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AT1-RECEPTOR BLOCKADE AND INSULIN SENSITIVITY IN HYPERTENSIVE SUBJECTS: THE ROLE OF CAPILLARY RECRUITMENT: PP.11.435

Objective: Blocking the renin-angiotensin system (RAS) improves insulin sensitivity in hypertensive subjects. However, the underlying mechanisms are undefined. An effect of insulin that is crucial for stimulating glucose uptake is the ability of insulin to regulate its own delivery, and that of glucose, to muscle cells via recruitment of the microvasculature. This study was designed to investigate the effect of acute angiotensin II AT1 receptor blockade (ARB) on insulin-mediated microvascular function and insulin-mediated glucose uptake in hypertensive subjects. Design and Methods: A randomised, double-blind placebo-controlled trial was performed in 15 untreated mildly hypertensive subjects (age 53 ± 5 yrs; BMI 26.9 ± 2 kg/m2); BP 150/92 mmHg), to examine the effects of acute ARB treatment (irbesartan, 600 mg, oral single dose) or Ca2+-blockade (felodipine, 10 mg idem) as a pressor control on insulin-induced microvascular function and on insulin-mediated whole body glucose uptake (WBGU, mg/kg/min) during a hyperinsulinaemic euglycaemic clamp (50mU/kg/h). Effects of irbesartan and felodipine were compared to placebo. Skin capillary density (n/mm2) and capillary recruitment (peak n/mm2 during postocclusive reactive hyperaemia, PRH) were measured with capillaroscopy. All subjects were tested on a low sodium diet (100 mmol/day). Results: Compared to the basal state, hyperinsulinaemia increased baseline capillary density (56.8 ± 7.1 vs. 60.2 ± 8.3 n/mm2, P < 0.02). Relative to placebo, irbesartan, but not felodipine, increased insulin-induced capillary density (Ä cap density (median (interquartile range) +3.5 (−1.3 - +5.0) n/mm2, P < 0.02). Insulin-induced capillary recruitment was not altered by either treatment. Neither irbesartan nor felodipine enhanced WBGU. Conclusion: Our data demonstrate that acute AT1-blockade augments insulin-induced capillary density in mildly hypertensive subjects. Although glucose uptake did not increase significantly, the increased insulin-induced microvascular function found with ARB might point to improved insulin and glucose delivery as the underlying mechanism for the improved insulin sensitivity with longterm ARB treatment.