(Circulation. 2000;101:423.)
© 2000 American Heart Association, Inc.
Basic Science Reports |
Chronic NG-Nitro-L-Arginine Methyl Ester–Induced Hypertension
Novel Molecular Adaptation to Systolic Load in Absence of Hypertrophy
From the Charles A. Dana Research Institute and the Harvard-Thorndike Laboratory, Beth Israel Deaconess Medical Center, and Department of Medicine, Cardiovascular Division, Harvard Medical School, Boston, Mass.
Correspondence to Beverly H. Lorell, MD, Cardiovascular Division, Beth Israel Deaconess Medical Center, 330 Brookline Ave, Boston, MA 02215. E-mail blorell{at}caregroup.harvard.edu
Background—Chronic NG-nitro-L-arginine methyl ester (L-NAME), which inhibits nitric oxide synthesis, causes hypertension and would therefore be expected to induce robust cardiac hypertrophy. However, L-NAME has negative metabolic effects on protein synthesis that suppress the increase in left ventricular (LV) mass in response to sustained pressure overload. In the present study, we used L-NAME–induced hypertension to test the hypothesis that adaptation to pressure overload occurs even when hypertrophy is suppressed.
Methods and Results—Male rats received L-NAME (50 mg ·
kg-1 · d-1) or no drug for 6 weeks.
Rats with L-NAME–induced hypertension had levels of systolic
wall stress similar to those of rats with aortic stenosis
(85±19 versus 92±16 kdyne/cm). Rats with aortic stenosis
developed a nearly 2-fold increase in LV mass compared with controls.
In contrast, in the L-NAME rats, no increase in LV mass (1.00±0.03
versus 1.04±0.04 g) or hypertrophy of isolated myocytes
occurred (3586±129 versus 3756±135 µm2) compared
with controls. Nevertheless, chronic pressure overload was not
accompanied by the development of heart failure. LV systolic
performance was maintained by mechanisms of concentric
remodeling (decrease of in vivo LV chamber dimension relative to wall
thickness) and augmented myocardial calcium–dependent contractile
reserve associated with preserved expression of 
- and ß-myosin
heavy chain isoforms and sarcoplasmic reticulum Ca2+
ATPase (SERCA-2).
Conclusions—When the expected compensatory hypertrophic response is suppressed during L-NAME–induced hypertension, severe chronic pressure overload is associated with a successful adaptation to maintain systolic performance; this adaptation depends on both LV remodeling and enhanced contractility in response to calcium.
Key Words: nitric oxide • calcium • NG-nitroarginine methyl ester • hypertrophy • remodeling
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