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David J. Webb - One of the best experts on this subject based on the ideXlab platform.

  • blood pressure independent reduction in proteinuria and arterial stiffness after acute endothelin a receptor antagonism in chronic kidney disease
    Hypertension, 2009
    Co-Authors: Neeraj Dhaun, Iain M Macintyre, Vanessa Melville, Neil R. Johnston, Jane Goddard, Pajaree Lilitkarntakul, David J. Webb
    Abstract:

    Endothelin 1 is implicated in the development and progression of chronic kidney disease and associated cardiovascular disease. We, therefore, studied the effects of selective endothelin-A receptor antagonism with BQ-123 on key independent surrogate markers of cardiovascular risk (blood pressure, proteinuria and renal hemodynamics, arterial stiffness, and endothelial function) in patients with nondiabetic chronic kidney disease. In a double-blind, randomized crossover study, 22 subjects with proteinuric chronic kidney disease received, on 2 separate occasions, placebo or BQ-123. Ten of these subjects also received nifedipine (10 mg) as an active control for the antihypertensive effect of BQ-123. Blood pressure, pulse wave velocity, flow-mediated dilation, renal blood flow, and glomerular filtration rate were monitored after drug dosing. BQ-123 reduced blood pressure (mean arterial pressure: -7+/-1%; P<0.001 versus placebo) and increased renal blood flow (17+/-4%; P<0.01 versus placebo). Glomerular filtration rate remained unchanged. Proteinuria (-26+/-4%; P<0.01 versus placebo) and pulse wave velocity (-5+/-1%; P<0.001 versus placebo) fell after BQ-123, but flow-mediated dilation did not change. Nifedipine matched the blood pressure and renal blood flow changes seen with BQ-123. Nevertheless, BQ-123 reduced proteinuria (-38+/-3% versus 26+/-11%; P<0.001) and pulse wave velocity (-9+/-1% versus -3+/-1%; P<0.001) to a greater extent than nifedipine. Selective endothelin-A receptor antagonism reduced blood pressure, proteinuria, and arterial stiffness on top of standard treatment in renal patients. Furthermore, these studies suggest that the reduction in proteinuria and arterial stiffness is partly independent of blood pressure. If maintained longer term, selective endothelin-A receptor antagonism may confer cardiovascular and renal benefits in patients with chronic kidney disease.

  • endothelin a receptor antagonism and angiotensin converting enzyme inhibition are synergistic via an endothelin b receptor mediated and nitric oxide dependent mechanism
    Journal of The American Society of Nephrology, 2004
    Co-Authors: Jane Goddard, Neil R. Johnston, Corine Eckhart, Allan D Cumming, Andrew L Rankin, David J. Webb
    Abstract:

    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 versus placebo). BQ-123 increased effective renal blood flow (BQ-123, −0.1 ± 2.4%; BQ-123+E, 10.9 ± 4.2%; P versus BQ-123), reduced effective renal vascular resistance (BQ-123, −1.2 ± 3.1%; BQ-123+E, −12.8 ± 3.0%; P 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 versus BQ-123, P 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.

  • endothelin a receptor antagonism reduces blood pressure and increases renal blood flow in hypertensive patients with chronic renal failure a comparison of selective and combined endothelin receptor blockade
    Circulation, 2004
    Co-Authors: Jane Goddard, Neil R. Johnston, Ton J. Rabelink, Allan D Cumming, Andrew L Rankin, Malcolm F Hand, David J. Webb
    Abstract:

    Background— Endothelin (ET) is implicated in the pathophysiology of chronic renal failure (CRF). We therefore studied the systemic and renal hemodynamic effects of ET receptor antagonists in CRF and examined differences between selective ETA, selective ETB, and combined ETA/B receptor blockade. Methods and Results— We conducted a randomized, placebo-controlled, double-blind, 4-way crossover study comparing selective ET receptor antagonists BQ-123 (ETA) and BQ-788 (ETB), given alone and in combination, in acute studies in 8 hypertensive CRF patients and 8 matched healthy controls. BQ-123, alone and in combination with BQ-788, reduced blood pressure in CRF, particularly with BQ-123 alone (mean arterial pressure: controls −4±2%, CRF −13±2%, P<0.01 versus placebo). In CRF, in the face of this fall in blood pressure, BQ-123 substantially increased renal blood flow (38.8±23.9%, P<0.01 versus placebo) and reduced renal vascular resistance (−44.5±11.3%, P<0.01 versus placebo) when given alone but not when combine...

