Role of the Endothelin-1 System in the Luteolytic Process of Pseudopregnant Rabbits

The aim of this study was to better understand the role of the endothelin-1 (ET-1) system in the process of controlling the corpora lutea (CL) life span in rabbits. ET-1 (10 μg iv) administration at d 9 and 12 of pseudopregnancy induced a functional luteolysis within 24 h of injection, but it was ineffective at both d 4 and 6. Pretreatments with Bosentan, a dual ETA/ETB receptor antagonist, or cyclooxygenase (COX) inhibitor blocked the luteolytic action of ET-1 but not that induced by prostaglandin F2α (PGF2α). In CL cultured in vitro, ET-1 increased (P ≤ 0.01) both PGF2α production and luteal nitric oxide synthase activity but decreased (P ≤ 0.01) progesterone release. Addition of ETA receptor antagonist BQ123 or COX inhibitor blocked the ET-1 luteolytic effects. Positive staining for ET-1 receptors was localized in ovarian blood vessels, granulosa cells of large follicles, and luteal cells. Immunoblot analysis of ET-1 receptor protein revealed a strong band of approximately 48 kDa in d-9 CL. Up to d 6 of pseudopregnancy, ET-1 mRNA abundance in CL was poorly expressed but then increased (P ≤ 0.01) at d 9 and 13. ETA-receptor transcript increased (P ≤ 0.01) at d 6, remained at the same level up to d 13, and then declined to the lowest (P ≤ 0.01) levels at d 22. ETB-receptor mRNA increased (P ≤ 0.01) throughout the late-luteal stage from d 13 up to d 18. Our data suggest that the luteolytic action of ET-1 may be a result of PGF2α synthesis from both luteal and accessory cells, via the COX pathways.

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Analysis of vasocontractile responses to endothelin-1 in rabbit retinal vessels using an ETA receptor antagonist and an ETB receptor agonist

Life Sciences ◽

10.1016/0024-3205(93)90707-a ◽

1993 ◽

Vol 53 (6) ◽

pp. PL111-PL115 ◽

Cited By ~ 10

Author(s):

Kazuo Takei ◽

Tsuyoshi Sato ◽

Tomohito Nonoyama ◽

Takashi Miyauchi ◽

Katsutoshi Goto

Keyword(s):

Receptor Antagonist ◽

Receptor Agonist ◽

Retinal Vessels ◽

Endothelin 1 ◽

Eta Receptor ◽

Etb Receptor ◽

Eta Receptor Antagonist

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Differential regulation of renal regional blood flow by endothelin-1

AJP Renal Physiology ◽

10.1152/ajprenal.1996.271.6.f1166 ◽

1996 ◽

Vol 271 (6) ◽

pp. F1166-F1172 ◽

Cited By ~ 33

Author(s):

K. Gurbanov ◽

I. Rubinstein ◽

A. Hoffman ◽

Z. Abassi ◽

O. S. Better ◽

...

Keyword(s):

Blood Flow ◽

Receptor Antagonist ◽

Bolus Injection ◽

Regional Blood Flow ◽

Doppler Flowmetry ◽

Endothelin 1 ◽

Male Wistar Rats ◽

Eta Receptor ◽

Etb Receptor ◽

Eta Receptor Antagonist

The present study evaluated the effects and mechanisms of action of endothelin-1 (ET-1) on medullary and cortical blood flow (MBF and CBF, respectively). CBF and MBF were measured simultaneously by laser-Doppler flowmetry in anesthetized male Wistar rats. Bolus injection of ET-1 (1.0 nmol/kg iv) produced a sustained decrease in CBF (delta = -30%) and a transient increase in MBF (delta = +35%). The medullary vasodilation induced by ET-1 was observed with doses lower than that required to produce cortical vasoconstriction; was completely blocked by bosentan, a mixed ETA/B-receptor antagonist; and was mimicked by IRL-1620, a specific ETB-receptor agonist. In contrast, BQ-123, an ETA-receptor antagonist, failed to inhibit the ET-1-dependent medullary vasodilation but effectively blocked the cortical vasoconstriction induced by the peptide. Finally, inhibition of nitric oxide (NO) synthase completely abolished, whereas cylooxygenase inhibition attenuated, the effect of ET-1 on MBF. The data demonstrate that ET-1 exerts opposite effects on renal cortical and medullary circulation, i.e., ETA-receptor-mediated cortical vasoconstriction and ETB-mediated medullary vasodilation. Furthermore, the medullary vasodilation induced by ET-1 is dependent on the NO system and, to a lesser extent, on prostaglandin generation.

