ET-1-induced pulmonary vasoconstriction shifts from ETA- to ETB-receptor-mediated reaction after preconstriction

Endothelin-1 (ET-1) has been reported to induce pulmonary vasoconstriction via either ETA or ETB receptors, and vasorelaxation after ET-1 injection ha s been observed. Our study investigated the effects of ET-1 in isolated rab bit lungs, which were studied at basal tone (part I) and after preconstrict ion (U-46619; part II). Pulmonary arterial pressure (PAP) and lung weight g ain were monitored continuously. In part I, ET-1 (10(-8) M; n = 6; control) was injected after pretreatment with the ETA-receptor antagonist BQ-123 (1 0(-6) M; n = 6) or the ETB-receptor antagonist BQ-788 (10(-6) M; n = 6). Th e same protocol was carried out in part II after elevation of pulmonary vas cular tone. ET-1 induced an immediate PAP increase (Delta PAP 4.3 +/- 0.4 m mHg at 10 min) that was attenuated by pretreatment with BQ-123 (P < 0.05 at 10 min and P < 0.01 thereafter) and that was more pronounced after BQ-788 (P < 0.01 at 10 min and P < 0.001 thereafter). In part II, ET-1 induced an immediate rise in PAP with a maximum after 5 min (Delta PAP 6.3 +/- 1.4 mmH g), leveling off at Delta PAP 3.2 +/- 0.2 mmHg after 15 min. Pretreatment w ith BQ-123 failed to attenuate the increase. BQ-788 significantly reduced t he peak pressure at 5 min (0.75 +/- 0.4 mmHg; P < 0.001) as well as the pla teau pressure thereafter (P < 0.01). We conclude that ET-1 administration c auses pulmonary vasoconstriction independent of basal vascular tone, and, a t normal vascular tone, the vasoconstriction seems to be mediated via ETA r eceptors. BQ-788 treatment resulted in even more pronounced vasoconstrictio n, After pulmonary preconstriction, ETA antagonism exerted no effects on PA P, whereas ETB antagonism blocked the PAP increase. Therefore, ETA-induced pulmonary vasoconstriction is shifted from an ETA-related to an ETB-mediate d mechanism after pulmonary vascular preconstriction.