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 AT1R and AT2R (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 AT2R inhibitor PD123319 and the NO inhibitor L-NMMA (NG-monomethyl-L-arginine) in comparison with normal healthy age- and sex-matched controls. These increases probably reflect increased AT1R and AT2R 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.

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