Prolonged reduction of high blood pressure with human nitric oxide synthase gene delivery.
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.
Lin
K F
KF
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston 29425, USA.
Chao
L
L
Chao
J
J
D000818:Animals; D001120:Arginine; D001794:Blood Pressure / Q000187:drug effects; D002417:Cattle; D002460:Cell Line; D006152:Cyclic GMP / Q000378:metabolism; D003587:Cytomegalovirus / Q000235:genetics; D004247:DNA / Q000235:genetics; D004730:Endothelium, Vascular / Q000166:cytology / Q000378:metabolism; D015316:Genetic Therapy; D006801:Humans; D006973:Hypertension / Q000139:chemically induced / Q000503:physiopathology / Q000628:therapy*; D008297:Male; D019001:Nitric Oxide Synthase / Q000235:genetics* / Q000627:therapeutic use; D011401:Promoter Regions, Genetic / Q000235:genetics; D011651:Pulmonary Artery / Q000166:cytology / Q000378:metabolism; D051381:Rats; D011918:Rats, Inbred SHR / Q000502:physiology; D013997:Time Factors; D014162:Transfection
D004247:DNA; D001120:Arginine; D019001:Nitric Oxide Synthase; D006152:Cyclic GMP