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Autocrine effects of endothelin-1 on leukocyte-endothelial interaction: stimulation of endothelin B receptor subtype reduces endothelial adhesiveness via a nitric oxide-dependent mechanism

Blood ◽

10.1182/blood.v88.10.3894.bloodjournal88103894 ◽

1996 ◽

Vol 88 (10) ◽

pp. 3894-3900 ◽

Cited By ~ 18

Author(s):

T Murohara ◽

AM Lefer

Keyword(s):

Nitric Oxide ◽

Receptor Antagonist ◽

Receptor Subtype ◽

Endothelin 1 ◽

Eta Receptor ◽

Etb Receptor ◽

Endothelin B ◽

Eta Receptor Antagonist ◽

Inhibition Of Thrombin

The effects of endothelin-1 (ET-1) on P-selectin-mediated leukocyte endothelial interaction were examined in vitro. Adherence of autologous polymorphonuclear leukocytes (PMNs) to the endothelium was markedly enhanced by endothelial stimulation with either (2 U/mL) thrombin, (1 mumol/L) histamine, or (100 nmol/L) phorbol myristate acetate (PMA). In contrast, ET-1 alone (10 and 100 nmol/L) only slightly increased the number of adhering PMNs. The increased PMN adherence to thrombin- or histamine-stimulated endothelium, which was blocked by an anti-P-selectin monoclonal antibody, was also significantly attenuated by preincubation of coronary segments with (100 nmol/L) ET-1. We further investigated the mechanism of this anti-adherence action of ET-1 on thrombin-stimulated endothelial adhesiveness. Preincubation of coronary segments with a selective ETA receptor antagonist, BQ485 (1 mumol/L), had no effect on ET-1 inhibition of thrombin-induced PMN adherence. In contrast, preincubation with a selective ETB receptor antagonist, BQ788 (1 mumol/L) significantly reversed ET-1 inhibition of thrombin-induced PMN adherence, whereas the selective ETB receptor agonist BQ-3020 mimicked the inhibitory action of ET-1 on thrombin-induced PMN adherence. Furthermore, (100 mumol/L) N omega-nitro-L-arginine methyl ester (L-NAME), a nitric oxide synthase (NOS) inhibitor, significantly attenuated ET-1 inhibition of thrombin-stimulated PMN adherence. These results suggest that ET-1 may inhibit P-selectin-mediated leukocyte-endothelial interaction via ETB receptor stimulation and subsequent endothelial NO formation. This autocrine effect of ET-1 may be involved in pathophysiologic states such as early atherogenesis by preventing leukocyte-endothelial interaction in constricted blood vessels.

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Endothelin-1 induces mucosal mast cell degranulation and tissue injury via ETA receptors

Clinical Science ◽

10.1042/cs103s031s ◽

2002 ◽

Vol 103 (s2002) ◽

pp. 31S-34S ◽

Cited By ~ 8

Author(s):

Mihály BOROS ◽

László SZALAY ◽

József KASZAKI

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Receptor Antagonist ◽

Mast Cell Degranulation ◽

Tissue Response ◽

Mucosal Mast Cell ◽

Receptor Antagonists ◽

Endothelin 1 ◽

Eta Receptor ◽

Etb Receptor

The effects of endothelin-1 (ET-1) on mucosal mast cells are of special interest, since they may be an important component of the tissue response that occurs during ischaemic preconditioning or ischaemia/re-oxygenation injuries. Increasing doses of ET-1 were administered intravenously to anaesthetized rats. In a second series of experiments, animals were pretreated with the ETA receptor antagonists BQ-610 or ETR-P1/fl peptide, or with the ETB receptor antagonist IRL-1038. Intestinal perfusion changes were recorded, and the proportion of degranulated mast cells and the degree of mucosal damage were determined in ileal biopsies. ET-1 induced dose-dependent alterations in the haemodynamic and morphological parameters, and caused significant mast cell degranulation. These changes were inhibited significantly by pretreatment with the ETA receptor antagonists, but not with the ETB receptor antagonist. We conclude that a cross-talk exists between endothelial cell-derived humoral mediators and the intestinal mast cell system.

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Role of Endothelin-1 in the Migration of Human Olfactory Gonadotropin-Releasing Hormone-Secreting Neuroblasts

Endocrinology ◽

10.1210/en.2005-0060 ◽

2005 ◽

Vol 146 (10) ◽

pp. 4321-4330 ◽

Cited By ~ 8

Author(s):

Roberto G. Romanelli ◽

Tullio Barni ◽

Mario Maggi ◽

Michaela Luconi ◽

Paola Failli ◽

...

