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

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.

Endothelin-1 Increases Vascular Superoxide via Endothelin A –NADPH Oxidase Pathway in Low-Renin Hypertension

“…30,39 Furthermore, in vivo gene transfer of eNOS to spontaneously hypertensive rats has resulted in direct blood pressure reduction. 40 Consistent with these studies, our data showed that gene transfer of eNOS significantly decreased O 2 Ϫ levels in carotid arteries in DOCA-salt rats. Taken together, these experimental observations support the novel concept that NO generated by recombinant NOS, as a result of vascular gene transfer, provides an effective means of inactivating O 2 Ϫ and thereby improving vasomotor function.…”

Prolonged hypotensive effect of human tissue kallikrein gene delivery and recombinant enzyme administration in spontaneous hypertension rats

“…Recently, more attention has been paid to gene therapy for hypertension, which would produce a long-lasting effect without taking pills daily. The tested genes include those coding for atrial natriuretic peptide (Lin et al, 1997a), endothelial nitric oxide synthase (Lin et al, 1997b) and hKLK1 (Wang et al, 1995), among which hKLK1 gene has been proved to be more potential to achieve hypotensive effect. Here we present additional evidence that both hKLK1 gene delivery and rK1 administration can be used as alternative strategies for treating human hypertension.…”

Nitric Oxide Synthase Gene Therapy for Cardiovascular Disease

“…Hence, eNOS gene transfer may be an effective means in combating superoxide-induced vascular dysfunction and atherogenesis in hypertension. Moreover, a study in spontaneously hypertensive rats (SHR) has reported that a single injection of the naked eNOS plasmid DNA through the tail vein caused a significant reduction of blood pressure for 6 weeks, and a second injection maintained the effect up to 12 weeks (66). In this study, increased NO production was determined as increased urinary and serum nitrite /nitrate content as well as increased cGMP levels in the urine and aorta.…”