  • systemic eta receptor antagonism with bq 123 blocks et 1 induced forearm vasoconstriction and decreases peripheral vascular resistance in healthy men
    British Journal of Pharmacology, 2001
    Co-Authors: James C Spratt, Jane Goddard, Andrew L Rankin, Neil Patel, Fiona E Strachan, David J. Webb
    Abstract:

    The effect on systemic haemodynamics of BQ-123, a selective endothelin A (ETA) receptor antagonist, was investigated in healthy men by giving, on separate occasions, ascending intravenous doses of 100, 300, 1000 and 3000 nmol min−1 BQ-123, each for 15 min, in a randomized, placebo-controlled, double-blind study. The response of forearm blood flow to brachial artery infusion of endothelin-1 (ET-1; 5 pmol min−1 for 90 min) was also studied using bilateral forearm plethysmography, after systemic pre-treatment, on separate occasions, with one of two doses of BQ-123 (300 and 1000 nmol min−1 for 15 min) or placebo. Systemic BQ-123 dose-dependently decreased systemic vascular resistance (P<0.01 for all doses vs placebo) and mean arterial pressure (P<0.05 for 300 nmol min−1 and P<0.01 for 1000 and 3000 nmol min−1) during the 60 min following infusion. There were concurrent increases in heart rate and cardiac index. BQ-123, when infused systemically for 15 min, appeared to reach a maximum effect at 1000 nmol min−1. Intra-brachial ET-1 infusion, after pre-treatment with placebo, caused a slow onset progressive forearm vasoconstriction without systemic effects. This vasoconstriction was attenuated by pre-treatment with BQ-123 at 300 nmol min−1 and abolished by BQ-123 at 1000 nmol min−1 (P<0.01 vs placebo). These effects occurred at concentrations of BQ-123 in the plasma (510±64 nmol l−1) that were ETA receptor selective, and were not accompanied by an increase in plasma ET-1 that would have indicated ETB receptor blockade. We conclude that ETA-mediated vascular tone contributes to the maintenance of basal systemic vascular resistance and blood pressure in healthy men. Keywords: Endothelin, vasodilatation, BQ-123, human, systemic Introduction Endothelin-1, which was first identified by Yanagisawa et al. (1988), is a well characterized, potent and sustained vasoconstrictor and pressor agent involved in the endothelium-mediated regulation of vascular tone (Haynes & Webb, 1998). Two ET receptor subtypes have been identified at a molecular level and characterized pharmacologically in blood vessels. ETA receptors (Arai et al., 1990) have higher affinity for ET-1 than ET-3, are found on vascular smooth muscle cells, and mediate vasoconstriction. ETB receptors have equal affinity for ET-1 and ET-3 (Sakurai et al., 1990) and are found on vascular endothelial cells, where they mediate endothelium dependent vasodilatation (De Nucci et al., 1988; Tsukahara et al., 1994). ETB receptors are also present on vascular smooth muscle cells, where they may contribute to vasoconstriction (Clozel et al., 1992; Reizebos et al., 1994; Seo et al., 1994; Tschudi & Luscher, 1994). Local studies in human forearm resistance vessels using phosphoramidon, an endothelin converting enzyme inhibitor, and BQ-123, a selective ETA receptor antagonist, first demonstrated the importance of ET-1 in maintaining basal resistance vessel tone, in large part through an action on the ETA receptor (Haynes & Webb, 1994). These observations have since been confirmed by others (Berrazueta et al., 1997; Verhaar et al., 1998). Responses in the forearm resistance vessels are usually predictive of those in the systemic circulation (Webb, 1995), so these data suggested that systemic ETA receptor antagonism would produce systemic vasodilatation. Recently, however, acute systemic administration of the selective ETA antagonist, BQ-123, was reported to have no effect on systemic haemodynamics (Schmetterer et al., 1998; Montanari et al., 2000). We hypothesized that a systemic haemodynamic effect of ETA receptor blockade was not seen in these studies because the doses of BQ-123 used provided insufficient ETA receptor blockade to affect blood pressure. In addition, because healthy subjects have a number of reflex mechanisms that serve to defend blood pressure, we hypothesized that an important effect on systemic vascular resistance might have been missed by measurement of blood pressure alone. We also hypothesized that systemically effective ETA antagonism with BQ-123 might be associated with inhibition of the vasoconstriction to exogenous doses of infused ET-1 sufficient to cause modest effects on forearm vascular resistance. We, therefore, undertook two studies. First, we assessed the haemodynamic effects of increasing doses of BQ-123, using bioimpedance cardiography, with the aim of achieving a high degree of ETA selective receptor blockade. Second, we examined whether haemodynamically active doses of BQ-123 would antagonize the response to exogenous ET-1, by infusion of local doses of ET-1 into the forearm circulation, after administration of BQ-123 systemically, and measuring responses using forearm plethysmography.

