Pressor and pulmonary responses to ET‐1(1–31) in guinea‐pigs

Endothelin‐1(1–31) (ET‐1(1–31); 0.25 to 4 nmol kg −1 ; i.v.) induced, in the guinea‐pig, graded increases in MAP and an indomethacin‐sensitive enhancement of pulmonary insufflation pressure (PIP). At all doses, ET‐1(1–31) induced a monophasic pressor response, except at 4 nmol kg −1 , which caused a rapid and transient response (first phase: over first 10 min after injection) followed by a more slowly‐developing and sustained (second phase: between 10 and 45 min after injection) increase in MAP. ET‐1(1–31) was 4 to 10 fold less potent than ET‐1 on PIP responses. Phosphoramidon (5 and 10 mg kg −1 ) reduced both pressor and PIP effects of ET‐1(1–31). Thiorphan (0.25 and 2.5 mg kg −1 ) did not affect the pressor responses to ET‐1(1–31) although its PIP effects were markedly reduced by the NEP inhibitor. A selective endothelin‐converting enzyme (ECE) inhibitor, CGS 35066 (1 mg kg −1 ), significantly reduced the second phase pressor response and increase in PIP triggered by ET‐1(1–31). The second (but not the first) pressor phase of ET‐1(1–31) (4 nmol kg −1 ) was markedly reduced by BQ‐123 (selective ET A antagonist), whereas the increase of PIP was significantly reduced by BQ‐788 (selective ET B antagonist). Co‐administration of BQ‐123 plus BQ‐788 abolished ET‐1(1–31)‐induced increase in PIP, but blockade of the second pressor phase afforded by BQ‐123 was now reversed. In guinea‐pig isolated perfused lungs, ET‐1(1–31) (50 n M ) induced the release of prostacyclin and thromboxane A 2 , which was inhibited by BQ‐788 (5 n M ) or thiorphan (25 μ M ), but not BQ‐123 (1 μ M ). These results suggest that ET‐1(1–31) enhances MAP. Its sustained, but not transient, pressor effects are mediated via ET A receptor activation. Furthermore, ET‐1(1–31) increases airway resistance in vivo and triggers prostacyclin and thromboxane A 2 release from perfused lungs predominantly via ET B receptor activation. ET‐1(1–31) failed to display any selectivity of action towards either ET A or ET B receptors in these models. We suggest that, in order to raise MAP, ET‐1(1–31) requires conversion to ET‐1, predominantly by ECE and to a lesser extent neutral endopeptidase 24.11, whereas the reverse holds true regarding its pharmacological effects in airways.British Journal of Pharmacology (2002) 136 , 819–828. doi: 10.1038/sj.bjp.0704782