Endothelin B receptors located on the endothelium provide cardiovascular protection in the hamster

2002 ◽  
Vol 103 (s2002) ◽  
pp. 280S-283S ◽  
Author(s):  
Jean-Claude HONORÉ ◽  
Caroline PROTEAU ◽  
Pedro D'ORLÉANS-JUSTE
Keyword(s):  
Receptor Antagonist ◽  
Pressor Response ◽  
Receptor Activation ◽  
Protective Role ◽  
Pressor Responses ◽  
Cardiomyopathic Hamsters ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Endothelin B ◽  
Eta Receptor Antagonist

Endothelins (ETs) act through two receptors, namely ETA and ETB. In the cardiovascular system, the activation of both receptors leads to vasoconstriction. However, ETB receptors also mediate endothelium-dependent vasodilatation and clearance of plasma ET-1. With regard to these latter properties, we wanted to assess the contribution of ETB receptors and the effects of selective and mixed ET receptor blockade on vascular tone in control Syrian Golden hamsters and in Bio 14.6 cardiomyopathic hamsters after bolus injection of ET-1 and IRL-1620, a selective ETB agonist. In 12-week-old anaesthetized control hamsters, ET-1 (0.5nmol/kg) induced a sustained pressor response which was only partly reduced by the selective ETA receptor antagonist BQ-123, suggesting a contribution of ETB receptor activation to the vasoconstrictive effects of ET-1. This was confirmed by injection of the selective ETB receptor agonist IRL-1620 (1 nmol/kg). However, the pressor response to this agonist was always preceded by a transient vasodilatation, indicating activation of endothelium-located ETB receptors. When the selective ETB receptor antagonist BQ-788 was administered, the hypotensive phase following IRL-1620 injection was abolished. Interestingly, BQ-788 or a mixture of BQ-788 and BQ-123 significantly potentiated the pressor responses to ET-1. In 12-week-old Bio 14.6 cardiomyopathic hamsters, ET-1 and IRL-1620 induced haemodynamic responses similar to those observed in control hamsters, although the IRL-1620-induced pressor increase was lower. No difference in cardiac prepro ET-1 mRNA expression was observed between the two strains of hamsters. In conclusion, we suggest that endothelium-located ETB receptors are involved in the physiological antagonism of ET-dependent protracted pressor effects, and thus may play a protective role in both normal hamsters and those with cardiomyopathy.

scholarly journals 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 ◽  
1996 ◽  
Vol 88 (10) ◽  
pp. 3894-3900 ◽  
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.

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

Endocrinology ◽  
2005 ◽  
Vol 146 (10) ◽  
pp. 4321-4330 ◽  
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.

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

Life Sciences ◽  
1993 ◽  
Vol 53 (6) ◽  
pp. PL111-PL115 ◽  
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

Differential regulation of renal regional blood flow by endothelin-1

1996 ◽  
Vol 271 (6) ◽  
pp. F1166-F1172 ◽  
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.

Human Endothelin Subtype A Receptor Enhancement during Tissue Culture via de Novo Transcription

Neurosurgery ◽  
2002 ◽  
Vol 50 (1) ◽  
pp. 127-136 ◽  
Author(s):  
Jacob Hansen-Schwartz ◽  
Carl-Henrik Nordström ◽  
Lars Edvinsson
Keyword(s):  
Organ Culture ◽  
Receptor Antagonist ◽  
De Novo ◽  
Cerebral Arteries ◽  
Maximal Response ◽  
Messenger Ribonucleic Acid ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

ABSTRACT OBJECTIVE Endothelin (ET) has, since its discovery, increasingly been considered a key player in the pathophysiological processes of cerebral vasospasm in the course of subarachnoid hemorrhage, although it remains unclear how ET is involved. We present data that indicate an inherent capacity of human cerebral arteries to change their sensitivity to ET. METHODS Human cerebral arteries were obtained from patients undergoing intracranial tumor surgery. The vessels were divided into segments and subjected to organ culture for 48 hours. The vessels were then examined by using in vitro pharmacological methods and molecular biological techniques. RESULTS After organ culture of the cerebral arteries, both the sensitivity to and potency of ET were enhanced (maximal response, 152 ± 9%; −log (50% effective concentration), 10.3 ± 0.3), in comparison with data for fresh cerebral arteries. Contractions were inhibited by both FR139317 (a specific ETA receptor antagonist) and bosentan (a mixed ETA and ETB receptor antagonist), in a manner indicating the sole presence of contractile ETA receptors. An inconsistent dilative response to the selective ETB receptor agonist sarafotoxin 6c was observed; the response was preserved in some segments and abolished in others, and potentiation of the precontraction was observed in yet other segments. No isolated contractile response to sarafotoxin 6c was observed, however. In reverse transcription-polymerase chain reaction assays, both ETA and ETB receptor messenger ribonucleic acid was detected. CONCLUSION These results demonstrate that human cerebral arteries are capable of enhancing the function of ETA receptors.

