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Query: UMLS:C0432222 (SEM)
 47,337 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vasomotor effects of the endothelins (ETs) are mediated by activation of receptor subtypes termed ETA and ETB. The present study aimed to characterize the interaction of ETA and ETB receptor activation in the cerebral circulation. Ring segments obtained from rat basilar artery were used for measurement of isometric force under resting tension or following precontraction with prostaglandin F2 alpha. In some segments, the endothelium was removed mechanically. In precontracted arteries, ET-1 elicited contraction only. In the presence of the ETA receptor antagonist, BQ-123 (10(-5) M), however, ET-1 induced a concentration-related relaxation with a pD2 value of 8.93 +/- 0.16 (mean +/- SEM, n = 15). The relaxant action was abolished following preincubation with an ETB receptor antagonist, IRL-1038 (3 x 10(-6) M), or with a nitric oxide synthase inhibitor, NG-nitro-L-arginine (10(-5) M). These results indicate that the relaxation was mediated by ETB receptor activation coupled to the release of nitric oxide. Under resting tension, ET-1 elicited concentration-related contraction (pD2: 8.03 +/- 0.04, n = 37). In arteries devoid of a functional endothelium, the concentration-effect curve was shifted to the left yielding a pD2 value of 8.88 +/- 0.11 (n = 31). Similarly, in endothelium-intact arteries contraction to ET-1 was augmented following nitric oxide synthase inhibition or ETB receptor blockade with 3 x 10(-6) M BQ-788 (pD2: 8.94 +/- 0.18, n = 19). The results suggested that, in the isolated rat basilar artery, ET-1 induced coactivation of the contraction-mediating ETA receptor and the relaxation-mediating ETB receptor. The coactivation resulted in opposing vasomotor effects, but the contraction covered relaxation under normal conditions. However, force development by ET-1 was suppressed by its endothelium-dependent relaxant action.
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PMID:Endothelium-dependent relaxation counteracting the contractile action of endothelin-1 is partly due to ETB receptor activation. 908 81

1. Obstructive jaundice predisposes the kidney to acute renal failure. Endothelin (ET), a potent renal vasoconstrictor and modulator of the tubular action of arginine vasopressin, has been suggested to play a pathogenetic role in acute renal failure. In the present study we therefore investigated renal function and the renal ET system in rats on day 4 after bile-duct ligation (BDL) or sham-operation (SO), without (n = 7 in each group) and with treatment with bosentan, a combined ETA/ETB receptor blocker, (n = 5 in each group). 2. On day 4 after BDL, serum bilirubin had increased to 226 +/- 10 mumol/l (SEM) as compared with 6 +/- 2 mumol/l in SO rats. Endogenous creatinine clearance, an index of glomerular filtration rate, was significantly reduced to 0.7 +/0 0.1 ml min-1 g-1 of kidney weight after BDL as compared with 1.1 +/- 0.1 ml min-1 g-1 of kidney weight after SO (P < 0.05). Bosentan prevented the decrease in glomerular filtration rate (1.0 +/- 0.2 ml min-1 g-1 of kidney weight), as well as polyuria and defective concentrating ability, in BDL rats. 3. Plasma ET concentration on day 4 after surgery (28.2 +/- 1.5 pmol/l) was higher (P < 0.01) in BDL than in SO rats (12.9 +/- 1.5 pmol/l) and rose further in bosentan-treated BDL and SO rats (43.4 +/- 5.1 compared with 21.9 +/- 6.6 pmol/l). Urinary ET excretion was significantly higher in BDL rats than in SO rats (1.58 +/- 0.22 compared with 1.28 +/- 0.18 pmol 24 h-1 100 g-1 of body weight; P < 0.05). 4. ET synthesis by glomeruli isolated from BDL rats was lower [81 +/- 19 fmol h-1 (mg of protein)-1] than that from SO-rats [139 +/- 28 fmol h-1 (mg of protein)-1; P < 0.05], whereas papillary ET synthesis was higher in BDL [10 +/- 3 fmol h-1 (mg of protein)-1] than in SO rats [4 +/- 1 fmol h-1 (mg of protein)-1; P < 0.05]. 5. The results indicate that BDL is associated with increased plasma ET concentration and suppression of GFR. Enhanced renal inner medullary collecting-duct ET synthesis, which is reflected by increased urinary ET excretion, may reduce distal tubular water absorption in BDL rats. Increased circulating and renal papillary ET synthesis may thus contribute to renal dysfunction and predispose the kidney to acute renal failure in obstructive jaundice.
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PMID:Renal endothelin system in obstructive jaundice: its role in impaired renal function of bile-duct ligated rats. 920 18

