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 microg/min), L-NMMA (N(G)-monomethyl-L-arginine; 3 mg/kg of body weight), AngII (angiotensin II; 8 and 16 ng/min), the selective AT(2)R (AngII type 2 receptor) inhibitor PD123319 (10 and 20 microg/min) and AngII (16 ng/min)+PD123319 (20 microg/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 microg/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, AT(1)R (AngII type 1 receptor) and AT(2)R activity produce arterial stiffness changes in subjects with INSR. Evidence of increased AT(1)R- and AT(2)R-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.

The results suggest the functional expression of AT2 receptors in small vessels that determine the inflection of the digital volume pulse wave in patients with INSR, possibly as an indicator of early vascular damage.

Relatively little is known about the functional expression of cardiovascular angiotensin type 2 (AT 2 )-receptors in healthy young adult humans. We performed a randomised, placebo-controlled crossover study of the effects of intravenous administration of the selective AT 2 -receptor antagonist PD 123319 on haemodynamics and arterial stiffness in normal volunteers. Sixteen normal subjects aged 29.9 ± 13.8 years (range 18-30 years) received an intravenous infusion of PD 123319 (10 mcg/minute for 5 minutes) and placebo, separated by one week. Haemodynamics (cardiac index, stroke index and systemic vascular resistance) were measured non-invasively using a BioZ.com thoracic impedance detection system. Blood pressure was measured from an arm cuff using oscillometry. Stiffness index, a measure of arterial stiffness, was measured using a PulseTrace recorder. No significant changes in blood pressure (p=0.92), cardiac index (p=0.52), stroke index (p=0.61), systemic vascular resistance index (p=0.32) or stiffness index (p=0.57) was demonstrated following PD 123319 infusion, compared with placebo.

The negative inotropic effect of L-NMMA may be a result of an increase in coronary vascular resistance and a resultant decrease in myocardial perfusion. The reduction in CI may also result from a direct reduction of the normal positive inotropic effect of NO by L-NMMA which is closely correlated with its effects on SVRI.