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 resulted in the sustained release of human angiotensinogen, which decreased from 19.4 to 11.8 pmol/mL over 45 minutes. Active human renin at doses of 3, 10, and 30 ng/mL perfusate for 15 minutes increased Ang I release 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 experiments aimed at the quantification of renin-induced vasoconstriction, captopril decreased the perfusion pressure and lowered Ang II concentrations to nondetectable levels, whereas Ang I values increased sharply. When renin (30 ng/mL) was infused for 15 minutes, renin values in the perfusate decreased to barely detectable levels within minutes after termination of the infusion. However, Ang I values remained high for at least 30 minutes thereafter. The addition of a human renin inhibitor during renin infusion caused Ang I values to promptly decrease within minutes to undetectable levels. Hindlimbs from non-transgenic control rats released no detectable amounts of Ang I, with or without human renin. Finally, by in situ hybridization we documented the presence of human angiotensinogen message in the vessels of the hindlimb. We conclude that renin acts on angiotensinogen at a site in the vascular wall. The cleavage depends on renin and not on other lysosomal proteases.(ABSTRACT TRUNCATED AT 250 WORDS)
Müller
D N
DN
Franz Volhard Clinic, Rudolph Virchow University Hospitals, Berlin, Germany.
Hilgers
K F
KF
Bohlender
J
J
Lippoldt
A
A
Wagner
J
J
Fischli
W
W
Ganten
D
D
Mann
J F
JF
Luft
F C
FC
D000803:Angiotensin I / Q000378:metabolism; D000808:Angiotensinogen / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D030801:Animals, Genetically Modified; D001808:Blood Vessels / Q000378:metabolism; D006614:Hindlimb / Q000098:blood supply; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D017403:In Situ Hybridization; D066298:In Vitro Techniques; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D012083:Renin / Q000378:metabolism / Q000494:pharmacology*; D000092502:Renin Inhibitors
D000803:Angiotensin I; D000808:Angiotensinogen; D007093:Imidazoles; D012333:RNA, Messenger; D012083:Renin; D000092502:Renin Inhibitors; C065581:remikiren