  • endogenous endothelin maintains coronary artery tone by endothelin type a receptor stimulation in patients undergoing coronary arteriography
    Heart, 2000
    Co-Authors: Zenon S Kyriakides, Elias Bofilis, Dimitrios Th. Kremastinos, Dimitris Tousoulis, Aristomenis Antoniadis, David J. Webb
    Abstract:

    OBJECTIVE—To examine the contribution of endothelin type A (ETA) receptor stimulation by endogenously generated endothelin-1 (ET-1) to the maintenance of coronary vascular tone in humans. DESIGN—Controlled clinical study. SETTING—Tertiary cardiovascular referral centre. PATIENTS—14 subjects were studied, seven with normal coronary arteries and seven with coronary artery disease, mean (SEM) age, 53 (2) years. INTERVENTIONS—After diagnostic coronary arteriography, BQ-123 (a selective ETA receptor antagonist; 100 nmol/min) in 0.9% saline, was infused into the left coronary artery at a rate of 1 ml/min for 60 minutes. Eight control subjects received saline alone. MAIN OUTCOME MEASURES—Blood flow velocity in the left anterior descending coronary artery, measured using a Doppler flow guidewire; coronary arteriography performed at baseline and immediately at the end of the BQ-123 or saline infusion to measure the diameter of proximal and distal left anterior descending coronary artery segments. RESULTS—The diameter of the proximal segment increased by 6 (2)%, while that of the distal segment increased by 12 (3)% after BQ-123 (both p < 0.05 v baseline). Coronary blood flow increased from 75 (10) to 92 (10) ml/min and coronary vascular resistance decreased from 1.99 (0.36) to 1.44 (0.22) mm Hg/ml/min after BQ-123 (both p < 0.05 v baseline). The response to BQ-123 of patients with and without coronary artery disease was similar. There was no effect of saline in the controls. CONCLUSIONS—Endogenously produced ET-1 contributes to the maintenance of basal coronary artery tone in humans by ETA receptor stimulation. The role of ETB receptors remains to be defined. Keywords: endothelins; arteries; blood flow; coronary circulation; angiography

Gloria E P Souza - One of the best experts on this subject based on the ideXlab platform.

  • orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats reversal by endothelin receptor antagonists but not non steroidal anti inflammatory drugs
    Pain, 2006
    Co-Authors: Juliana Geremias Chichorro, Aleksander R Zampronio, Gloria E P Souza
    Abstract:

    Abstract The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 μg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4 ± 1.3, carrageenan 21.2 ± 3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10 mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ETA or ETB receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3 ± 1.8, CION 32.4 ± 5.3 s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ETA (atrasentan, 3–10 mg/kg) or ETB (A-192621, 5–20 mg/kg) receptors caused significant inhibitions lasting 1–2.5 h (peaks ∼65–90%). Bosentan (dual ETA/ETB receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6 h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ETA and/or ETB receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

  • orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats reversal by endothelin receptor antagonists but not non steroidal anti inflammatory drugs
    Pain, 2006
    Co-Authors: Juliana Geremias Chichorro, Aleksander R Zampronio, Gloria E P Souza
    Abstract:

    Abstract The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 μg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4 ± 1.3, carrageenan 21.2 ± 3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10 mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ETA or ETB receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3 ± 1.8, CION 32.4 ± 5.3 s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ETA (atrasentan, 3–10 mg/kg) or ETB (A-192621, 5–20 mg/kg) receptors caused significant inhibitions lasting 1–2.5 h (peaks ∼65–90%). Bosentan (dual ETA/ETB receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6 h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ETA and/or ETB receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

  • Orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats: reversal by endothelin receptor antagonists but not non-steroidal anti-inflammatory drugs.
    Pain, 2006
    Co-Authors: Juliana Geremias Chichorro, Aleksander R Zampronio, Gloria E P Souza
    Abstract:

    The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 microg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4+/-1.3, carrageenan 21.2+/-3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ET(A) or ET(B) receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3+/-1.8, CION 32.4+/-5.3s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ET(A) (atrasentan, 3-10 mg/kg) or ET(B) (A-192621, 5-20 mg/kg) receptors caused significant inhibitions lasting 1-2.5h (peaks approximately 65-90%). Bosentan (dual ET(A)/ET(B) receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ET(A) and/or ET(B) receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

Gastone G Nussdorfer - One of the best experts on this subject based on the ideXlab platform.

  • endothelin 1 1 31 acting as an eta receptor selective agonist stimulates proliferation of cultured rat zona glomerulosa cells
    FEBS Letters, 2000
    Co-Authors: Giuseppina Mazzocchi, Gian Paolo Rossi, Ludwik K Malendowicz, Hunter C Champion, Gastone G Nussdorfer
    Abstract:

    Endothelin-1 (ET-1)[1–31] is a novel hypertensive peptide that mimics many of the vascular effects of the classic 21 amino acid peptide ET-1[1–21]. However, at variance with ET-1[1–21] that enhances aldosterone secretion from cultured rat zona glomerulosa (ZG) cells by acting via ETB receptors, ET-1[1–31] did not elicit such effect. Both ET-1[1–21] and ET-1[1–31] raised the proliferation rate of cultured ZG cells, the maximal effective concentration being 10−8 M. This effect was blocked by the ETA-receptor antagonist BQ-123 and unaffected by the ETB-receptor antagonist BQ-788. Quantitative autoradiography showed that ET-1[1–21] displaced both [125I]PD-151242 binding to ETA receptors and [125I]BQ-3020 binding to ETB receptors in both rat ZG and adrenal medulla, while ET-1[1–31] displaced only [125I]BQ-3020 binding. The tyrosine kinase (TK) inhibitor tyrphostin-23 and the p42/p44 mitogen-activated protein kinase (MAPK) inhibitor PD-98059 abolished the proliferogenic effect of ET-1[1–31], while the protein kinase-C (PKC) inhibitor calphostin-C significantly reduced it. ET-1[1–31] (10−8 M) stimulated TK and MAPK activity of dispersed ZG cells, an effect that was blocked by BQ-123. The stimulatory action of ET-1[1–31] on TK activity was annulled by tyrphostin-23, while that on MAPK activity was reduced by calphostin-C and abolished by either tyrphostin-23 and PD-98059. These data suggest that ET-1[1–31] is a selective agonist of the ETA-receptor subtype, and enhances proliferation of cultured rat ZG cells through the PKC- and TK-dependent activation of p42/p44 MAPK cascade.

