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 ( approximately 250 µM) were removed from control and IR rats, and intraluminal diameter was used to assess vascular response to pharmacological probes. Studies with sodium nitroprusside showed that vascular relaxation did not differ between IR and control groups. In contrast, maximal vascular relaxation to acetylcholine (10(-9) to 10(-4) mol/L) in phenylephrine preconstricted arteries was decreased in the IR group (44 +/- 4%) versus control (89 +/- 5%) (P <.01). N-nitro-L-arginine (LNNA) pretreatment 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 acetylcholine did not affect maximal relaxation in either group. When potassium chloride (KCl) was used fro preconstriction, relaxation to acetylcholine in the IR group was similar to that found with phenylephrine preconstriction (41 +/- 4% v 44 +/- 4%, respectively); however, KCl preconstriction significantly decreased acetyolcholine-induced relaxation in control rats (89 +/- 5% to 43 +/- 5%; P >.01). CONCLUSION: Insulin resistance impairs endothelium-dependent relaxation in small mesenteric arteries. It appears that insulin resistance transforms the primary relaxant factor from endothelial-derived hyperpolarizing factor to nitric oxide. These findings suggest that hypertension and atherosclerosis associated with the IR syndrome are caused, at least in part, by endothelial dysfunction.
Miller
AW
University of Georgia Colleges of Pharmacy, Augusta VA Medical Center, Augusta, Georgia, USA
Hoenig
ME
Ujhelyi
MR