Endothelin derivatives showing potent effects in the guinea pig trachea

Germain, Michel; Battistini, Bruno; Filep, János G.; Sirois, Pierré; Fournier, Alain

doi:10.1016/0196-9781(93)90153-8

Cited by 3 publications

(3 citation statements)

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“…ET-l and IRL 1620 were synthesized in our laboratories by solid-phase methodology (Germain et al, 1993). The purity of the preparations were greater than 97% as measured by high performance liquid chromatography.…”

Section: Drugs and Chemicalsmentioning

confidence: 99%

Characterization of receptors mediating vascular responses to endothelin‐1 in the conscious rat

Filep

Clozel

Fournier

et al. 1994

British J Pharmacology

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1 The present study has determined the receptors mediating the vascular responses (pressor and depressor actions and vascular permeability effect) to endothelin-I (ET-1) in the conscious rat by using the novel non-peptide ETA/ETB receptor antagonist, bosentan (Ro 47-0203, 4-tert-butyl-N-[6-(2 hydroxyethoxy)-5-(2-methoxy-phenoxy)-2,2'-bipyrimidine4-yl]benzene-sulphonamide), the ETA receptor-selective antagonist, FR 139317 and the ETB receptor-selective peptide agonist, IRL 1620. 2 Bolus injection of ET-l (1 amol kg-', i.v.) resulted in a prolonged pressor effect (maximum increase in mean arterial blood pressure (MABP) was 47± 3 mmHg, n = 6) preceded by a transient depressor response (maximum decrease in MABP was 17 ± 1 mmHg). Both these responses were inhibited by bosentan (1-20mgkg-', i.v. bolus) in a dose-dependent manner. The maximum inhibition of ETinduced depressor and pressor responses did not exceed 53 and 87%, respectively. FR 139317 (2.5mgkg-', i.v.) attenuated the pressor response to ET-1 by 75% without affecting the depressor response. Furthermore, FR 139317, but not bosentan, prolonged the depressor action of ET-1. Corresponding to changes in blood pressure, a small transient tachycardia (Aheart rate 15 ± 5 beats min 1) followed by a sustained bradycardia (Aheart rate -48 ± 10 beats min-', n = 6) was observed following injection of 1 nmol kg-' ET-1. FR 139317 and bosentan (10 mg kg-') inhibited ET-1-induced bradycardia by 79% and 71%, respectively. ET-l-induced tachycardia was significantly attenuated by bosentan, but not FR 139317. 3 The ETB receptor agonist, IRL 1620 (0.1-2umolkg-', i.v.) produced biphasic dose-dependent changes in MABP with an initial transient fall followed by a prolonged pressor action. The maximum decrease and increase in MABP were 11 ± 2 and 19 ± 3 mmHg, respectively (n = 5). These changes in MABP were accompanied by a transient tachycardia (Aheart rate 9± 3 beats min-) and prolonged bradycardia (Aheart rate -17±11 beats min' ), respectively. Pretreatment of the animals with FR 139317 (2.5 mg kg-', i.v.) did not affect IRL 1620 (1 nmol kg-')-induced changes in MABP and heart rate, whereas both the depressor and pressor actions of IRL 1620 and the accompanying tachycardia and bradycardia were almost completely inhibited by bosentan (10mgkg-1). 4 ET-1 (1 nmol kg-') enhanced albumin extravasation in the upper and lower bronchi, spleen, kidney, stomach and duodenum (up to 246%) as measured by the extravasation of Evans blue dye. FR 139317 (2.5mgkg-') completely inhibited ET-l-induced protein extravasation in the stomach and duodenum, whereas 40-75% inhibition was observed in the other vascular beds studied. The permeability effect of ET-l was almost completely inhibited by bosentan (10mgkg-') in all vascular beds studied. 5 IRL 1620 (0.4 or 1 nmol kg-', i.v.) enhanced albumin extravasation (up to 219%) in the upper and lower bronchi, spleen and kidney in a dose-dependent manner. Unlike ET-1, IRL 1620 failed to increase albumin extravasation in the stomach and duodenum. 6 The presen...