Endothelin (ET)-1 peripheral levels are high in children with respect to values of adults, but its pathophysiological significance remains to be established. In these conditions the interaction of ET-1 with its receptors may constitute a clue to the understanding of ET-1 function. Because a direct determination of ET binding sites in the heart of children is lacking, in this study we have attempted an assessment of the ET receptor status in cardiac tissue of infants (<1 year; 0.39 +/- 0.26 (SD) years, n=6) and children (1-14 years; 6.3 +/- 4.9 years, n=7) as well as an evaluation of the receptor modulation as a function of age, associated to the observed decrease of plasma ET levels between infants and children. ET-1 binding sites have also been evaluated in atrium and ventricle membranes of adult subjects recipient of cardiac transplantation (CHF) and of post-mortem cardiac specimens (autopsy) of non cardiac patients. Considering all the pediatric patients (infants +/- children) studied, an affinity constant (Kd) value of 38.2 +/- 6.1 (SEM) pM and a density (Bmax) value of 166.2 +/- 11.6 fmol/mg protein has been obtained for atrium. Similar values have been found in the ventricle. These values are significantly higher with respect to those obtained in adults: for atrial membranes, Kd = 22.2 +/- 9.7 and 11.6 +/- 1.8 pM; Bmax = 58.4 +/- 22.8 and 42.1 +/- 8.9 fmol/mg protein, respectively in explanted hearts and in post mortem specimens. No significant differences have been found in the binding parameters between infants and children, while, considering our results as a whole, a significant inverse correlation between Bmax and subject age (p<0.001) is suggested. The ET-A/ET-B ratio, evaluated by competition experiments with the specific ET-A antagonist BQ-123, was about 70:30 in pediatric patients, in both atrium and ventricle, without any difference between infants and children. Similar values for ET-A/ET-B ratio in adult CHF patients, in contrast to a reduction (significant only in ventricle) of the percent of ET-A subtype in autopsy, has been found. This is the first study concerning a direct evaluation of ET receptor status in children's hearts; the higher density of binding sites, associated to the elevation of plasma levels, could suggest a enhanced biological function of ET in children.
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PMID:High density of endothelin binding sites in the hearts of infants and children. 1006 32

1. Exogenously administered endothelin (ET) modulates the activity of cardiovascular and respiratory neurons in the central nervous system (CNS) and, thus, affects arterial blood pressure (ABP) and ventilation. However, a physiological role(s) for endogenous ET in the CNS has not been elucidated. To address this question, we examined ABP and ventilation in mutant mice deficient in ET-1, ETA and ETB receptors and endothelin-converting enzyme-1, which were made by gene targeting. 2. Respiratory frequency and volume was measured in mice by whole body plethysmography when animals breathed normal room air and hypoxic and hypercapnic gas mixtures. A few days after respiratory measurements, a catheter was implanted into the femoral artery under halothane anaesthesia. On the following day, the ABP of awake mice was measured through the indwelling catheter and heart rate was calculated from the ABP signal. After 2 h ABP measurement, arterial blood was collected through the catheter and pH and the partial pressures of O2 and CO2 were measured by a blood gas analyser. 3. Compared with corresponding controls, the mean (+/- SEM) ABP in ET-1+/- and ETB-deficient mice was significantly higher (118 +/- 2 vs 106 +/- 3 mmHg for ET-1+/- (n = 22) and ET-1+/+ (n = 17) mice, respectively; 127 +/- 3 vs 109 +/- 4 mmHg for ETB-/s (n = 9) and ETB+/s (n = 9) mice, respectively; P < 0.05 for both). In ET-1+/- mice, PCO2 tended to be higher and PO2 was significantly lower than corresponding values in ET-1+/+ mice. Under resting conditions, there was no significant difference in respiratory parameters between mutants and their corresponding controls. However, reflex increases of ventilation to hypoxia and hypercapnia were significantly attenuated in ET-1+/-, ET-1-/- and ETA-/- mice. 4. In another series of experiments in ET-1+/- mice, we found that sympathetic nerve activity (SNA) was augmented and reflex excitation of phrenic nerve activity (PNA) in response to hypoxia and hypercapnia was blunted. Attenuation of the reflex PNA response to hypercapnia was also observed in the medulla-spinal cord preparation from ET-1-/- mice. 5. Elevation of ABP in ETB-deficient mice was most likely due to a peripheral mechanism, because SNA and respiratory reflexes were not different from those in control animals. 6. We conclude that endogenous ET-1 plays an important role in the central neural control of circulation and respiration and that ETA receptors mediate this mechanism.
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PMID:Endothelin in the central control of cardiovascular and respiratory functions. 1062 68

