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

1. 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. 2. 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). 3. 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. 4. In guinea-pig isolated perfused lungs, ET-1(1-31) (50 nM) induced the release of prostacyclin and thromboxane A(2), which was inhibited by BQ-788 (5 nM) or thiorphan (25 microM), but not BQ-123 (1 microM). 5. 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. 6. 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.