Left but not right cardiac hypertrophy in atrial natriuretic peptide receptor-deficient mice is prevented by angiotensin type 1 receptor antagonist losartan.
Mice with a genetic deletion of the atrial natriuretic peptide (ANP) receptor, guanylyl cyclase A (GC-A -/-), have chronic arterial hypertension and cardiac hypertrophy from the first day of life. To characterize the role of the angiotensin II and endothelin systems in the development of this cardiovascular phenotype, the effects of chronic treatment with either the angiotensin type I (AT1) receptor antagonist losartan or the endothelin A receptor antagonist BSF208075 were tested. Losartan almost completely reversed systemic arterial hypertension and left ventricular hypertrophy of GC-A -/- mice. This was accompanied by a marked regression of the left ventricular mRNA expression of cardiac hypertrophy markers such as ANP and brain natriuretic peptide and a significant reduction of left ventricular and pulmonary interstitial collagen accumulation. BSF208075 had no effect on any of these cardiovascular parameters. Intriguingly, GC-A -/- mice also showed a very marked right ventricular hypertrophy, which was not reversed by losartan or BSF208075 treatment. Analyses of components of the renin-angiotensin system (RAS) revealed an inhibition of renal and systemic RAS contrasting with increased local left ventricular angiotensin II levels in GC-A -/- mice. Collectively, the results suggest that RAS plays a more important role than the endothelin system in the pathogenesis of arterial hypertension as well as left ventricular hypertrophy and fibrosis in GC-A gene-disrupted mice.
Holtwick
Rita
R
Institute of Pharmacology and Toxicology, Universitätsklinikum Essen, Essen, Germany.
Baba
Hideo A
HA
Ehler
Elisabeth
E
Risse
Dorothée
D
Vobeta
Melanie
M
Gehrmann
Joseph
J
Pierkes
Melanie
M
Kuhn
Michaela
M
D057911:Angiotensin Receptor Antagonists; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use*; D006162:Guanylate Cyclase / Q000097:blood / Q000172:deficiency*; D006439:Hemodynamics; D017379:Hypertrophy, Left Ventricular / Q000235:genetics / Q000517:prevention & control*; D019808:Losartan / Q000627:therapeutic use*; D051379:Mice; D017461:Receptors, Atrial Natriuretic Factor / Q000097:blood / Q000172:deficiency*
D057911:Angiotensin Receptor Antagonists; D000959:Antihypertensive Agents; D006162:Guanylate Cyclase; D017461:Receptors, Atrial Natriuretic Factor; C091715:atrial natriuretic factor receptor A; D019808:Losartan