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Section: Drugs and Chemicalsmentioning

confidence: 99%

Characterization of receptors mediating vascular responses to endothelin‐1 in the conscious rat

Filep

Clozel

Fournier

et al. 1994

British J Pharmacology

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“…Thirdly, ET-1 analogues with one or no disulphide bonds were inactive. In contrast, these peptides have intrinsic activity for the ETB receptor and were used as pharmacological tools by Germain et al (1993) to describe an ETB receptor population in the rat trachea. Fourthly, both ET-1 actions were antagonized by compounds with apparent selectivity for ETA receptors.…”

Section: Discussionmentioning

confidence: 99%

“…Thirdly, ET-1 analogues with one or no disulphide bonds were inactive. In contrast, these peptides have intrinsic activity for the ETB receptor and were used as pharmacological tools by Germain et al (1993) (Salas et al, 1992). The implication(s) of these latter findings is being further investigated.…”

Section: Discussionmentioning

confidence: 99%

Involvement of ET_A receptors in the facilitation by endothelin‐1 of non‐adrenergic non‐cholinergic transmission in the rat urinary bladder

Donoso

Salas

Sepulveda

et al. 1994

British J Pharmacology

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1 Endothelin-1 (ET-1; 3-10 nM) raised the tone of rat bladders bathed in buffer containing atropine (1 gtM) plus guanethidine (3.4 JAM). In addition, ET-1 potentiated, in a concentration-dependent fashion (1-10 nM), the contractions evoked by both transmural nerve stimulation and applications of exogenous adenosine 5'-triphosphate (ATP). 2 The threshold concentration of ET-1 required to facilitate non-adrenergic non-cholinergic (NANC) transmission and potentiate ATP-induced contractions, was about 10 fold lower than that required to increase the bladder tone (3 nM). 3 The ET-1-induced increase in basal tension reached its maximal effect within 60-90 s. In contrast, the 7.8 JAM ATP-induced contractions increased by 50% within the first minute following incubation with 1O nM ET-1 but required about 5 min to develop the maximal effect. 4 The ET-1-induced potentiation of NANC or ATP responses was long-lasting and persisted in spite of extensive washing. The recovery of the bladder excitability depended on the concentration of ET-1. Following the application of 3 nM ET-1, recovery required 30 min; applications of 10 nM ET-1 required at least 60 min for full recovery. 5The ET-1-induced potentiation of responses was selective for ATP and related structural analogues.ET-1 did not modify the contractions induced by acetylcholine, 5-hydroxytryptamine, prostaglandin F2, or bradykinin. 6 The potency of ET-2 was similar to that of ET-1. ET-3 and ET-C-terminal hexapeptide were inactive up to 100 M. Sarafotoxin S6b was 2 to 3 fold less potent than ET-1 whereas sarafotoxin S6c (100 nM) was inactive. AGETB-9 and AGETB-89, two ETB receptor agonists, were also inactive (up to 100 nM). 7 Removal of one or both disulphide bonds in ET-1 and tryptophan-21 formylation of ET-1, resulted in inactive peptides (up to 100 nM). 8 The ET-1 receptor antagonists, BE-18257B and FR 139317, blocked both the ET-1-induced rise in tone and the potentiation of ATP responses in a concentration-dependent fashion. FR 139317 was at least 30 fold more potent than BE-18257B. Both antagonists blocked at lower concentrations the ET-l increase in bladder tone as compared to the ATP potentiation. The antagonism was slowly reversible. 9 Results are consistent with the presence of ETA receptors in the rat bladder, which mediate both actions of ET-1. The interaction of ET-1 with purinergic mechanisms is discussed.

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Pharmacological Characterization of the ET A Receptor in the Vascular Smooth Muscle Comparing its Analogous Distribution in the Rat Mesenteric Artery and in the Arterial Mesenteric Bed

et al. 1996

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Endothelin derivatives showing potent effects in the guinea pig trachea

Cited by 3 publications

References 41 publications

Characterization of receptors mediating vascular responses to endothelin‐1 in the conscious rat

Characterization of receptors mediating vascular responses to endothelin‐1 in the conscious rat

Involvement of ET_A receptors in the facilitation by endothelin‐1 of non‐adrenergic non‐cholinergic transmission in the rat urinary bladder

Pharmacological Characterization of the ET A Receptor in the Vascular Smooth Muscle Comparing its Analogous Distribution in the Rat Mesenteric Artery and in the Arterial Mesenteric Bed

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Endothelin derivatives showing potent effects in the guinea pig trachea

Cited by 3 publications

References 41 publications

Characterization of receptors mediating vascular responses to endothelin‐1 in the conscious rat

Characterization of receptors mediating vascular responses to endothelin‐1 in the conscious rat

Involvement of ETA receptors in the facilitation by endothelin‐1 of non‐adrenergic non‐cholinergic transmission in the rat urinary bladder

Pharmacological Characterization of the ET A Receptor in the Vascular Smooth Muscle Comparing its Analogous Distribution in the Rat Mesenteric Artery and in the Arterial Mesenteric Bed

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Involvement of ET_A receptors in the facilitation by endothelin‐1 of non‐adrenergic non‐cholinergic transmission in the rat urinary bladder