Mechanisms of hypertension in transgenic rats expressing the mouse Ren-2 gene.
Transgenic (TG) rats carrying the mouse Ren-2 gene (Ren-2d)27 are a newly established monogenetic model in hypertension research. To gain an insight into the mechanisms of this form of hypertension we determined the effects of a 13-day therapy with losartan (10 mg/kg) or lisinopril (20 mg/kg) on the blood pressure (BP) and plasma levels of angiotensin (ANG) peptides of mature female TG hypertensive and Sprague-Dawley (SD) rats. The contribution of endothelium-derived nitric oxide (NO) to the maintenance of their hypertension and the response to therapy was evaluated by systemic injection of either NG-monomethyl-L-arginine (L-NMMA) or endothelin-1. Hypertension in TG rats was associated with decreased plasma ANG I, no differences in plasma ANG II, and plasma ANG-(1-7) near the detectable level. Lisinopril lowered BP more than losartan in both TG hypertensive and normotensive controls. In both strains, the chronic fall in BP produced by lisinopril was accompanied by significant increases in plasma ANG I and ANG-(1-7), while losartan augmented plasma ANG I and ANG II in both strains and plasma ANG-(1-7) in TG rats. Inhibition of NO synthase reversed the fall in BP produced by either lisinopril or losartan in SD controls. In contrast, administration of L-NMMA to TG rats given the same therapy did not. The transient endothelium-mediated relaxing phase of the depressor response to systemic injections of endothelin-1 was attenuated by losartan and lisinopril in TG rats. These studies indicate that hypertension in female TG rats is mediated by the RAS.(ABSTRACT TRUNCATED AT 250 WORDS)
Moriguchi
A
A
Hypertension Center, Bowman Gray School of Medicine, Wake Forest University, Winston Salem, North Carolina 27157.
Brosnihan
K B
KB
Kumagai
H
H
Ganten
D
D
Ferrario
C M
CM
D000804:Angiotensin II / Q000097:blood; D000818:Animals; D030801:Animals, Genetically Modified; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001713:Biphenyl Compounds / Q000627:therapeutic use; D001794:Blood Pressure / Q000187:drug effects; D016232:Endothelins / Q000494:pharmacology; D005260:Female; D015870:Gene Expression; D006439:Hemodynamics / Q000187:drug effects; D006973:Hypertension / Q000188:drug therapy / Q000235:genetics* / Q000503:physiopathology*; D007093:Imidazoles / Q000627:therapeutic use; D017706:Lisinopril / Q000627:therapeutic use; D019808:Losartan; D051379:Mice / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D012016:Reference Values; D013777:Tetrazoles / Q000627:therapeutic use; D019323:omega-N-Methylarginine
D000959:Antihypertensive Agents; D001713:Biphenyl Compounds; D016232:Endothelins; D007093:Imidazoles; D013777:Tetrazoles; D000804:Angiotensin II; D019323:omega-N-Methylarginine; D001120:Arginine; D017706:Lisinopril; D019808:Losartan