EFFECTS OF HUMAN RENIN IN THE VASCULATURE OF RATS TRANSGENIC FOR HUMAN ANGIOTENSINOGEN

Transgenic rats, which express the human angiotensinogen gene, provide a unique model for studying local vascular effects of human renin. We examined the cleavage of human angiotensinogen to angiotensin I (Ang I) by human renin and its inhibition by a human renin inhibitor in an isolated perfused hindlimb preparation from such rats. Perfusion resul ted in the sustained release of human angiotensinogen, which decreased from 19.4 to 11.8 pmol/mL over 45 minutes. Active human renin at dose s of 3, 10, and 30 ng/mL perfusate for 15 minutes increased Ang I rele ase from undetectable levels (mean+/-SEM) to 31.9+/-3.3, 147.1+/-26.2, and 206.4+/-17.1 fmol/mL, respectively, by 9 minutes. In separate exp eriments aimed at the quantification of renin-induced vasoconstriction , captopril decreased the perfusion pressure and lowered Ang II concen trations to nondetectable levers, whereas Ang I values increased sharp ly. When renin (30 ng/mL) was infused for 15 minutes, renin values in the perfusate decreased to barely detectable levels within minutes aft er termination of the infusion. However, Ang I values remained high fo r at least 30 minutes thereafter. The addition of a human renin inhibi tor during renin infusion caused Ang I values to promptly decrease wit hin minutes to undetectable levels. Hindlimbs from nontransgenic contr ol rats released no detectable amounts of Ang I, with or without human renin. Finally, by in situ hybridization we documented the presence o f human angiotensinogen message in the vessels of the hindlimb. We con clude that renin acts on angiotensinogen at a site in the vascular wal l. The cleavage depends on renin and not on other lysosomal proteases. Transgenic rats are a novel model that may be used to test the functi onal importance of the local human renin-angiotensin system in experim ental animals.