  • mechanisms and receptor subtypes involved in the stimulatory action of endothelin 1 on rat adrenal zona glomerulosa
    International Journal of Molecular Medicine, 1999
    Co-Authors: Piera Rebuffat, Ludwik K Malendowicz, G Mazzocchi, Carlo Macchi, Giuseppe Gottardo, Gastone G Nussdorfer
    Abstract:

    : Endothelin (ET)-1 is the prototype of a family of 21-amino acid residue hypertensive peptides, acting through two subtypes of receptors, named ETA and ETB. ETs and their receptors are expressed in the adrenal cortex and medulla, and ET-1 enhances both corticosteroid and catecholamine release. ET-1 concentration-dependently (from 10(-11) to 10(-8) M) increased aldosterone secretion of both dispersed rat zona glomerulosa (ZG) cells and adrenal slices containing a core of medullary chromaffin tissue, but the response of the latter preparations was significantly more intense than that of the formers. The stimulatory effect of 10(-8) M ET-1 on dispersed ZG cells was blocked by the ETB-receptor antagonist BQ-788 (10(-7) M), but not by the ETA-receptor antagonist BQ-123 (10(-7) M); conversely, both ET-receptors antagonists counteracted aldosterone response of adrenal slices to ET-1. The -adrenoceptor antagonist l-alprenolol (10(-6) M) did not affect aldosterone response of dispersed ZG cells to ET-1 (10(-8) M), but it significantly lowered that of adrenal slices. l-Alprenolol also counteracted the aldosterone response of adrenal slices to the pure activation of ETB or ETA receptors, as obtained by using the selective ETB-receptor agonist BQ-3020 (10(-8) M) or ET-1 (10(-8) M) plus BQ-788 (10(-7) M). ET-1 concentration-dependently (from 10(-9) to 10(-8)/10(-7) M) stimulated catecholamine release by adrenal slices, and the effect was counteracted by both BQ-123 and BQ-788 (10(-7) M). Collectively, our findings suggest that, when the integrity of adrenal tissue is preserved, a two-fold mechanism underlies the aldosterone secretagogue action of ET-1 in the rat: i) a direct mechanism mediated by ETB receptors located on ZG cells; and ii) an indirect mechanism involving the ETA and ETB receptor-mediated local release of catecholamines, which in turn stimulate ZG cells in a paracrine manner.

  • endothelins stimulate deoxyribonucleic acid synthesis and cell proliferation in rat adrenal zona glomerulosa acting through an endothelin a receptor coupled with protein kinase c and tyrosine kinase dependent signaling pathways
    Endocrinology, 1997
    Co-Authors: Giuseppina Mazzocchi, Gian Paolo Rossi, Piera Rebuffat, Ludwik K Malendowicz, A Markowska, Gastone G Nussdorfer
    Abstract:

    The effects of endothelins (ET) on the proliferative activity of the rat adrenal cortex have been investigated in vivo, using an in situ perfusion technique of the intact left gland. The chemicals were dissolved in the perfusion medium, and the perfusion continued for 120 min. ET-1 concentration dependently increased the mitotic index and [3H]thymidine incorporation into DNA in the zona glomerulosa (ZG; 6- and 3-fold increases, respectively, at a 10−8 m concentration), but not in the inner adrenocortical layers, where the basal proliferative activity was negligible. The effect of 10−8 m ET-1 was blocked by the ETA receptor antagonist BQ-123, whereas the ETB receptor antagonist BQ-788 was ineffective. ET-2 and ET-3 (10−8 m) enhanced DNA synthesis in the ZG, but their effects were less intense than that of 10−8 m ET-1 and were directly related to their binding potency for the ETA receptor subtype (ET-1 > ET-2 ≫ ET-3). The selective ETB receptor agonists BQ-3020, IRL-1620, and sarafotoxin-6B were ineffective...

  • endothelin adrenocortical secretagogue effect is mediated by the b receptor in rats
    Hypertension, 1996
    Co-Authors: Anna S Belloni, Gian Paolo Rossi, Paola G Andreis, Giuliano Neri, Giovanna Albertin, Achille C Pessina, Gastone G Nussdorfer
    Abstract:

