This Article Full Text Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Müller, D. N. Articles by Luft, F. C. Search for Related Content PubMed PubMed Citation Articles by Müller, D. N. Articles by Luft, F. C.

(Hypertension. 1995;26:272-278.)
© 1995 American Heart Association, Inc.

Articles

Effects of Human Renin in the Vasculature of Rats Transgenic for Human Angiotensinogen

Dominik N. Müller; Karl F. Hilgers; Jürgen Bohlender; Andrea Lippoldt; Jürgen Wagner; Walter Fischli; Detlev Ganten; Johannes F. E. Mann; Friedrich C. Luft

From the Franz Volhard Clinic, Rudolph Virchow University Hospitals, and the Max Delbrück Center for Molecular Medicine, Humboldt University, Berlin, Germany; University of Erlangen-Nürnberg (Germany); and Hoffmann–La Roche, Basel, Switzerland.

Correspondence to Friedrich C. Luft, MD, Franz Volhard Clinic, Wiltberg Strasse 50, 13122 Berlin, FRG.

Abstract 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 nontransgenic 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. Transgenic rats are a novel model that may be used to test the functional importance of the local human renin-angiotensin system in experimental animals.

Key Words: rats, transgenic • angiotensinogen • angiotensin • renin • hindlimb • renin-angiotensin system

This article has been cited by other articles:

				R. Willenbrock, M. Scheuermann, G. Thibault, Markus Haass, K. Hohnel, J. Bohlender, F. C. Luft, and Rainer Dietz Angiotensin inhibition and atrial natriuretic peptide release after acute volume expansion in rats with aortocaval shunt Cardiovasc Res, June 1, 1999; 42(3): 733 - 742. [Abstract] [Full Text] [PDF]

				D. Methot, D. W. Silversides, and T. L. Reudelhuber In Vivo Enzymatic Assay Reveals Catalytic Activity of the Human Renin Precursor in Tissues Circ. Res., May 14, 1999; 84(9): 1067 - 1072. [Abstract] [Full Text] [PDF]

				R. WILLENBROCK, I. PAGEL, M. SCHEUERMANN, K. HÖHNEL, H. S. MACKENZIE, B. M. BRENNER, and R. DIETZ Renal Function in High-Output Heart Failure in Rats: Role ofEndogenous Natriuretic Peptides J. Am. Soc. Nephrol., March 1, 1999; 10(3): 572 - 580. [Abstract] [Full Text]

				F. C. Luft, E. Mervaala, D. N. Muller, V. Gross, F. Schmidt, J. K. Park, C. Schmitz, A. Lippoldt, V. Breu, R. Dechend, et al. Hypertension-Induced End-Organ Damage : A New Transgenic Approach to an Old Problem Hypertension, January 1, 1999; 33(1): 212 - 218. [Abstract] [Full Text] [PDF]

				D. N. Muller, K. F. Hilgers, S. Mathews, V. Breu, W. Fischli, R. Uhlmann, and F. C. Luft Effects of Human Prorenin in Rats Transgenic for Human Angiotensinogen Hypertension, January 1, 1999; 33(1): 312 - 317. [Abstract] [Full Text] [PDF]

				S. A Doggrell and L. Brown Rat models of hypertension, cardiac hypertrophy and failure Cardiovasc Res, July 1, 1998; 39(1): 89 - 105. [Full Text] [PDF]

				D. N. Muller, W. Fischli, J.-P. Clozel, K. F. Hilgers, J. Bohlender, J. Menard, A. Busjahn, D. Ganten, and F. C. Luft Local Angiotensin II Generation in the Rat Heart : Role of Renin Uptake Circ. Res., January 23, 1998; 82(1): 13 - 20. [Abstract] [Full Text] [PDF]

				K. F. Hilgers, E. Bingener, C. Stumpf, D. N. Muller, R. E. Schmieder, and R. Veelken Angiotensinases Restrict Locally Generated Angiotensin II to the Blood Vessel Wall Hypertension, January 1, 1998; 31(1): 368 - 372. [Abstract] [Full Text] [PDF]

				J. Bohlender, J. Menard, F. C. Luft, and D. Ganten Dose Effects of Human Renin in Rats Transgenic for Human Angiotensinogen Hypertension, April 1, 1997; 29(4): 1031 - 1038. [Abstract] [Full Text]

				J. Bohlender, A. Fukamizu, A. Lippoldt, T. Nomura, R. Dietz, J. Menard, K. Murakami, F. C. Luft, and D. Ganten High Human Renin Hypertension in Transgenic Rats Hypertension, January 1, 1997; 29(1): 428 - 434. [Abstract] [Full Text] [PDF]

				R. Willenbrock, M. Scheuermann, K. Hohnel, F. C. Luft, and R. Dietz Acute and Chronic Neutral Endopeptidase Inhibition in Rats With Aortocaval Shunt Hypertension, June 1, 1996; 27(6): 1259 - 1266. [Abstract] [Full Text]

				J. Bohlender, J. Menard, J. Wagner, F. C. Luft, and D. Ganten Human Renin-Dependent Hypertension in Rats Transgenic for Human Angiotensinogen Hypertension, March 1, 1996; 27(3): 535 - 540. [Abstract] [Full Text]