Recently we have reported that insulin attenuates norepinephrine (NE)-
induced vasoconstriction via a cyclic GMP-NO synthase pathway. Because
hypercholesterolemia has been associated with abnormal endothelial fu
nction, we investigated whether insulin-mediated vasodilation is impai
red in hypercholesterolemia. To assess vasoreactivity, NE (12.5, 25, 5
0, and 100 ng/min), NE (100 ng/min) combined with insulin (8, 16, 24,
and 32 mu U/min), and NE (100 ng/min) combined with sodium nitroprussi
de (0.01, 0.1, 1, 10, and 100 ng/min) were infused into dorsal hand ve
ins. Changes in venous diameter were measured by ultrasonography, usin
g a 7.5-MHz transducer. Twenty-two healthy, normotensive hypercholeste
rolemic subjects (HC; mean total cholesterol 6.93 mmol/L, HDL 1.45 mmo
l/L, LDL 4.81 mmol/L) and 18 age-matched normal control subjects (NC;
mean total cholesterol 4.81 mmol/L, HDL 1.16 mmol/L, LDL 3.18 mmol/L)
were studied. All HC had normal glucose tolerance test results. Baseli
ne vein diameters were similar between groups, and the vasoconstrictor
response to NE was not significantly different between HC and NC. Ins
ulin significantly attenuated NE-induced vasoconstriction in NC but no
t in HC (P<0.01). Both groups were able to venodilate with sodium nitr
oprusside. To investigate the effects of cholesterol reduction on vasc
ular reactivity, venoreactivity studies were repeated in 12 HC after t
reatment with 20 to 40 mg/d lovastatin for 6 weeks. There were no sign
ificant venoreactivity changes with the treatment. Plasma LDL choleste
rol concentration was inversely correlated to venodilator effect of in
sulin (r=-0.42, P<0.02). In conclusion, insulin-mediated vasodilation
is impaired in patients with high cholesterol. Absence of normal insul
in-mediated but not sodium nitroprusside-induced venodilation in hyper
cholesterolemia suggests that insulin-mediated vasodilation is endothe
lium dependent.