Mechanisms of Impaired Endothelial Function Associated with Insulin Resistance

Background: The insulin-resistant (IR) syndrome is causally related to hypertension and cardiovascular events; however, the underlying mechanism remains elusive. The current study was designed to determine (1) whether the IR syndrome causes vascular dysfunction and (2) whether insulin resistance alters the activity of the individual endothelium-derived relaxing factors.

Methods and Results: Insulin resistance was induced in Sprague-Dawley rats by a 4-week fructose-rich diet. Subsequently, mesenteric arteries (~250 μM) were removed from control and 1R rats, and intraluminal diameter was used to assess vascular response to pharmaco logical probes. Studies with sodium nitroprusside showed that vascular relaxation did not differ between IR and control groups. In contrast, maximal vascular relaxation to acetylcho line (10 ^-9 to 10^-4 mol/L) in phenylephrinc preconstricted arteries was decreased in the IR group (44 ± 4%) versus control (89 ± 5%) (P < .01). N-nitro-L-arginine (LNNA) pretreat ment further impaired acetylcholine-induced maximal relaxation in the IR group from 44 ± 4% to 12 ± 3%; P < .01. In control rats, maximal relaxation was only slightly impaired by the addition of LNNA (89 ± 5% to 68 ± 6%; P <.05). The addition of indomethacin to ace tylcholine did not affect maximal relaxation in either group. When potassium chloride (KCl) was used for preconstriction, relaxation to acetylcholine in the IR group was similar to that found with phenylephrine preconstriction (41 ± 4% v 44 ± 4%, respectively); how ever, KCl preconstriction significantly decreased acetylcholine-induced relaxation in con trol rats (89 ± 5% to 43 ± 5%; P > .01).

Conclusion: Insulin resistance impairs endothelium-dependent relaxation in small mesen teric arteries. It appears that insulin resistance transforms the primary relaxant factor from endothelial-derived hyperpolarizing factor to nitric oxide. These findings suggest that hyper tension and atherosclerosis associated with the IR syndrome are caused, at least in part, by endothelial dysfunction.