    Abstract We investigated the gene expression and localization of endothelin-1 (ET-1) receptor subtypes ETA and ETB in the rat adrenal cortex as well as their involvement in the corticosteroid secretagogue effect of ET-1 in vitro. Reverse transcription–polymerase chain reaction with primers specific for ETA and ETB cDNAs demonstrated the expression of both receptor genes in homogenates of adrenocortical tissue. However, in isolated zona glomerulosa and zona fasciculata cells, only ETB mRNA was detected. Autoradiographic examination of the selective displacement of 125I–ET-1 binding by BQ-123 and BQ-788 (specific ligands for ETA and ETB, respectively) indicated that zona glomerulosa possesses both ETA and ETB, whereas zona fasciculata is exclusively provided with ETB. ET-1 enhanced in a concentration-dependent manner aldosterone and corticosterone secretions of dispersed zona glomerulosa and zona fasciculata cells, respectively. The ETB antagonist BQ-788 markedly reduced the secretory response of zona glomerulosa cells and completely suppressed that of zona fasciculata cells, whereas the ETA antagonist BQ-123 was ineffective. These findings indicate that in the rat, the adrenocortical secretagogue action of ET-1 is mediated by the ETB receptor subtype and that the ETA receptor is not directly involved in such an effect.

Juliana Geremias Chichorro - One of the best experts on this subject based on the ideXlab platform.

  • orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats reversal by endothelin receptor antagonists but not non steroidal anti inflammatory drugs
    Pain, 2006
    Co-Authors: Juliana Geremias Chichorro, Aleksander R Zampronio, Gloria E P Souza
    Abstract:

    Abstract The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 μg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4 ± 1.3, carrageenan 21.2 ± 3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10 mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ETA or ETB receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3 ± 1.8, CION 32.4 ± 5.3 s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ETA (atrasentan, 3–10 mg/kg) or ETB (A-192621, 5–20 mg/kg) receptors caused significant inhibitions lasting 1–2.5 h (peaks ∼65–90%). Bosentan (dual ETA/ETB receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6 h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ETA and/or ETB receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

  • orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats reversal by endothelin receptor antagonists but not non steroidal anti inflammatory drugs
    Pain, 2006
    Co-Authors: Juliana Geremias Chichorro, Aleksander R Zampronio, Gloria E P Souza
    Abstract:

    Abstract The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 μg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4 ± 1.3, carrageenan 21.2 ± 3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10 mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ETA or ETB receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3 ± 1.8, CION 32.4 ± 5.3 s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ETA (atrasentan, 3–10 mg/kg) or ETB (A-192621, 5–20 mg/kg) receptors caused significant inhibitions lasting 1–2.5 h (peaks ∼65–90%). Bosentan (dual ETA/ETB receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6 h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ETA and/or ETB receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

  • Orofacial cold hyperalgesia due to infraorbital nerve constriction injury in rats: reversal by endothelin receptor antagonists but not non-steroidal anti-inflammatory drugs.
    Pain, 2006
    Co-Authors: Juliana Geremias Chichorro, Aleksander R Zampronio, Gloria E P Souza
    Abstract:

    The susceptibility of changes in responsiveness to noxious cold stimulation of rats submitted to chronic constriction of the infraorbital nerve (CION) or carrageenan to drug inhibition was compared. Nocifensive responses were measured as total time rats engaged in bilateral facial grooming with both forepaws over the first 2 min following tetrafluoroethane spray application to the snout. Carrageenan (50 microg, s.c. into upper lip) caused short-lived ipsilateral cold hyperalgesia (peak at 3 h: vehicle 8.4+/-1.3, carrageenan 21.2+/-3.0 s) which was markedly suppressed by i.p. indomethacin (4 mg/kg), celecoxib (10mg/kg) or s.c. dexamethasone (0.5 mg/kg), endothelin ET(A) or ET(B) receptor antagonists (BQ-123 and BQ-788, respectively; 10 nmol/lip). CION caused ipsilateral cold hyperalgesia between Days 2 and 12, which peaked on Days 4 (sham 15.3+/-1.8, CION 32.4+/-5.3s) to 6. Established peak CION-induced cold hyperalgesia was unaffected by indomethacin and celecoxib, whereas dexamethasone, BQ-123, BQ-788, and i.v. injections of selective antagonists of ET(A) (atrasentan, 3-10 mg/kg) or ET(B) (A-192621, 5-20 mg/kg) receptors caused significant inhibitions lasting 1-2.5h (peaks approximately 65-90%). Bosentan (dual ET(A)/ET(B) receptor antagonist, 10 mg/kg, i.v.) abolished CION-induced cold hyperalgesia for up to 6h. Thus, once established, CION-induced orofacial hyperalgesia to cold stimuli appears to lack an inflammatory component, but is alleviated by endothelin ET(A) and/or ET(B) receptor antagonists. If this CION injury model bears predictive value to trigeminal neuralgia (i.e., paroxysmal orofacial pain triggered by various stimuli), endothelin receptors might constitute new targets for treatment of this disorder.

