ENDOTHELIN-1 INHIBITS PAF-INDUCED PAW EDEMA AND PLEURISY IN THE MOUSE

1 The current study analyses the effects of endothelin-I (ET-1) on paw oedema and pleurisy induced by platelet activating factor (PAF) and other inflammatory agents in the mouse. 2 Combined subplantar injection of ET-1 (0.5 pmol/paw) did not modify oedema caused by histamine (1 to 100-mu-mol/paw), 5-hydroxytryptamine (1 to 100-mu-mol/paw) or bradykinin (1 to 100 nmol/paw) but markedly inhibited the response to PAF (0.95 to 3.8 nmol/paw). The selective action of ET-1 against PAF-induced (1.9 nmol/paw) oedema was dose-dependent, reaching a maximum at 0.5 pmol/paw and lasted up to 2 h. 3 ET-1 (0.5 pmol/paw) also inhibited paw oedema (3-4 h) caused by zymosan (500-mu-g/paw). In contrast, it did not modify either the early (1-4 h) or late (48-72 h) phases of the oedematogenic response to carrageenin (300-mu-g/paw), when given either together with or 24 h after the carrageenin. 4 Intrathoracic injection of PAF (1.9 nmol/cavity) induced pleurisy characterized by an increase in pleural exudate volume, and in accumulation of Evans Blue which was maximal at 30 min and lasted up to 4 h. When injected together with PAF, ET-1 (0.5 pmol/cavity) virtually abolished PAF-induced pleurisy. 5 It is concluded that ET-1 is a potent inhibitor of PAF-induced inflammation in the mouse. Its mechanism of anti-inflammatory action in this species, in contrast to what has been found in other species, does not appear to derive from its potent vasoconstrictor properties as ET-1, at the doses used, failed to affect oedematogenic responses to other inflammatory mediators.