Does compensatory nitric oxide and angiotensin II receptor activity reduce arterial stiffness in early-stage insulin resistance?

Abstract

Increased arterial stiffness is influenced by both functional and structural properties of the vessel wall, including changes in content of smooth muscle, elastin and collagen, reduced endothelial production of NO and increased release of endothelin-1 or AngII (angiotensin II). The RAS (renin-angiotensin) system is likely to be central to increases in arterial stiffness, since the changes in arterial structure observed with enhanced AngII activity are similar to the same pathophysiological changes that contribute to arterial stiffness. The role of AT(1)R and AT(2)R (AngII type 1 and type 2 receptors respectively) in the development of arterial stiffening, particularly in the early stages of insulin resistance, is however unclear. In this issue of Clinical Science, Brillante and co-workers have observed that in insulin-resistant subjects exhibiting reduced arterial stiffness, wave reflection from small-to-medium-sized, but not large, arteries was increased following separate intravenous infusions of AngII, the selective AT(2)R inhibitor PD123319 and the NO inhibitor L-NMMA (N(G)-monomethyl-L-arginine) in comparison with normal healthy age- and sex-matched controls. These increases probably reflect increased AT(1)R and AT(2)R expression/activity in addition to up-regulation of basal NO release in the small-to-medium-sized arteries. These changes may be compensatory mechanisms related to early vascular damage and may have clinical implications for treatment in hypertensive patients with evidence of the metabolic syndrome.

The central arterial burden of the metabolic syndrome is similar in men and women: the SardiNIA Study

“…16,17 Several mechanisms may explain the 'accelerated ageing' of the aortic wall compared with the carotid wall in patients with MetS. MetS is characterized by activation of the renin-angiotensin system, 18 an important humoral factor involved in regulating the turnover of extracellular matrix proteins and a strong regulator of matrix metalloproteinase and tissue inhibitor of metalloproteinases, 19 as well as of cytokines released by adipose tissue. 20 Glycation of matrix proteins also exerts an adverse effect on the structure and function of large arteries.…”

Association between the triglyceride-glucose index and arterial stiffness: A meta-analysis

“…Angiotensin II type 1 receptor also binds directly to endothelial NO synthase and inhibits its activity, leading to a decrease in NO production. [45,46] At the same time, increased aldosterone levels activate endothelial mineralocorticoid receptors and ultimately lead to increased sodium channel activity, which can lead to several adverse consequences, including remodeling of the cortical actin skeleton, increased vascular permeability, and inflammation. [47] In vitro animal studies have shown that enhanced endothelial cell mineralocorticoid activity is associated with vascular fibrosis and stiffness.…”

Arterial stiffness in insulin resistance: The role of nitric oxide and angiotensin II receptors

“…In summary, the combined vasodilator effects of increased basal NO levels and increased AT2R expression in INSR subjects are likely to be signifi cant contributors to the observed increased arterial compliance in the early stages of INSR states, and may represent an early response to vascular damage, 58 some of which is induced by increased AT1R expression. AT1R blockade may therefore be a useful treatment for INSR states, with its triple effect of blocking harmful AT1R-mediated vascular effects, increased AT2R expression, 59 and increased AII formation with unopposed AT2R activation.…”