Dose effects of human renin in rats transgenic for human angiotensinogen.

We examined the effect of chronic human renin infusion and human renin inhibition on blood pressure in a unique transgenic rat model. We infused incremental doses of human renin (1 to 500 ng/h) with minipumps for 10 days into rats harboring the human angiotensinogen gene [TGR (hAOGEN)1623]. We measured blood pressure and heart rate continuously by telemetry. We found that human renin at 5 ng/h was necessary to increase blood pressure, whereas 10 ng/h caused systolic blood pressure to increase to 215 +/- 13 mm Hg. Heart rate decreased initially but then increased by 100 beats per minute compared with basal values. Drinking behavior also increased. Doses as high as 500 ng/h did not increase blood pressure further. A linear relationship was found between the log of plasma renin activity and systolic blood pressure that increased in slope from days 2 to 9. Rat angiotensinogen levels were low and not influenced by human renin infusion. Human angiotensinogen levels remained stable until 500 ng/h human renin was infused, at which time they decreased by 50% at 9 days. Rat renin gene expression (RNase protection assay) was decreased by human renin infusion, whereas rat and human angiotensinogen gene expressions in liver and kidney as well as angiotensin-converting enzyme gene expression in kidney were not affected. The human renin inhibitor Ro 42-5892 was given by gavage repeatedly to rats receiving human renin at 40 ng/h. Ro 42-5892 lowered blood pressure promptly to basal values. High human renin hypertension in this model is dose dependent, features a steeper relationship between blood pressure and plasma renin activity over time, and is associated with tachycardia and increased drinking. We conclude that the human angiotensinogen transgenic rat offers new perspectives in the study of human renin-induced hypertension.

[1]  J. Ménard,et al.  Human renin-dependent hypertension in rats transgenic for human angiotensinogen. , 1996, Hypertension.

[2]  B. Lévy,et al.  Chronic infusion of low-dose angiotensin II potentiates the adrenergic response in vivo. , 1996, Journal of hypertension.

[3]  D. Ganten,et al.  Effects of human renin in the vasculature of rats transgenic for human angiotensinogen. , 1995, Hypertension.

[4]  D. Ganten,et al.  Chronic dexamethasone treatment suppresses hypertension development in the transgenic rat TGR(mREN2)27 , 1995, Journal of hypertension.

[5]  D. Ganten,et al.  Contribution of a 12 kDa protein to the angiotensin II-induced stabilization of angiotensinogen mRNA: interaction with the 3' untranslated mRNA. , 1995, Journal of Molecular Endocrinology.

[6]  O. Costerousse,et al.  Regulation of ACE gene expression and plasma levels during rat postnatal development. , 1994, The American journal of physiology.

[7]  E. Vicaut,et al.  ACE in three tunicae of rat aorta: expression in smooth muscle and effect of renovascular hypertension. , 1994, The American journal of physiology.

[8]  D. Ganten,et al.  Mechanism by Which Angiotensin II Stabilizes Messenger RNA for Angiotensinogen , 1994, Hypertension.

[9]  J. Zhu,et al.  Nuclear angiotensin receptors induce transcription of renin and angiotensinogen mRNA. , 1993, Hypertension.

[10]  C. Weber,et al.  Hemodynamics, biochemical effects, and pharmacokinetics of the renin inhibitor remikiren in healthy human subjects , 1993, Clinical pharmacology and therapeutics.

[11]  D. Ganten,et al.  Species specificity of renin kinetics in transgenic rats harboring the human renin and angiotensinogen genes. , 1992, Proceedings of the National Academy of Sciences of the United States of America.

[12]  K. Fuxe,et al.  High blood pressure in transgenic mice carrying the rat angiotensinogen gene. , 1992, The EMBO journal.

[13]  W. Neidhart,et al.  Ro 42‐5892 Is a Potent Orally Active Renin Inhibitor in Primates , 1991, Hypertension.

[14]  J. Laragh,et al.  Half-life, hemodynamic, renal, and hormonal effects of prorenin in cynomolgus monkeys. , 1991, The American journal of physiology.

[15]  E. G. Erdös,et al.  Angiotensin I converting enzyme and the changes in our concepts through the years. Lewis K. Dahl memorial lecture. , 1990, Hypertension.

[16]  S. Whitebread,et al.  Preliminary biochemical characterization of two angiotensin II receptor subtypes. , 1989, Biochemical and biophysical research communications.

[17]  B. Waeber,et al.  True Versus Immunoreactive Angiotensin II in Human Plasma , 1985, Hypertension.

[18]  B. Zimmerman,et al.  Interaction between sympathetic and renin-angiotensin system. , 1984, Journal of hypertension.

[19]  J. Ménard,et al.  Characterization of plasma and cerebrospinal fluid human angiotensinogen and des-angiotensin I-angiotensinogen by direct radioimmunoassay. , 1984, The Journal of clinical endocrinology and metabolism.

[20]  J. Ménard,et al.  Influence of converting-enzyme inhibition on rat des-angiotensin I-angiotensinogen. , 1984, The American journal of physiology.

[21]  C. Auffray,et al.  Purification of mouse immunoglobulin heavy-chain messenger RNAs from total myeloma tumor RNA. , 2005, European journal of biochemistry.

[22]  B. Morris,et al.  Effect of angiotensin II and sodium depletion on angiotensinogen production. , 1980, The American journal of physiology.

[23]  R. Fraser,et al.  The Relation of Arterial Pressure and Plasma Angiotensin II Concentration: A Change Produced by Prolonged Infusion of Angiotensin II in the Conscious Dog , 1979, Circulation research.

[24]  W F Ganong,et al.  The renin-angiotensin system. , 1978, Annual review of physiology.

[25]  A. Cowley,et al.  Quantification of Baroreceptor Influence on Arterial Pressure Changes Seen in Primary Angiotensin‐Induced Hypertension in Dogs , 1976, Circulation research.

[26]  J. Brown,et al.  Increase of plasma renin-substrate concentration after infusion of angiotensin in the rat. , 1973, Clinical science.

[27]  G. Bianchi,et al.  Pathogenesis of arterial hypertension after the constriction of the renal artery leaving the opposite kidney intact both in the anaesthetized and in the conscious dog. , 1972, Clinical science.

[28]  J. Laragh,et al.  PROLONGED INFUSIONS OF ANGIOTENSIN II AND NOREPINEPHRINE AND BLOOD PRESSURE, ELECTROLYTE BALANCE, AND ALDOSTERONE AND CORTISOL SECRETION IN NORMAL MAN AND IN CIRRHOSIS WITH ASCITES. , 1965, The Journal of clinical investigation.

[29]  M. Sokolow,et al.  The natural history and course of hypertension with papilledema (malignant hypertension). , 1953, American heart journal.

[30]  Clifford Wilson,et al.  RENAL CHANGES IN MALIGNANT HYPERTENSION: EXPERIMENTAL EVIDENCE , 1939 .

[31]  H. Goldblatt,et al.  STUDIES ON EXPERIMENTAL HYPERTENSION I. THE PRODUCTION OF PERSISTENT ELEVATION OF SYSTOLIC BLOOD PRESSURE BY MEANS OF RENAL ISCHEMIA , 1934 .