Development of cardiomyocyte hypotrophy in rats under prolonged treatment with a low dose of a nitric oxide synthesis inhibitor.
Chronic administration of the nitric oxide (NO) synthesis inhibitor N(omega)-nitro-L-arginine methyl ester (L-NAME) to rats causes hypertension and morphological abnormalities in the heart, consisting mainly of ventricular hypertrophy and foci of necrosis and fibrosis. Since these phenomena have usually been described with high (or moderate) doses of L-NAME, this study was undertaken to evaluate the effects of a low dose of L-NAME on arterial blood pressure, heart weight index, left ventricular weight index, amount of ventricular fibrosis, and cardiomyocyte size. Male Wistar rats received L-NAME (7.5 mg/kg per day) in the drinking water for 2, 4, and 6 months, whereas control animals received tap water alone. At this dose, L-NAME caused 90% inhibition (P<0.001) of brain NO synthase (NOS) activity. The chronic L-NAME treatment caused an approximately 15% reduction in body weight of the animals, and no death was observed. The tail-cuff pressure was markedly (P<0.01) elevated in L-NAME-treated rats. A significant (P<0.05) reduction in both heart weight index (13-20% decrease) and left ventricular weight index (20-34% decrease) at 2, 4, and 6 months of treatment was observed in L-NAME-treated rats. The cardiomyocyte size in subendocardial, subepicardial, and midmyocardial regions of the left ventricles was time-dependently reduced, irrespective of the region studied, as measured at 2 (11% decrease), 4 (28% decrease, P<0.05), and 6 (45% decrease, P<0.05) months of chronic L-NAME treatment. The amount of fibrous tissue was unaltered at 2 and 4 months, but a small (but significant) increase in the amount of fibrous tissue was detected at 6 months (7.1+/-0.2 %, P<0.05) compared to that of control animals (5.9+/-0.2%). Our results show that chronic treatment of rats with a low dose of L-NAME for prolonged periods (up to 6 months) causes arterial hypertension accompanied by significant reductions in heart weight, left ventricular weight indexes, and cardiomyocyte size.
de Oliveira
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CF
Department of Pharmacology, Faculty of Medical Sciences, State University of Campinas (UNICAMP), PO Box 6111, 13081-970;, Campinas, Brazil.
Cintra
K A
KA
Teixeira
S A
SA
De Luca
I M
IM
Antunes
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E
De Nucci
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G
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000201:enzymology; D006332:Cardiomegaly / Q000139:chemically induced* / Q000473:pathology*; D004791:Enzyme Inhibitors / Q000633:toxicity*; D005355:Fibrosis / Q000139:chemically induced / Q000473:pathology; D017379:Hypertrophy, Left Ventricular / Q000139:chemically induced / Q000473:pathology; D008297:Male; D009206:Myocardium / Q000473:pathology* / Q000648:ultrastructure; D019331:NG-Nitroarginine Methyl Ester / Q000633:toxicity*; D019001:Nitric Oxide Synthase / Q000037:antagonists & inhibitors*; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; D009929:Organ Size / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar
D004791:Enzyme Inhibitors; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; D019331:NG-Nitroarginine Methyl Ester