Our results show that glucocorticoids at clinically relevant concentrations exert specific actions on expression of adhesion molecules on activated neutrophils, which are mediated through ligation of glucocorticoid receptors and induction of protein synthesis, and suggest a novel mechanism by which anti-inflammatory corticosteroids may inhibit leukocyte accumulation.

1 Although recent observations suggest that endothelin-l (ET-1) may play a role in the pathogenesis of asthma, to date little is known about the effects of ET-1 on parameters other than bronchoconstriction. The objectives of the present experiments were to study whether intravenously administered ET-1 could exert pro-inflammatory actions in the guinea-pig lung and to assess the involvement of endothelin ETA and ETB receptors in these events by using the ETA receptor-selective antagonist, FR 139317, the novel ETA/ETB receptor antagonist, bosentan and the ETB receptor-selective agonist, IRL 1620. 2 Bolus i.v. injection of ET-1 (0.1-1 nmol kg-') to anaesthetized guinea-pigs evoked dose-dependent increases in mean arterial blood pressure which lasted for 6-12 min. This was accompanied by a dose-dependent haemoconcentration (8-15% plasma volume losses) and increases (up to 546%) in albumin extravasation in the trachea, upper and lower bronchi, but not in the pulmonary parenchyma. Qualitatively similar changes were observed following i.v. injection of the ETB receptor agonist, IRL 1620 (0.3 and 1 nmol kg-'), although IRL 1620 appeared to be about 3 times less potent than ET-1. The ETA receptor-selective antagonist, FR 139317 (2.5 mg kg-') inhibited the ET-1 (1 nmol kg-')-induced pressor response, haemoconcentration and albumin extravasation by 75, 77 and 60-70%, respectively, whereas it did not attenuate IRL 1620 (1 nmol kg-')-induced changes. The ETA/ETB receptor antagonist, bosentan (10mgkg-') almost completely inhibited the pressor, haemoconcentration and permeability effects of both ET-I and IRL 1620. 3 ET-1, but not IRL 1620 (0.1-1 nmol kg-1), produced a dose-dependent neutropenia with relative lymphocytosis and monocytosis, but did not induce influx of neutrophil granulocytes into pulmonary tissues or the bronchoalveolar space. ET-1 (1 nmol kg-')-induced neutropenia was prevented by pretreatment of the animals with FR 139317 (2.5 mg kg-'), bosentan (10 mg kg-') or adrenaline (90 nmol kg-'), indicating that ET-1 caused intravascular sequestration of neutrophil granulocytes. 4 ET-1 or IRL 1620 (10-II_ 10-6 M) alone did not activate alveolar macrophages in vitro, whereas at a concentration of 10-8 M, ET-1, but not IRL 1620, markedly potentiated superoxide production in response to f-Met-Leu-Phe (10-9-10-7 M) and platelet-activating factor (PAF, 10-9-10-7 M), but not to phorbol 12-myristate 13-acetate (10-9 M). ET-1 did not affect f-Met-Leu-Phe-or PAF-induced increases in intracellular free calcium concentration. This potentiating effect of ET-1 was abolished by FR 139317 (1.5 X 10-7 M). 5 We conclude that, in addition to evoking airway contractions, ET-1 exerts pro-inflammatory actions via activation of the ETA and to a lesser extent the ETB receptors, and therefore, might contribute to the airway inflammation present in asthma. These findings also suggest the therapeutic potential of ETA/ETB receptor and perhaps ETA receptor-selective antagonists in this disease.

1 The objective of the present experiments was to assess the involvement of endothelin-A (ETA) receptors in mediating the effects of endothelin-1 on microvascular permeability in conscious rats.2 Bolus injection of endothelin-1 (0.1 and 1 nmol kg-', i.v.) resulted in a dose-dependent prolonged pressor effect preceded by a transient depressor response. These changes were accompanied by a dose-dependent loss of plasma volume. Endothelin-1 (1 nmol kg-') enhanced the vascular permeability of the upper and lower bronchi, kidney, stomach, duodenum and spleen (up to 270%) as measured by the extravasation of Evans blue dye. 3 Pretreatment of the animals with the selective ETA receptor antagonist, BQ-123 (1 mg kg-1, i.v.) significantly blunted the pressor response to endothelin-1 without affecting the depressor response.BQ-123 inhibited by 87% the endothelin-l (1 nmol kg-')-induced plasma volume loss. BQ-123 markedly attenuated protein extravasation elicited by endothelin-l in the upper and lower bronchi and kidney, whereas it completely inhibited the permeability effect of endothelin-l in the stomach and duodenum. BQ-123 by itself had no significant effect on the parameters studied. 5 The present findings suggest that endothelin-1 enhances microvascular permeability, in part, via the activation of ETA receptors.