Bronchopulmonary and Pressor Activities of Endothelin-1 (ET-1), ET-2, ET-3, and Big ET-1 in the Guinea Pig

Abstract

In anesthetized and ventilated guinea pigs, intravenous injection of ET-1, ET-2, or ET-3 induced similar rapid and dose-related increases in pulmonary inflation pressure (PIP) and mean arterial blood pressure (MABP). Indomethacin inhibited the increase in PIP evoked by ET-1, ET-2, or ET-3, whereas the changes in MABP following injection of the various ET isotypes were not significantly affected. Injection of ET-1, ET-2, or ET-3 via the pulmonary artery of isolated guinea pig lungs induced similar dose-dependent increases in PIP and pulmonary perfusion pressure (PPP), thromboxane B2 (TxB2) release, and formation of lung edema. Indomethacin (5 microM), added to the perfusion medium, significantly inhibited the alterations of PIP, PPP, TxB2 release, and lung edema formation evoked by the three ET isoforms. Intravenous injection of 1 nmol/kg of big ET-1 to guinea pigs did not induce significant changes in PIP and MABP. When administered at a dose of 10 nmol/kg, big ET-1 provoked marked slow-developing and sustained increases in PIP and MABP. When big ET-1 was incubated in vitro with either alpha-chymotrypsin or pepsin and injected into guinea pigs at a dose of 1 nmol/kg, marked rapid bronchoconstrictor and pressor responses were observed. The present results demonstrate that ET-1, ET-2, and ET-3 exert comparable bronchopulmonary and pressor activities in the guinea pig. On the contrary, big ET-1 exhibits moderate direct bronchoconstrictor and pressor effects and its hydrolysis by proteases appears to be essential for expression of its full activity.