Mitsuo Yano - One of the best experts on this subject based on the ideXlab platform.

  • Clearance of Circulating Endothelin-1 by ETB Receptors in Rats
    Biochemical and Biophysical Research Communications, 1994
    Co-Authors: Takahiro Fukuroda, Kiyofumi Ishikawa, Toru Fujikawa, Mitsuo Yano, Satoshi Ozaki, Masaru Nishikibe
    Abstract:

    Exogenous endothelin (ET) is rapidly cleared from the circulation. We investigated which ET receptor subtypes (ETA and ETB) participate in ET-1 clearance. Following an intravenous (i.v.) bolus dose of [125I]ET-1 in anesthetized rats, radioactivity was rapidly cleared from the circulation and trapped by the lungs, kidneys and liver. Tissue distribution of the radioactivity was significantly inhibited in the lungs and kidneys, but not in the liver by infusion of the ETB antagonist BQ-788 (0.1 mg/kg/min i.v.), and the ET-1 clearance rate was reduced, while the ETA antagonist BQ-123 had no such effect. Furthermore, in isolated perfused rat lungs, about 80% of bolus-injected [125I]ET-1 was retained by the lungs after one passage. The retention of ET-1 was significantly inhibited by infusion of 1 μM BQ-788, but not BQ-123. These results suggest that ETB receptors play an important role in the clearance of ET-1.

  • a novel eta antagonist bq 123 inhibits endothelin 1 induced phosphoinositide breakdown and dna synthesis in rat vascular smooth muscle cells
    FEBS Letters, 1992
    Co-Authors: Satoru Eguchi, Masaki Ihara, Mitsuo Yano, Yukio Hirata, Fumiaki Marumo
    Abstract:

    Abstract The effects of a novel cyclic pentapeptide (BQ-123), an endothelin (ET) antagonist selective for the ETA receptor subtype, on phosphoinositide breakdown and DNA synthesis stimulated by ET-1 were studied in cultured rat vascular smooth muscle cells (VSMC). BQ-123 competitively inhibited the binding of [125I]ET-1 to VSMC with the apparent Ki of 4 × 10−9 M. BQ-123 dose-dependently inhibited formation of inositol-1,4,5-trisphosphate and [3H]thymidine uptake stimulated by ET-1. These data suggest that the ET-1-induced DNA synthesis in VSMC is mainly mediated by ETA receptor subtype.

  • different distribution of endothelin receptor subtypes in pulmonary tissues revealed by the novel selective ligands bq 123 and ala1 3 11 15 et 1
    Biochemical and Biophysical Research Communications, 1992
    Co-Authors: Kyoko Nakamichi, Masaki Ihara, Kiyofumi Ishikawa, Toshihiko Saeki, Masahiko Kobayashi, Mitsuo Yano
    Abstract:

    Summary We have demonstrated the different distribution of two distinct endothelin (ET) receptor subtypes in porcine pulmonary tissues using a radioligand binding assay. The clear differentiation of the subtypes was made possible by the discovery of two compounds, BQ-123 and [Ala1,3,11,15]ET-1 (4AlaET-1), that are highly selective for ETA and ETB receptors, respectively. In the bronchus and lung parenchyma, BQ-123 inhibited 65% and 30% of [125I]ET-1 binding on the sensitive sites, while 4AlaET-1 displaced 25% and 60%, respectively. The combination of the two compounds completely inhibited ET-1 binding in both tissues. An autoradiographic study of [125I]ET-1 binding using BQ-123 and 4AlaET-1 also supported the different localization of two ET receptor subtypes in pulmonary tissues. In particular, the blood vessels and bronchi are rich in ETA, but the lung parenchyma is rich in ETB.