The receptors underlying the endothelin-dependent component of lung plasma extravasation and leucocyte infiltration induced by oleic acid were assessed in mice. Oleic acid (1mg·kg-1 intravenously), but not endothelin-1 (up to 1nmol·kg-1 intravenously), increased accumulation of Evans blue in the lungs (excluding the trachea and main bronchi) from 11.8±3.9 to 98.6±10.7µg 1h after injection. Bosentan, the antagonist of endothelin receptors (ETA and ETB) or the selective ETB receptor antagonists Ro 46-8443 or A-192621 (administered 1h before oleic acid at doses of 30, 10 and 30mg·kg-1 respectively) reduced the effect of oleic acid by 71%, 58% and 79% respectively. However, the selective ETA receptor antagonist A-127722.5 (10mg·kg-1) was inactive. Oleic acid (2mg·kg-1, intravenously) raised the number of total leucocytes, mononuclear cells and neutrophils in broncho-alveolar lavage fluid 4h after injection. Bosentan and Ro 46-8443 (at doses of 30 and 10mg·kg-1 respectively) inhibited the neutrophil infiltration induced by oleic acid by approx. 80%. None of the antagonists modified control (basal) pulmonary microvascular permeability or total and differential cell counts. Thus, endogenous endothelins, acting via ETB receptor-dependent mechanisms, play a major role in oleic acid-induced lung injury in the mouse by promoting infiltration of circulating neutrophils and enhancement of pulmonary microvascular plasma extravasation. These findings suggest that either ETB or mixed ETA/ETB receptor antagonists might be beneficial in the treatment of the adult respiratory distress syndrome.

14 Jan 2000·Cardiovascular ResearchQ1 · MEDICINE

Endothelin-dependent effects limit flow-induced dilation of conductance coronary vessels after blockade of nitric oxide formation in conscious dogs

Q1 · MEDICINE

Article

Author: Robert Parent ; Michel Lavallée

OBJECTIVETo determine whether endothelin (ET)-dependent effects limit shear stress-induced dilation of large epicardial coronary arteries after blockade of nitric oxide (NO) formation.METHODSIn conscious dogs instrumented for measuring coronary blood flow (CBF) and external diameter (CD) of the circumflex coronary artery, flow-dependent CD dilation was elicited by intracoronary (i.c.) adenosine (500 ng kg-1 min-1).RESULTSI.c. adenosine increased CBF by 28 +/- 4 from 38 +/- 5 ml min-1 and CD by 0.25 +/- 0.03 from 3.53 +/- 0.07 mm without other hemodynamic effects. After N omega-nitro-L-arginine methyl ester (L-NAME), baseline CD fell (P < 0.01) to 3.35 +/- 0.08 mm but CBF was not significantly altered (36 +/- 5 ml min-1). CBF increases caused by adenosine were smaller (17 +/- 2 ml min-1, P < 0.05) and CD responses were nearly abolished (0.02 +/- 0.01 mm, P < 0.01). I.c. Ro 61-1790, an ETA receptor blocker, given after L-NAME did not significantly influence baseline CBF (36 +/- 5 ml min-1) but increased (P < 0.01) CD to 3.45 +/- 0.09 mm. CBF responses to adenosine were not significantly altered by Ro 61-1790 but CD responses (0.10 +/- 0.01 mm) were partially restored (P < 0.01). In contrast, blockade of ETB receptors with Ro 46-8443 after L-NAME had no further effects on CD and CBF responses to adenosine.CONCLUSIONETA receptor-mediated effects limit flow-dependent dilation of large epicardial coronary arteries in conscious dogs. Suppression of the L-arginine/NO-dependent pathway with L-NAME reveals significant ET-dependent effects.

01 Jan 1995·Journal of Cardiovascular PharmacologyQ4 · MEDICINE

Are There Different ETB Receptors Mediating Constriction and Relaxation?

Q4 · MEDICINE

Article

Author: Clozel, Martine ; Gray, Gillian A.

Because certain antagonists of endothelin (ET) ETB receptors (such as the mixed ETA+ETB antagonist PD 142893 or the selective ETB receptor antagonist BQ-788) were shown to antagonize the ETB-mediated dilatation to ET-1 but not the ETB-mediated constriction to ET-1, the existence of two subtypes of to ET-1, the existence of two subtypes of ETB receptors was suggested. The goal of the present study was to further explore this absence of functional antagonism of ETB-mediated constriction by so-called ETB receptor antagonists. In rat tracheal rings denuded of epithelium, Ro 46-8443, a selective ETB receptor antagonist, did not shift the concentration-response curve of ET-1 but antagonized sarafotoxin S6c-induced contractions. However, the ET-1-mediated contractions could be attributed to ETB receptor activation, because BQ-123 had no inhibitory effect except at high doses of ET-1. Preincubation of tracheal rings with BQ-123 (10(-5) M) to block ETA receptors revealed an antagonist effect of Ro 46-8443 on contractions induced by ET-1. By analogy with these pharmacologic experiments, desensitization of ETB receptors by preincubation with sarafotoxin S6c did not modify contractile responses to ET-1 except when the tracheal rings were exposed to BQ-123. We conclude that on rat tracheal rings, ET-1 and sarafotoxin S6c activate a common ETB receptor. However, blockade of ETB receptors is not sufficient for inhibition of ET-1-mediated responses because of cross-talk between receptors that allows ETA to compensate for a blockade of ETB receptors. This study suggests that the endothelial ETB receptor mediating dilatation and the smooth muscle cell ETB receptor mediating constriction may not represent two different subtypes.

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Indication	Highest Phase	Country/Location	Organization	Date
Cardiovascular Diseases	Preclinical	-	F. Hoffmann-La Roche Ltd.	-

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