(Circulation. 1996;94:785-791.)
© 1996 American Heart Association, Inc.
Articles |
Contribution of Local Renin-Angiotensin System to Cardiac Hypertrophy, Phenotypic Modulation, and Remodeling in TGR(mRen2)27 Transgenic Rats
the Department of Pharmacology (K.O., S.K., H.I.) and the First Department of Pathology (H.W.), Osaka (Japan) City University Medical School, and the Max Delbruck Center for Molecular Medicine (D.G.), Berlin-Buch, Germany.
Correspondence to Shokei Kim, MD, Department of Pharmacology, Osaka City University Medical School, 1-4-54 Asahimachi, Abenoku, Osaka 545, Japan.
Background The transgenic rat TGR(mRen2)27, carrying the mouse Ren-2 gene, is a new model to elucidate the role of the local renin-angiotensin system in vivo. However, the role of the local renin-angiotensin system in the heart remains to be determined in TGR(mRen2)27.
Methods and Results TGR(mRen2)27 were treated with various antihypertensive drugs for 6 weeks to examine the effects on cardiac hypertrophy and gene expression. Cardiac mRNAs were examined by Northern blot analysis. In TGR(mRen2)27, left ventricular hypertrophy was associated with a decrease in 
-myosin heavy chain expression of 31% and an increase in skeletal -actin and atrial natriuretic polypeptide expression by 2.6- and 21-fold, respectively (P<.05), thereby showing the shift of myocardium to a fetal phenotype. Furthermore, cardiac collagen and laminin expressions were increased in TGR(mRen2)27 (P<.05), suggesting the occurrence of cardiac remodeling. Although treatment of TGR(mRen2)27 with a high dose of TCV-116 (angiotensin AT1 receptor antagonist) or manidipine (calcium antagonist) combined with atenolol (ß1-adrenergic receptor blocker) completely normalized blood pressure, TCV-116 regressed cardiac hypertrophy and suppressed the changes in cardiac mRNA levels of TGR(mRen2)27 much more potently than manidipine with atenolol. Furthermore, the inhibitory effects of a low dose of TCV-116 on cardiac hypertrophy and altered gene expressions of TGR(mRen2)27 were greater than those of doxazosin (1-adrenergic receptor blocker) combined with atenolol, despite their similar hypotensive effects.
Conclusions Our present observations provide evidence that the cardiac renin-angiotensin system in TGR(mRen2)27 is responsible for cardiac hypertrophy, phenotypic modulation, and remodeling.
Key Words: genes • renin • angiotensin • hypertrophy • remodeling
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