We assessed the role of angiotensin (Ang) II type 1 receptor (AT1) and endothelin type A and B (ETA & ETB) receptor in cardiovascular hypertrophy associated with angiotensin II-induced hypertension (200 ng/kg.min s.c. for 10 or 17 days). Antagonism of AT1 receptors was obtained by oral administration of losartan (10 or 30 mg/kg.day) and blockade of ETA and ETB receptors was obtained by oral administration of bosentan (30 mg/kg.day). Losartan and bosentan were administered 24 h before and during the 10 days of angiotensin II (prevention) or they were given after the development of hypertension i.e. from day 10 to 17 of angiotensin II (treatment). Tail-cuff pressure (TCP) was measured before and at the end of the period of administration of antagonists. At the end of experiments, cross sectional area (CSA, mm2) of the carotid was measured after perfusion and fixation at 100 mmHg and heart weight index (HWI, mg/g body weight) was determined. Results are mean +/- SEM. [table: see text] In addition to its blood pressure lowering effect, both doses of losartan prevented and reversed the cardiovascular hypertrophy induced by angiotensin II. Similarly, bosentan prevented and reversed the effect of angiotensin II on cardiovascular structure independently of arterial pressure. These results indicate that the effect of angiotensin II on blood pressure, heart and carotid structure is exclusively mediated by AT1 receptors. The influence of bosentan suggests that endothelin plays an important role in local action of angiotensin II independently of blood pressure level.
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PMID:[Cardiac and vascular hypertrophy in hypertension due to angiotensin II. Effect of losartan and bosentan]. 1098 42

Both nitric oxide (NO) and endothelin-1 (ET-1) are important mediators in the regulation of vascular tone during pregnancy and preeclampsia. This study was designed to investigate the ET-1-induced hypotensive effect in late pregnant rats (P) and in NO-deprived hypertensive pregnant rats (TP), a model of preeclampsia. From day 13 of pregnancy Wistar rats were fed a control or an N(omega)-nitro-L-arginine-enriched diet. On gestational day 20, mean arterial pressure (MAP +/- SEM, in mm Hg) and heart rate (HR) were measured with a carotid catheter in anesthetized rats after a bolus intravenous injection of several agonists and antagonists. After 7 days of chronic NO synthase inhibition, there was a significant increase in MAP (+45 +/- 3.9, P < .01) and 24-h urinary nitrate excretion was significantly decreased (P < .05). ET-1 bolus injection (0.1 nmol/kg) was rapidly followed by a significant decrease in MAP and a slight delayed increase, with no change in HR. The magnitude of the decrease had significantly dropped off in P (-30 +/- 2.2) as compared to that in TP (-46 +/- 5.1) and in virgin rats (-51 +/- 6.3) (P < .05). In P and TP, in vivo depressor effect was also obtained with sarafotoxin S6c, a specific ETB agonist, and blocked by the specific ETB antagonist BQ-788. After inhibition of cyclooxygenase with acetylsalicylic acid, the ET-1-induced hypotension was not modified either in P or in TP. In conclusion, the present data highlight an enhanced ETB receptor mediated hypotensive effect of ET-1 in anesthetized TP as compared to P. The magnitude of the hypotensive effect of ET-1 observed in TP is of the same order as that in virgin rats and neither NO nor vasodilator prostaglandins seem to be involved in TP. The enhanced hypotensive effect of ET-1 could be a beneficial counter-balancing mechanism in this rat model of preeclamptic pathology where an increased sensitivity to vasoconstrictor agents is generally described.
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PMID:Hypotensive effect of endothelin-1 in nitric oxide-deprived, hypertensive pregnant rats. 1141 40

