Characterization of a native angiotensin from an anciently diverged serine protease inhibitor in lamprey

Angiotensinogen belongs to family A serine protease inhibitors (SERPIN family) and we have cloned and characterized SERPIN genes in two lamprey species, which possess all the properties of angiotensinogen. The putative angiotensinogens in lampreys can be considered as an evolutionary link between SERPIN and other angiotensinogen according to the phylogenetic analyses. The inferred sea lamprey angiotensinogen gene was expressed abundantly in liver and to a lesser extent in other tissues. The predicted lamprey angiotensin I (Ang I) sequence was unique and different from the teleost-type Ang I identified previously by the incubation of lamprey plasma with its kidney extract. Therefore, we characterized and compared the biochemical and physiological properties of this native lamprey Ang II (LpAng II) (EEDYDERPYMQPF) with teleost-type Ang II (NRVYVHPF). Using a newly developed RIA for LpAng II, plasma levels in Japanese lamprey were measured (157.4±35.2 fmol/ml, n=6), but teleost-type Ang II was undetectable. In conscious cannulated lamprey, LpAng II at 100 pmol/kg elicited a transient vasodepressor effect. At doses higher than 300 pmol/kg, a biphasic cardiovascular response with an initial vasodepressor effect followed by a transient rebound vasopressor effect was observed in a dose-dependent manner. However, teleost-type Ang II was not vasoactive up to 1 nmol/kg. In Japanese eel, LpAng II injection up to 3 nmol/kg did not alter the cardiovascular parameters. Our results suggested that the renin–angiotensin system first appeared in cyclostomes, and LpAng II could be important for the regulation of cardiovascular dynamics in lampreys because of its potent and acute vasoactive effect.