Insulin stimulates both endothelin and nitric oxide activity in the human forearm

Background-The mechanism of the hemodynamic effect of insulin in the skelet al muscle circulation has not been fully elucidated. The purpose of this st udy was to assess whether the hemodynamic response to insulin involves the concurrent release of endothelin (ET-1) and nitric oxide (NO), 2 substances with opposing vasoactive properties, Methods and Results-Bioactivity of ET-1 and NO was assessed without insulin and during insulin infusion in the forearm circulation of healthy subjects by use of blockers of ET-I receptors and by NO synthesis inhibition, In th e absence of hyperinsulinemia, ET-1 receptor blockade did not result in any significant change in forearm blood flow from baseline (P=0.29). Intra-art erial insulin administration did not significantly modify forearm blood flo w (P=0.88). However, in the presence of hyperinsulinemia, ET-1 receptor ant agonism was associated with a significant vasodilator response (P<0.001). I n the presence of ET-1 receptor blockade, the vasoconstrictor response to N O inhibition by N-G-monomethyl-L-arginine was significantly higher after in sulin infusion than in the absence of hyperinsulinemia (P=0.006). Conclusions-These findings suggest that in the skeletal muscle circulation, insulin stimulates both ET-I and NO activity. An imbalance between the rel ease of these 2 substances may be involved in the pathophysiology of hypert ension and atherosclerosis in insulin-resistant states associated with endo thelial dysfunction.