PROLONGED REDUCTION OF HIGH BLOOD-PRESSURE WITH HUMAN NITRIC-OXIDE SYNTHASE GENE DELIVERY

Endothelium-derived nitric oxide (NO) in peripheral vessels has been s hown to modulate vascular resistance and blood pressure. We explored t he effect of a continuous supply of human endothelial NO synthase (eNO S) on the blood pressure of spontaneously hypertensive rats (SHR) by s omatic gene delivery. A DNA construct containing the human eNOS gene f used to the cytomegalovirus promoter/enhancer was injected into SHR th rough the tail vein. A single injection of the naked eNOS plasmid DNA caused a significant reduction of systemic blood pressure for 5 to 6 w eeks 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, th e 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 pre ssure 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 versu s 202.7+/-2.79 mm Hg, mean+/-SEM, n=6, P<.01). Human eNOS gene deliver y induces significant increases in urinary and aortic cGMP levels and urinary and serum nitrite/nitrate content (P<.05), while no significan t differences in body weight, heart rate, water intake, food consumpti on, or urine excretion were observed. These results indicate that soma tic delivery of the human eNOS gene induces a prolonged reduction of h igh blood pressure and raises the potential of using eNOS gene therapy for hypertension and cardiovascular diseases.