Arterial stiffness and haemodynamic response to vasoactive medication in subjects with insulin-resistance syndrome

Abstract

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.

Arterial stiffness in diabetes mellitus

“…Studies in patients with impaired glucose regulation as well as type 2 DM have both shown reduced vasodilation in response to acetylcholine administration, the gold standard for diagnosing endothelial dysfunction [85,86]. In diabetic subjects with microvascular disease compared to those without, basal NO levels were reduced, and NO levels further decreased with increasing severity of microvascular disease [84]. Thus, while initial increase in NO levels may be compensatory with early insulin resistance, there is baseline abnormal response to vasodilation agents, and ultimately NO dysregulation may lead to arterial stiffness and herald the onset of microvascular changes [87].…”

“…The combination of both of these factors ultimately leads to reduction in NO bioavailability [82,83] Interestingly, there is emerging evidence that prior to eventual depletion of NO, early insulin resistance may in fact be associated with increased NO levels and low to normal arterial stiffness. Compared to controls, normotensive patients with early insulin resistance showed reduced baseline arterial stiffness indices, yet infusion of an NO synthase inhibitor resulted in greater increase arterial stiffness [84]. Studies in patients with impaired glucose regulation as well as type 2 DM have both shown reduced vasodilation in response to acetylcholine administration, the gold standard for diagnosing endothelial dysfunction [85,86].…”

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

“…46 Increased vascular sensitivity to AII-induced vasoconstriction has previously been reported in patients with type 2 diabetes mellitus, 56 suggesting upregulation of AT1R activity in these individuals. In support of this, in a previously described comparative study of subjects with early INSR and age and sex-matched NCs, 28 infusion of AII (8, 16 ng/min for 3 minutes) produced a signifi cantly greater increase in RI in INSR subjects. The increase in RI could not be attributed to reduced basal NO levels because, as previously discussed, we have, in fact, demonstrated increased basal NO activity in these subjects.…”

“…27 Recently, we observed that normotensive patients with the early INSR syndrome (using the International Diabetes Federation criteria) had significantly reduced baseline arterial stiffness indices (large arterial stiffness index: SI, and refl ection index: RI, a measure of small to medium-sized arterial stiffness) using digital photo plethysmography compared with age and sex-matched normal controls (NCs). 28 Intravenous infusion of L-NMMA (3 mg/kg) in both groups produced a signifi cantly greater increase in small to medium artery stiffness (signifi cantly increased % change in RI) in INSR subjects compared with the NCs. We concluded that increased basal NO production may contribute to the reduced baseline arterial stiffness indices observed in INSR subjects, and may be a compensatory mechanism to early vascular change in these individuals.…”

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

“…In this issue of Clinical Science, Brillante et al [10] report a cross-sectional comparison study of subjects without and with insulin resistance in which they examined small-to-medium and large arterial stiffness as well as AT 1 R, AT 2 R and basal NO activity. Compared with normal control subjects, insulin-resistant subjects had slightly lower small-to-medium and large arterial stiffness, as assessed by RI and SI respectively.…”