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1 Hypertension and Vascular Disease Center, Wake Forest University School of Medicine, Winston-Salem, North Carolina, United States
* To whom correspondence should be addressed. E-mail: cferrari{at}wfubmc.edu.
The generation of the Lew.Tg(mRen2) congenic hypertensive rat strain, developed through a back-cross of the hypertensive [mRen2]27 transgenic rat with normotensive Lewis rats, provides a new model by which primary hypertension can be studied without the genetic variability found in the original strain. The purpose of this study was to characterize the Lew.Tg(mRen2) rats by dually investigating the effects of type 1 angiotensin II (Ang II) receptor (AT1) blockade and angiotensin converting enzyme (ACE) activity inhibition on the angiotensin-(1-7) [Ang-(1-7)]/angiotensin converting enzyme 2 (ACE2) axis of the renin-angiotensin system (RAS) in thisnew hypertensive model. The control of blood pressure elicited by 12-day administration of either lisinopril (mean difference change = 92 ± 2, p < 0.05) or losartan (mean difference change = 69 ± 2, p < 0.05) was associated with 54% and 33% increases in cardiac ACE2 mRNA and 54% and 43% increases in cardiac ACE mRNA, respectively. Lisinopril induced a 3.1-fold (p < 0.05) increase in renal cortical expression of ACE2 while losartan increased ACE2 mRNA 3.5-fold (p < 0.05). Both treatment regimens increased renal ACE mRNA 2.6-fold (p < 0.05). The two therapies augmented ACE2 protein activity, as well as increased cardiac and renal AT1 receptor mRNAs. ACE inhibition reduced plasma Ang II levels (81%, p < 0.05) and increased plasma Ang-(1-7) (265%, p < 0.05), while losartan had no effect on the peptides. In contrast with what had been shown in normotensive rats, ACE inhibition decreased renal Ang II excretion and transiently decreased Ang-(1-7) excretion, whereas, losartan treatment was associated with a consistent decrease in Ang-(1-7) urinary excretion rates. In response to the treatments, the expression of both renal cortical renin and angiotensinogen mRNAs were significantly augmented. In summary, the paradoxical effects of blockade of Ang II synthesis and activity on urinary excretion rates of the peptides and plasma angiotensins levels suggest that in Lew.Tg(mRen2) congenic rats a failure of compensatory ACE2 and Ang-(1-7)-dependent vasodepressor mechanisms may contribute both to the development and progression of hypertension driven by increased formation of endogenous Ang II.
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