the relationship between vascular endothelial function and syndrome X. Methods Using atrial pacing techniques, the changes of endothelin concentration in coronary circulation were measured in 8 patients with syndrome X and 6 age matched normal subjects. Results In the syndrome X group, the changes of plasma endothelin were greater than those of the normal controls ( P 0.05). Conclusion The increase of plasma endothelin in coronary circulation in patients with syndrome X may suggest the presence of endothelial dysfunction.
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Activation of the endothelin-1 system plays a key role in the pathogenesis of pulmonary arterial hypertension (PAH). The endothelin-1 receptor antagonist bosentan inhibits the action of endothelin-1 at both receptor subtypes (ET(A) and ET(B) receptors) and has been approved for PAH therapy since 2001. Recent data were presented at an international symposium in Barcelona in February 2006.
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Ambrisentan
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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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Activation of the endothelin system has been demonstrated in the plasma and lung tissue of PAH (Pulmonary Artery Hypertension) patients. Although it is not clear if the increases in endothelin plasma levels are a cause or a consequence of PH (Pulmonary Hypertension), the data supports a prominent role for the endothelin system in the pathogenesis of PAH. Bosentan is an endothelin receptor antagonist used in the treatment of Primary pulmonary hypertension (PPH) which is a progressive disease with high mortality and administration of the orally active, dual endothelin receptor antagonist bosentan improves exercise endurance, haemodynamics, and functional class over the short term. First-line bosentan therapy was found to improve survival in patients with advanced primary pulmonary hypertension.International Journal of Human and Health Sciences Vol. 03 No. 01 January’19. Page : 10-13
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Objective To observe the Plasma concentrations of Endothelin-1 in depressive patients.Methods Plasma Endothelin-1 levels were measured by ELISA in 42 depressive patients and controls.Results Plasma ET-1 level in the depression group was significantly elevated than that in the control group.Conclusion Vascular endothelial cells function is impaired.
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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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