Keyword(s):

Receptor Antagonist ◽

Receptor Activation ◽

Dependent Manner ◽

Endothelin 1 ◽

Eta Receptor ◽

Etb Receptor ◽

Migratory Pattern ◽

Biochemical Analyses ◽

Eta Receptor Antagonist ◽

Dose Dependent

FNC-B4 neuroblasts that express both neuronal and olfactory markers have been established and cloned. These cells express GnRH and both the endothelin-1 (ET-1) gene and protein and respond in a migratory manner to GnRH in a dose-dependent manner. Previous research has shown that FNC-B4 cells produce and respond to ET-1 by regulating the secretion of GnRH through endothelin type A receptors and by stimulating their proliferation through endothelin type B (ETB) receptors. In this study, we found that FNC-B4 cells are able to migrate in response to ET-1 through the involvement of ETB receptors. Combined immunohistochemical and biochemical analyses showed that ET-1 triggered actin cytoskeletal remodeling and a dose-dependent increase in migration (up to 6-fold). Whereas the ETB receptor antagonist (B-BQ788) blunted the ET-1-induced effects, the ETA receptor antagonist (A-BQ123) did not. Moreover, we observed that FNC-B4 cells were independently and selectively stimulated by ET-1 and GnRH. We suggest that ET-1, through ETB receptor activation, may be required to maintain an adequate proliferative stem cell pool in the developing olfactory epithelium and the subsequent commitment to GnRH neuronal migratory pattern. The coordinate interaction between ET receptors and GnRH receptor participates in the fully expressed GnRH-secreting neuron phenotype.

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Effects of 17 beta-estradiol on coronary microvascular responses to endothelin-1

AJP Heart and Circulatory Physiology ◽

10.1152/ajpheart.1996.271.3.h1117 ◽

1996 ◽

Vol 271 (3) ◽

pp. H1117-H1124 ◽

Cited By ~ 2

Author(s):

K. G. Lamping ◽

D. W. Nuno

Keyword(s):

Nitric Oxide ◽

Left Ventricle ◽

Receptor Antagonist ◽

Male And Female ◽

Small Arteries ◽

Endothelin 1 ◽

Eta Receptor ◽

Etb Receptor ◽

Eta Receptor Antagonist ◽

Dose Dependent

The objective of this study was to examine the effects of 17 beta-estradiol on responses of coronary microvessels to endothelin-1 (ET-1). With the use of isolated pressurized coronary microvessels from the left ventricle of male or female dogs, constrictions to ET-1 were similar in vessels from male and female dogs. 17 beta-Estradiol (1 microM) attenuated constriction to ET-1 of small arteries from both male (percent constriction at 10 microM control: 39 +/- 9%, estradiol: 3 +/- 2%; P < 0.05) and female (percent constriction at 10 microM control: 39 +/- 8%, estradiol: 6 +/- 3%; P < 0.05) dogs similarly. In contrast, testosterone (1 microM) had no effect on constriction to ET-1. Constrictions to ET-1 were completely abolished by BQ-123 (1 microM), a selective ETA-receptor antagonist, and enhanced by BQ-788 (1 microM), a selective ETB-receptor antagonist. Constrictions to ET-1 alone were not altered by indomethacin (Indo, 10 microM) or NG-nitro-L-arginine (L-NNA, 100 microM). 17 beta-Estradiol produced dose-dependent relaxation of coronary microvessels preconstricted with ET-1 that was similar to the response to testosterone and progesterone. Indo or L-NNA alone had no effect on relaxation to 17 beta-estradiol. However, the combination of Indo and L-NNA attenuated Taxation to 17 beta-estradiol (percent dilation at 1 microM control: 64 +/- 13%; Indo plus L-NNA: 21 +/- 6%; P < 0.05) but did not affect relaxation to testosterone. Thus 17 beta-estradiol attenuated constrictions of coronary microvessels to ET-1 more than did similar concentrations of testosterone. The ability of 17 beta-estradiol to modulate responses to endothelin may involve release of vasodilator prostaglandins and/or nitric oxide by 17 beta-estradiol.

