title: Effect of angiotensin II blockade on a new congenic model of hypertension derived from transgenic Ren-2 rats.
abstract: The generation of the Lew.Tg(mRen2) congenic hypertensive rat strain, developed through a backcross 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 (AT(1)) blockade and angiotensin-converting enzyme (ACE) activity inhibition on the ANG-(1-7)/ACE2 axis of the renin-angiotensin system in this new 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, whereas 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 AT(1) receptor mRNAs. ACE inhibition reduced plasma ANG II levels (81%, P < 0.05) and increased plasma ANG-(1-7) (265%, P < 0.05), whereas 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 was significantly augmented. 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.
authors.affiliation: Hypertension and Vascular Disease Center, Wake Forest Univ. School of Medicine, Winston-Salem, NC 27157, USA.
authors.forename: Jewell A
authors.initials: JA
authors.lastname: Jessup
authors.forename: Patricia E
authors.initials: PE
authors.lastname: Gallagher
authors.forename: David B
authors.initials: DB
authors.lastname: Averill
authors.forename: K Bridget
authors.initials: KB
authors.lastname: Brosnihan
authors.forename: E Ann
authors.initials: EA
authors.lastname: Tallant
authors.forename: Mark C
authors.initials: MC
authors.lastname: Chappell
authors.forename: Carlos M
authors.initials: CM
authors.lastname: Ferrario
mesh_terms: D000803:Angiotensin I / Q000097:blood / Q000652:urine; D000804:Angiotensin II / Q000037:antagonists & inhibitors / Q000097:blood / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D057911:Angiotensin Receptor Antagonists; D000085962:Angiotensin-Converting Enzyme 2; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology; D000818:Animals; D020296:Animals, Congenic; D030801:Animals, Genetically Modified; D003433:Crosses, Genetic; D006977:Hypertension, Renal / Q000235:genetics* / Q000378:metabolism; D007700:Kinetics; D017706:Lisinopril / Q000494:pharmacology; D019808:Losartan / Q000494:pharmacology; D008297:Male; D008957:Models, Genetic; D010446:Peptide Fragments / Q000097:blood / Q000652:urine; D007703:Peptidyl-Dipeptidase A / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011917:Rats, Inbred Lew; D012083:Renin / Q000235:genetics*; D012084:Renin-Angiotensin System / Q000187:drug effects / Q000502:physiology; D013997:Time Factors
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D057911:Angiotensin Receptor Antagonists; D000806:Angiotensin-Converting Enzyme Inhibitors; D010446:Peptide Fragments; D012333:RNA, Messenger; D000804:Angiotensin II; D000803:Angiotensin I; D017706:Lisinopril; D007703:Peptidyl-Dipeptidase A; C000705329:Ace2 protein, rat; D000085962:Angiotensin-Converting Enzyme 2; D012083:Renin; D019808:Losartan