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EXPERIMENTAL STUDY

Renin angiotensin system-dependent hypertrophy as a contributor to heart failure in hypertensive rats: different characteristics from renin angiotensin system-independent hypertrophy

Yasushi Sakata, MD^*, Tohru Masuyama, MD, PhD, FACC^*, Kazuhiro Yamamoto, MD, PhD, FACC^*, Reiko Doi, MD, PhD^*, Toshiaki Mano, MD, PhD^*, Tsunehiko Kuzuya, MD, PhD^*, Takeshi Miwa, PhD, Hiroshi Takeda, MD, PhD and Masatsugu Hori, MD, PhD, FACC^*

^* Department of Internal Medicine and Therapeutics, Osaka University, Suita, Japan
Genome Information Research Center, Osaka University, Suita, Japan
Department of Medical Information Science, Osaka University Graduate School of Medicine, Suita, Japan

Manuscript received September 20, 1999; revised manuscript received July 24, 2000, accepted September 11, 2000.

Address for correspondence: Dr. Tohru Masuyama, Department of Internal Medicine and Therapeutics (A8), Osaka University Graduate School of Medicine, 2-2 Yamadaoka, Suita 565-0871, Japan
masuyama{at}medone.med.osaka-u.ac.jp

OBJECTIVES

This study aimed to characterize the difference between renin angiotensin system (RAS)-dependent and RAS-independent hypertrophy and their differential contribution to the transition to heart failure.

BACKGROUND

Hypertensive left ventricular (LV) hypertrophy develops with RAS activation in the heart; however, LV hypertrophy develops even without RAS activation.

METHODS

Left ventricular geometry and function were assessed in Dahl salt-sensitive rats placed on an 8% NaCl diet from seven weeks old (hypertensive rats) and in those placed on an 0.3% NaCl diet (control rats, n = 8). The hypertensive rats were randomized to no treatment (n = 8) or treatment with the angiotensin type 1 receptor (AT₁R) antagonist candesartan (1 mg/kg per day, n = 10) after the baseline echocardiography study.

RESULTS

From 7 to 13 weeks, AT₁R blockade at a subdepressor dose did not restrain the development of LV hypertrophy but prevented narrowing of LV diastolic dimension, leading to the normalization of abnormally decreased end-systolic wall stress in the untreated rats. Progressive development of LV hypertrophy in spite of lower than normal end-systolic wall stress (excessive hypertrophy) after 13 weeks was suppressed by the AT₁R blockade. Elevation of LV end-diastolic pressure and prolongation of Tau were associated with histological evidence of myocyte hypertrophy and massive interstitial fibrosis in the untreated rats, and none of these was evident in the treated rats.

CONCLUSIONS

Renin-angiotensin system activation and AT₁R signaling may be dispensable for the development of early adaptive LV hypertrophy and closely linked to the transition to heart failure.

Abbreviations and Acronyms   ACE = angiotensin-converting enzyme   AT = angiotensin   AT1 R = angiotensin II type-1 receptor   CAND(+) = experimental group receiving candesartan   CAND(–) = experimental group receiving placebo   ECE = endothelin-converting enzyme   ET = endothelin   LV = left ventricular   LVMI = the ratio of left ventricular mass to body weight   mRNA = messenger RNA   RAS = renin angiotensin system   Tau = time constant of left ventricular isovolumic pressure fall

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