Nitric Oxide

Table of Contents

Hypertension. 1997;30:307-313
doi: 10.1161/01.HYP.30.3.307

(Hypertension. 1997;30:307.)
© 1997 American Heart Association, Inc.

Articles

Prolonged Reduction of High Blood Pressure With Human Nitric Oxide Synthase Gene Delivery

Kuei-Fu Lin; Lee Chao; Julie Chao

From the Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston.
Correspondence to Julie Chao, PhD, or Lee Chao, PhD, Department of Biochemistry and Molecular Biology, Medical University of South Carolina, 171 Ashley Ave, Charleston, SC 29425.

Abstract Endothelium-derived nitric oxide (NO) in peripheral vessels has been shown to modulate vascular resistance and blood pressure. We explored the effect of a continuous supply of human endothelial NO synthase (eNOS) on the blood pressure of spontaneously hypertensive rats (SHR) by somatic gene delivery. A DNA construct containing the human eNOS gene fused to the cytomegalovirus promoter/enhancer was injected into SHR through the tail vein. A single injection of the naked eNOS plasmid DNA caused a significant reduction of systemic blood pressure for 5 to 6 weeks in SHR, and the effect continued for up to 10 to 12 weeks after a second injection. The differences were significant from 2 to 12 weeks postinjections (n=6, P<.01). In a separate experiment, L-arginine, the substrate of eNOS, was supplied in drinking water at a concentration of 7.5 g/L for 11 weeks after eNOS gene delivery. A maximal blood pressure reduction of 21 mm Hg in SHR was observed with eNOS DNA compared with that of control SHR injected with vector DNA (181.9±1.46 versus 202.7±2.79 mm Hg, mean±SEM, n=6, P<.01). Human eNOS gene delivery induces significant increases in urinary and aortic cGMP levels and urinary and serum nitrite/nitrate content (P<.05), while no significant differences in body weight, heart rate, water intake, food consumption, or urine excretion were observed. These results indicate that somatic delivery of the human eNOS gene induces a prolonged reduction of high blood pressure and raises the potential of using eNOS gene therapy for hypertension and cardiovascular diseases.

Key Words: nitric oxide synthase • inbred SHR • somatic gene therapy • blood pressure • hypertension

l-arginine and l-citrulline

l-citrulline and l-arginine supplementation retards the progression of high-cholesterol-diet-induced atherosclerosis in rabbits

1. Toshio Hayashi * , †,
2. Packiasamy A. R. Juliet *,
3. Hisako Matsui-Hirai *,
4. Asaka Miyazaki *,
5. Akiko Fukatsu *,
6. Jun Funami *,
7. Akihisa Iguchi *, and
8. Louis J. Ignarro ‡ , § , †

+ Author Affiliations

1. ^*Department of Geriatrics, Nagoya University Graduate School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan; and ^‡Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California, 650 Charles E. Young Drive South, Los Angeles, CA 90095

1. Contributed by Louis J. Ignarro, August 6, 2005

Abstract

The objective of this study was to evaluate the influence of ingested l-arginine, l-citrulline, and antioxidants (vitamins C and E) on the progression of atherosclerosis in rabbits fed a high-cholesterol diet. The fatty diet caused a marked impairment of endothelium-dependent vasorelaxation in isolated thoracic aorta and blood flow in rabbit ear artery in vivo, the development of atheromatous lesions and increased superoxide anion production in thoracic aorta, and increased oxidation-sensitive gene expression [Elk-1 and phosphorylated cAMP response element-binding protein]. Rabbits were treated orally for 12 weeks with l-arginine, l-citrulline, and/or antioxidants. l-arginine plus l-citrulline, either alone or in combination with antioxidants, caused a marked improvement in endothelium-dependent vasorelaxation and blood flow, dramatic regression in atheromatous lesions, and decrease in superoxide production and oxidation-sensitive gene expression. These therapeutic effects were associated with concomitant increases in aortic endothelial NO synthase expression and plasma and cGMP levels. These observations indicate that ingestion of certain NO-boosting substances, including l-arginine, l-citrulline, and antioxidants, can abrogate the state of oxidative stress and reverse the progression of atherosclerosis. This approach may have clinical utility in the treatment of atherosclerosis in humans.