Negative chronotropic and inotropic effects of endothelin isopeptides in mammalian cardiac muscle

1997 ◽  
Vol 273 (1) ◽  
pp. H119-H127 ◽  
Author(s):  
Y. Zhu ◽  
H. T. Yang ◽  
M. Endoh
Keyword(s):  
Receptor Antagonist ◽  
Positive Inotropic Effect ◽  
Dominant Role ◽  
Negative Inotropic Effect ◽  
Camp Level ◽  
Inotropic Effect ◽  
Inotropic Effects ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist

In isolated rabbit right atria, endothelin (ET) isopeptides ET-1 and ET-3 elicited a concentration-dependent negative chronotropic effect (NCE) in the presence of isoproterenol (Iso): ET-1 was approximately 10 times more potent than ET-3. The NCE of ET-1 was abolished by the ETA- and ETB-receptor antagonist TAK-044 (1 microM) or the ETA-receptor antagonist BQ-123 (10 microM), but it was not affected by the ETB-receptor antagonist RES-701-1 or BQ-788. ET-1 decreased the adenosine 3',5'-cyclic monophosphate (cAMP) level in the presence of Iso in rabbit atria. Pretreatment with pertussis toxin (PTX) markedly attenuated the NCE of ET-1 and abolished the decrease in the cAMP level induced by ET-1. In isolated dog ventricular trabeculae, ET-1 elicited a pronounced negative inotropic effect (NIE), whereas ET-3 induced a small but significant positive inotropic effect in the presence of Iso. The NIE was abolished by the ETA-receptor antagonist BQ-123 (1 microM) and partially attenuated by the ETB-receptor antagonist RES-701-1. The positive inotropic effect of ET-3 was abolished by RES-701-1. Although pretreatment with PTX markedly attenuated the NIE of ET-1, cAMP levels in dog ventricular muscle were not decreased by ET-1. These results indicate that activation of an ETA receptor that is coupled to the PTX-sensitive G protein plays a dominant role in the NCE and NIE of ET-1. The NCE of ET-1 may, in part, be due to a decrease in cAMP level. By contrast, the NIE of ET-1 does not involve an alteration of cAMP accumulation. The present findings imply that ET isopeptides might antagonize the cardiostimulatory action of catecholamines mediated by beta-adrenoceptors when the blood level of both endogenous regulators are increased under cardiovascular pathophysiological situations.

Positive inotropic responses mediated by endothelin ETA and ETB receptors in human myocardial trabeculae

2000 ◽  
Vol 99 (3) ◽  
pp. 161-168 ◽  
Author(s):  
Ole SAETRUM OPGAARD ◽  
Sebastian MÖLLER ◽  
René DE VRIES ◽  
Lars EDVINSSON ◽  
Pramod R. SAXENA
Keyword(s):  
Receptor Antagonist ◽  
Positive Inotropic Effect ◽  
Inotropic Effect ◽  
Maximum Effect ◽  
Inotropic Effects ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Eta Receptor Antagonist ◽  
The Right ◽  
Inotropic Responses

The aim of the present study was to determine possible inotropic effects mediated by endothelin ETA and ETB receptors in human myocardial trabeculae from the right atrium and the left ventricle. Isolated trabeculae from human hearts were paced at 1.0 Hz in tissue baths, and changes in isometric contractile force upon exposure to agonist were studied. Endothelin-1 (ET-1) and ET-3 had a strong positive inotropic effect in all trabeculae. ET-1 was significantly more potent than ET-3 in both atrial (P < 0.001) and ventricular (P < 0.05) trabeculae. Preincubation with the ETA receptor antagonist FR139317 (1 μM) decreased significantly (P < 0.005) the potency of ET-1 in both atrial and ventricular trabeculae, without any significant changes in Emax (maximum effect obtained with an agonist). The ETB receptor agonist IRL 1620 had a positive inotropic effect only in some trabeculae, and the ETB receptor antagonist BQ 788 (1 μM) almost completely blocked this effect. These results suggest that both ETA and ETB receptors mediate positive inotropic responses at both the atrial and ventricular level in the human heart.

