Blood pressure and renin-angiotensin system resetting in transgenic rats with elevated plasma Val5-angiotensinogen.
OBJECTIVE
Increases in plasma angiotensinogen (Ang-N) due to genetic polymorphisms or pharmacological stimuli like estrogen have been associated with a blood pressure (BP) rise, increased salt sensitivity and cardiovascular risk. The relationship between Ang-N, the resetting of the renin-angiotensin system, and BP still remains unclear. Angiotensin (Ang) II-induced genetic hypertension should respond to lisinopril treatment.


METHODS
A new transgenic rat line (TGR) with hepatic overexpression of native (rat) Ang-N was established to study high plasma Ang-N. The transgene contained a mutation producing Val(5)-Ang-II, which was measured separately from nontransgenic Ile-Ang-II in plasma and renal tissue.


RESULTS
Male homozygous TGR had increased plasma Ang-N (~20-fold), systolic BP (ΔBP+26 mmHg), renin activity (~2-fold), renin activity/concentration (5-fold), total Ang-II (~2-fold, kidney 1.7-fold) but decreased plasma renin concentrations (-46%, kidney -85%) and Ile(5)-Ang-I and II (-93%, -94%) vs. controls. Heterozygous TGR exhibited ~10-fold higher plasma Ang-N and 17 mmHg ΔBP. Lisinopril decreased their SBP (-23 vs. -13 mmHg in controls), kidney Ang-II/I (~3-fold vs. ~2-fold) and Ile(5)-Ang-II (-70 vs. -40%), and increased kidney renin and Ile(5)-Ang-I (>2.5-fold vs. <2.5-fold). Kidney Ang-II remained higher and renin lower in TGR compared with controls.


CONCLUSIONS
High plasma Ang-N increases plasma and kidney Ang-II levels, and amplifies the plasma and renal Ang-II response to a given change in renal renin secretion. This enzyme-kinetic amplification dominates over the Ang-II mediated feedback reduction of renin secretion. High Ang-N levels thus facilitate hypertension via small increases of Ang II and may influence the effectiveness of renin-angiotensin system inhibitors.
Division of Angiology and Hypertension, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
Jürgen
J
Bohlender
Michael
M
Bader
Joël
J
Ménard
Jürg
J
Nussberger
D000804:Angiotensin II / Q000097:blood; D000808:Angiotensinogen / Q000097:blood*; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects / Q000502:physiology*; D025461:Feedback, Physiological / Q000502:physiology; D005838:Genotype; D006973:Hypertension / Q000097:blood*; D007668:Kidney / Q000737:chemistry / Q000378:metabolism / Q000473:pathology; D017706:Lisinopril / Q000494:pharmacology; D008297:Male; D051381:Rats; D017207:Rats, Sprague-Dawley / Q000235:genetics; D055647:Rats, Transgenic; D012083:Renin / Q000097:blood; D012084:Renin-Angiotensin System / Q000502:physiology*
D000808:Angiotensinogen; D000804:Angiotensin II; D017706:Lisinopril; D012083:Renin