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Effect of Endothelin-1 on Corticosteroid Secretion by the Frog Adrenal Gland Is Mediated by an EndothelinA Receptor*

Endocrinology ◽

10.1210/endo.138.10.5448 ◽

1997 ◽

Vol 138 (10) ◽

pp. 4358-4363 ◽

Cited By ~ 2

Author(s):

Franck Cartier ◽

Isabelle Remy-Jouet ◽

Alain Fournier ◽

Hubert Vaudry ◽

Catherine Delarue

Keyword(s):

Adrenal Gland ◽

Receptor Antagonist ◽

Receptor Agonist ◽

Receptor Subtype ◽

Endothelin 1 ◽

Eta Receptor ◽

Etb Receptor ◽

Eta Receptor Antagonist ◽

Corticosteroid Secretion

Abstract We have previously reported that endothelin-1 (ET-1) stimulates the in vitro secretion of corticosterone and aldosterone from the adrenal gland of the frog Rana ridibunda. The aim of the present study was to investigate the pharmacological profile of the endothelin receptor subtype involved in the corticotropic effect of ET-1. The mixed ETA/ETB receptor antagonist Ro 47–0203 (10−5m) totally blocked the stimulatory effect of ET-1 (5 × 10−9m) on corticosterone and aldosterone secretion. The action of ET-1 was also inhibited by the selective ETA receptor antagonist BQ-485 (10−7m). In contrast, the selective ETB receptor antagonist IRL 1038 (10−6m) did not affect the response of the frog adrenal gland to ET-1. In addition, the selective ETB receptor agonist IRL 1620 (10−6m) did not mimic the stimulatory effect of ET-1. The high affinity ETC receptor agonist endothelin-3 (ET-3) stimulated corticosteroid secretion, but was 400 times less potent than ET-1. Moreover, the action of ET-3 was also blocked by BQ-485 (10−7m). These data indicate that the stimulatory effects of ET-1 and ET-3 on corticosteroid secretion by the frog adrenal gland are mediated by an ETA receptor subtype.

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Unique Response of Human Arteries to Endothelin B Receptor Agonist and Antagonist

Clinical Science ◽

10.1042/cs0900091 ◽

1996 ◽

Vol 90 (2) ◽

pp. 91-96 ◽

Cited By ~ 24

Author(s):

James J. Liu ◽

Joan R. Chen ◽

Brian F. Buxton

Keyword(s):

Receptor Antagonist ◽

Minor Role ◽

Maximal Contraction ◽

Endothelin 1 ◽

Mammary Arteries ◽

Internal Mammary ◽

Eta Receptor ◽

Etb Receptor ◽

Human Arteries ◽

Endothelium Dependent Relaxation

1. The role of the ETB receptor in human arteries has not been well studied because of the lack of specific ETB receptor antagonists. In the present studies the specific ETB receptor antagonist BQ-788 and the specific ETB agonist IRL-1620 were used to characterize the function of the ETB receptor in human radial arteries and internal mammary arteries. 2. The results showed that the ETB antagonist BQ-788 significantly inhibited endothelin-1-induced contraction in internal mammary arteries, but not in radial arteries. In internal mammary arteries, BQ-788 at a concentration of 10 μmol/l shifted the endothelin-1-induced concentration-dependent curve to the right by one order. By comparison, the ETA receptor antagonist BQ-610 at 1 μmol/l produced a much more potent inhibitory effect (three-order shifting) on endothelin-1-induced contraction in internal mammary arteries, and also potently inhibited the contraction in radial arteries. 3. The ETB agonist IRL-1620 caused a contraction in internal mammary arteries, but not in radial arteries, although the response of radial arteries to endothelin-1 was very strong. The contraction induced by IRL-1620 was weaker than that induced by endothelin-1; however, the maximal contraction to IRL-1620 was obtained at 3 nmol/l, which was lower than that with endothelin-1 (maximal contraction at 10 nmol/l). 4. In internal mammary arteries the contraction to endothelin-1 and IRL-1620 gradually changed to relaxation with high concentrations of endothelin-1 (from 30 nmol/l) and IRL-1620 (from 3 nmol/l), whereas it did not in radial arteries; suggesting that the ETB receptor on human arterial smooth muscle cells may mediate contraction at low agonist concentrations and relaxation at high agonist concentrations. 5. The ETB agonist IRL-1620, endothelin-1 and endothelin-3 did not cause endothelium-dependent relaxation in either precontracted radial arteries or internal mammary arteries, although endothelium-dependent relaxation was fully induced by acetylcholine in these two arterial preparations. 6. In conclusion, the present studies demonstrate that the responses of internal mammary arteries and radial arteries to an ETB antagonist and an ETB agonist are significantly different from those of animal vascular vessels, and also from each other. The ETB receptor may play only a minor role in endothelium-dependent relaxation of these human arteries. Endothelin-1-induced contraction is mediated by both the ETA (major) and the ETB (minor) receptors in internal mammary arteries, but only by the ETA receptor in radial arteries. These studies may help to determine therapeutic strategy.

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