scholarly journals Pharmacological Modulation of Mucosa-Related Impairment of β-Adrenoceptor-Mediated Relaxation in Human Detrusor

2015 ◽  
Vol 95 (3) ◽  
pp. 300-308 ◽  
Author(s):  
Stefan Propping ◽  
Melanie Roedel ◽  
Manfred P. Wirth ◽  
Ursula Ravens
Keyword(s):  
Receptor Antagonist ◽  
Force Measurement ◽  
P2x Receptor ◽  
Nitric Oxide Synthase Inhibitor ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Set Up ◽  
Eta Receptor Antagonist ◽  
Synthase Inhibitor ◽  
Human Detrusor

Objectives: The mucosa of human detrusor strips impairs catecholamine-induced relaxation. In order to elucidate which signal transduction pathways are involved in this cross talk between the mucosa and detrusor, we have studied the effects of several pharmacological agonists and antagonists on noradrenaline-mediated relaxation in intact and mucosa-denuded detrusor strips. Patients and Methods: Strips of detrusor tissue were obtained from patients who had undergone cystectomy for bladder cancer and were set up for force measurement. KCl- or carbachol-precontracted strips were relaxed with increasing concentrations of noradrenaline in the absence and in the presence of nitric oxide synthase inhibitor, L-NAME; P2X-receptor antagonist, PPADS; ETA-receptor antagonist, BQ-123; ETB-receptor antagonist, BQ-788; cyclooxygenase inhibitor, diclofenac; AT1-receptor antagonist, candesartan; and NK1-receptor antagonist, L-703,606. Results: In intact strips, KCl-stimulated force was enhanced by all blockers; carbachol-stimulated force increased with L-703,606. In denuded strips, only L-NAME augmented the KCl-stimulated contraction. Noradrenaline relaxed the precontracted detrusor strips to a significantly larger extent and at lower concentrations in denuded than in intact strips. L-NAME, PPADS and BQ-123/BQ-788 had little effect on noradrenaline-induced relaxation, whereas diclofenac, candesartan and L-703,606 sensitized intact carbachol-stimulated detrusor strips to noradrenaline-induced relaxation. Conclusion: Inhibition of the noradrenaline-induced relaxation of precontracted human detrusor strips by the mucosa is attenuated by diclofenac, candesartan and L-703,606 suggesting the involvement of prostanoids, angiotensin and neurokinin pathways. Further experiments are required to unravel the exact mechanisms.

Endothelin receptor subtypes in human versus rabbit pulmonary arteries

1994 ◽  
Vol 76 (5) ◽  
pp. 1976-1982 ◽  
Author(s):  
T. Fukuroda ◽  
M. Kobayashi ◽  
S. Ozaki ◽  
M. Yano ◽  
T. Miyauchi ◽  
...  
Keyword(s):  
Receptor Antagonist ◽  
Pulmonary Arteries ◽  
Receptor Subtypes ◽  
Binding Assays ◽  
High Concentration ◽  
Pulmonary Vasodilator ◽  
Eta Receptor ◽  
Etb Receptor ◽  
Human Pulmonary Artery ◽  
Eta Receptor Antagonist

We studied which endothelin (ET) receptor subtypes mediate ET-1-induced vasocontraction in the human pulmonary artery (PA) compared with the rabbit PA. ET-1 produced potent contraction in both human and rabbit isolated PAs. In human PA, ET-1-induced contraction was competitively antagonized by BQ-123 (an ETA receptor antagonist) with a pA2 value of 7.68. In rabbit PA, however, even a high concentration of BQ-123 (1 microM) did not affect the contraction. BQ-3020 (an ETB receptor agonist) produced potent contraction in rabbit PA but not in human PA. Binding assays of the membrane preparations showed that human and rabbit PAs contained ETA and ETB receptors in ratios of 93:7 and 23:77, respectively. These results suggest interspecies differences in the ET receptor subtypes that mediate ET-1-induced vasocontraction; ETA receptors are dominant in the human PA, whereas ETB receptors are dominant in the rabbit PA. Furthermore, the predominance of ETA receptors in human PA was supported by autoradiographical studies. If ET-1 acts as a physiological and/or pathophysiological vasocontractor in the human pulmonary circulation, an ETA receptor antagonist would function as a pulmonary vasodilator in humans.

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