Chronic N(G)-nitro-L-arginine methyl ester-induced hypertension : novel molecular adaptation to systolic load in absence of hypertrophy.
BACKGROUND
Chronic N(G)-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.


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 microm(2)) 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 alpha- and beta-myosin heavy chain isoforms and sarcoplasmic reticulum Ca(2+) 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.
Bartunek
J
J
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, MA 02215, USA.
Weinberg
E O
EO
Tajima
M
M
Rohrbach
S
S
Katz
S E
SE
Douglas
P S
PS
Lorell
B H
BH
D000818:Animals; D001024:Aortic Valve Stenosis / Q000473:pathology / Q000503:physiopathology*; D001794:Blood Pressure; D002118:Calcium / Q000378:metabolism; D006332:Cardiomegaly; D006152:Cyclic GMP / Q000378:metabolism; D006973:Hypertension / Q000139:chemically induced* / Q000473:pathology / Q000503:physiopathology*; D008285:Major Histocompatibility Complex; D008297:Male; D009200:Myocardial Contraction / Q000187:drug effects; D009206:Myocardium / Q000378:metabolism / Q000473:pathology*; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D007703:Peptidyl-Dipeptidase A / Q000235:genetics; D051381:Rats; D017208:Rats, Wistar; D013599:Systole; D014158:Transcription, Genetic
D007703:Peptidyl-Dipeptidase A; D006152:Cyclic GMP; D002118:Calcium; D019331:NG-Nitroarginine Methyl Ester