Hypertension in mice lacking the gene for endothelial nitric oxide synthase

Abstract

Nitric oxide (NO), a potent vasodilator produced by endothelial cells, is thought to be the endothelium-dependent relaxing factor (EDRF) which mediates vascular relaxation in response to acetylcholine, bradykinin and substance P in many vascular beds. NO has been implicated in the regulation of blood pressure and regional blood flow, and also affects vascular smooth-muscle proliferation and inhibits platelet aggregation and leukocyte adhesion. Abnormalities in endothelial production of NO occur in atherosclerosis, diabetes and hypertension. Pharmacological blockade of NO production with arginine analogues such as L-nitroarginine (L-NA) or L-N-arginine methyl ester affects multiple isoforms of nitric oxide synthase (NOS), and so cannot distinguish their physiological roles. To study the role of endothelial NOS (eNOS) in vascular function, we disrupted the gene encoding eNOS in mice. Endothelium-derived relaxing factor activity, as assayed by acetylcholine-induced relaxation, is absent, and the eNOS mutant mice are hypertensive. Thus eNOS mediates basal vasodilation. Responses to NOS blockade in the mutant mice suggest that non-endothelial isoforms of NOS may be involved in maintaining blood pressure.

Endothelial dysfunction and hypertension in aging

“…11,[31][32][33][34][35] ASSESSMENT OF ENDOTHELIAL FUNCTION In experimental studies, methods for assessment of endothelial function have been established by using a ring experiment protocol, endothelial functional alteration in expression of transcriptional factors and genes and genetic ablation of endothelial NO synthase (eNOS) in animal models. 36,37 It is clinically important to estimate the degree of endothelial dysfunction. Several methods have been used to assess endothelial function in humans.…”

“…36 Systolic blood pressure was elevated by approximately 30 mm Hg in eNOS knockout mice compared with that in wild-type mice. 37 In hypertensive patients also, endothelium-dependent vascular relaxation in coronary, forearm and renal arteries was found to be impaired, and endothelial dysfunction, which is involved in the development of atherosclerosis, was found to increase the risk of cardiovascular and cerebrovascular diseases. [9][10][11][12][13][14][15]27,35 As Panza et al 9 reported for the first time in 1990 that the dose-response curve obtained by acetylcholine in patients with hypertension was smaller than the curve in normal controls and that the dose-response curves obtained by sodium nitropreside were similar in the two groups, suggesting that endothelial function, but not smooth muscle function, is selectively impaired in patients with hypertension, a large number of studies have shown that hypertension is associated with endothelial dysfunction.…”

Endothelial nitric oxide synthase genetic variation and essential hypertension risk in Han Chinese: the Fangshan study

“…Knockout mice deficient in eNOS had hypertension as adults. 2 In contrast, induction of eNOS cDNA in mice reduced BP. 3 As the genomic sequence of eNOS is highly polymorphic, it is of added interest to these findings to confirm which variant(s) at eNOS might have a functional potential to affect the final bioavailability of eNOS, and thus the development of hypertension.…”

“…Evidence is mounting suggesting that enhanced production or bioavailability of the enzyme eNOS that synthesizes NO in endothelial cells may lead to the constitutive release of NO, which exerts vasoprotective effects in blood pressure (BP) regulation. 1,2 The eNOS spans 21 kb with 26 exons on chromosome 7q35-36. The candidacy for eNOS in the development of hypertension has a strong biological basis.…”

Influence of fat intake and BMI on the association of rs1799983 NOS3 polymorphism with blood pressure levels in an Iberian population

“…inhibiting vascular smooth muscle contraction) [5]. Indeed, it has been observed in an animal model that the disruption of NOS3 gene led to hypertension, while in humans the inhibition of NOS3 elevated BP [5,6].…”