Characterization and cardiovascular actions of endothelin-1 and endothelin-3 from the American alligator

The structures and biological activities of the isoforms of endothelin (ET) in a reptile are unknown. ET-3, whose primary structure is identical to human ET-3 except for the substitution Phe4 --> Tyr, and a peptide identical to human ET-1 were isolated from an extract of the lung of the alligator, Alligator mississipiensis. Bolus intravenous injections of alligator ET-3 (10, 30, and 100 pmol/kg) into anesthetized alligators produced dose-dependent decreases in systemic blood pressure (P(sys)) and systemic vascular resistance (R(sys)) without change in heart rate (HR), systemic blood flow (Q(sys)), pulmonary pressure (P(pul)), pulmonary vascular resistance (R(pul)), or pulmonary blood flow (Q(pul)). At a dose of 300 pmol/kg, the initial vasodilatation was followed by an increase in R(sys) and decreases in Q(sys) and P(pul). The response to intravenous human/alligator ET-1 (10, 30, 100, and 300 pmol/kg) was biphasic at all doses with initial decreases in P(sys) and R(sys) being followed by sustained increases in these parameters. In the pulmonary circulation, ET-1 produced a dose-dependent decrease in Q(pul) and an increase in R(pul) during the first phase of the response but no significant change during the second phase. There was no change in HR in response to ET-1. The vasodilatator action of arginine, but not ET-1, was attenuated by N(omega)-nitro-L-arginine methyl ester, indicating that the effect of the peptide is probably not mediated through increased synthesis of nitric oxide. The data demonstrate that the structure of the ET isoforms has been strongly conserved during the evolution of vertebrates but that cardiovascular actions differ significantly between the alligator and mammals, especially in the magnitude and duration of the hypotensive response.