INSR (insulin-resistance syndrome) affects 25% of the Australian population and is associated with increased cardiovascular risk. In the present study, we postulated that early cardiovascular changes in these individuals may be associated with an activated RAS (renin–angiotensin system). We studied 26 subjects: 13 with INSR [waist circumference, 99±6 cm; HOMA (homoeostasis model assessment) score, 2.5±0.3] and 13 NCs (normals controls; waist circumference, 77±2 cm; HOMA score, 1.4±0.2). All received intravenous GTN (glyceryl trinitrate; 10, 20 and 40 μg/min), L-NMMA (NG-monomethyl-L-arginine; 3 mg/kg of body weight), AngII (angiotensin II; 8 and 16 ng/min), the selective AT2R (AngII type 2 receptor) inhibitor PD123319 (10 and 20 μg/min) and AngII (16 ng/min)+PD123319 (20 μg/min). At the end of each infusion, arterial stiffness indices [SI (stiffness index) and RI (reflection index)] and haemodynamic parameters were measured. There was a significantly higher RI response to AngII (P=0.0004 for both 8 and 16 ng/min doses) and to PD123319 (P=0.004 and P=0.03 for 10 and 20 μg/min doses respectively) in subjects with INSR compared with NCs. Co-infusion of AngII and PD123319 did not lead to additive changes in RI. RI responses to L-NMMA and GTN were not significantly different in both groups. No significant differences in SI and haemodynamic responses were detected. In conclusion, AT1R (AngII type 1 receptor) and AT2R activity produce arterial stiffness changes in subjects with INSR. Evidence of increased AT1R- and AT2R-mediated responses in small-to-medium-sized arteries in INSR was found, and may play an early role in the pathogenesis of vascular changes in INSR before haemodynamic changes become apparent.

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