Animal studies suggest that endothelin A (ETA) receptor antagonism and angiotensin-converting enzyme (ACE) inhibition may be synergistic. This interaction and the role of ETB receptors and endothelial mediators were investigated in terms of systemic and renal effects in humans in two studies. In one study, six subjects received placebo, the ETA receptor antagonist BQ-123 alone, and BQ-123 in combination with the ETB receptor antagonist BQ-788 after pretreatment with the ACE inhibitor enalapril (E) or placebo. In the other, six subjects who were pretreated with E received placebo, BQ-123, and BQ-123 with concomitant inhibition of nitric oxide (NO) synthase or cyclo-oxygenase (COX). Both were randomized, double-blind, crossover studies. Mean arterial pressure was reduced by BQ-123, an effect that was doubled during ACE inhibition (mean area under curve +/- SEM; BQ-123, -2.3 +/- 1.8%; BQ-123+E, -5.1 +/- 1.1%; P < 0.05 versus placebo). BQ-123 increased effective renal blood flow (BQ-123, -0.1 +/- 2.4%; BQ-123+E, 10.9 +/- 4.2%; P < 0.01 versus BQ-123), reduced effective renal vascular resistance (BQ-123, -1.2 +/- 3.1%; BQ-123+E, -12.8 +/- 3.0%; P < 0.01 versus placebo and versus BQ-123), and increased urinary sodium excretion markedly (BQ-123, 2.6 +/- 12.8%; BQ-123+E, 25.2 +/- 12.6%; P < 0.05 versus BQ-123, P < 0.01 versus placebo and versus E) only during ACE inhibition. These effects were abolished by both ETB receptor blockade and NO synthase inhibition, whereas COX inhibition had no effect. In conclusion, the combination of ETA receptor antagonism and ACE inhibition is synergistic via an ETB receptor-mediated, NO-dependent, COX-independent mechanism. The reduction of BP and renal vascular resistance and associated substantial natriuresis make this a potentially attractive therapeutic combination in renal disease.
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PMID:Endothelin A receptor antagonism and angiotensin-converting enzyme inhibition are synergistic via an endothelin B receptor-mediated and nitric oxide-dependent mechanism. 1546 64

Congestive heart failure (CHF) causes lung remodelling with thickening of the alveolar septa and proliferation of myofibroblasts (MYF). Endothelin-1 (ET-1) is increased in CHF and may contribute to this process. CHF was induced in rats by myocardial infarction. After three weeks there was lung remodelling with thickening of alveolar septa and increases in 5'-bromodeoxyuridine uptake and vimentin expression (P < 0.05). The mitogenic and protein synthesis response of MYF to ET-1 (10 nM) were assessed by H-thymidine and H-leucine incorporation respectively. The mitogenic response in CHF (19.0 +/- 3.0%, mean +/- SEM) was less than for sham rats (35 +/- 5.4%, P < 0.05). This was associated with a lower production of ET-1 by CHF MYF (15.15 +/- 5.67 fmol/ml) compared to sham (33.66 +/- 13.22 fmol/ml; P < 0.05). Additionally, protein expression of ETA (0.36 +/- 0.038 AU) and ETB receptors (0.24 +/- 0.075 AU) were reduced in CHF compared to shams (0.65 +/- 0.086 AU and 0.81 +/- 0.21 AU respectively; P < 0.05). There is a downregulation of the ET system of lung MYF in CHF with reduced proliferation in response to ET-1. This may represent a protective adaptation to counteract lung remodelling in response to chronic exposure to high levels of ET-1.
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PMID:Downregulation of the endothelin system of lung myofibroblasts in congestive heart failure. 1952 9


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