The present study examined the endothelium-dependent and -independent responses of isolated mesenteric arteries to acetylcholine and the endothelium-independent vasodilator sodium nitroprusside in mesenteric arteries from fructose-induced hypertensive rats. Fructose feeding resulted in hyperinsulinemia and elevated blood pressure when compared to controls (plasma insulin, 5.9 +/- 0.4 v control 3.6 +/- 0.4 ng/mL, P < .05; systolic blood pressure, 154 +/- 5 v control 127 +/- 7 mm Hg, P < .05). The maximum contractile response of mesenteric arteries to norepinephrine did not differ between the control and fructose groups, either with or without the endothelium. In arteries with intact endothelia, precontracted with the approximate ED50 of norepinephrine, the percent maximum relaxation produced by acetylcholine in hypertensive rats was lower than the control arteries (62 +/- 7 v control 95 +/- 5, P < .05) without any change in sensitivity. In arteries precontracted with norepinephrine, the endothelium-independent vasodilator sodium nitroprusside produced a dose-dependent relaxation in arteries obtained from control and fructose groups, both with and without the endothelium. The maximum relaxation produced by sodium nitroprusside did not differ between control and fructose arteries, either with or without the endothelium; however, removal of the endothelium caused an increase in sensitivity of this agonist. These data suggest that in the insulin resistant and hyperinsulinemic fructose-hypertensive rats, there is a defective endothelium-dependent yet preserved endothelium-independent relaxation.

Abstract-The endothelial actions of insulin remain an area of intense research because they relate to both insulin sensitivity and vascular tone. Physiological doses of insulin evoke endothelium-dependent vasorelaxation in humans; however, this remains a pharmacological phenomenon in rat aortas. Because insulin may stimulate the divergent production of both nitric oxide and endothelin-1, we hypothesized that the lack of insulin-induced vasorelaxation at low/subthreshold concentrations may be due to the concurrent production of endothelin-1, which in turn serves to inhibit nitric oxide-dependent, insulin-mediated dilation. To investigate this, we studied the effects of subthreshold concentrations of insulin (100 mU/L) on norepinephrine-induced contraction in rat aortas following short-term and long-term endothelin blockade. In addition, the effects of tetrahydrobiopterin inhibition (with diaminohydroxyprimidine) on norepinephrine-induced contraction in the presence of insulin and endothelin receptor blockade were investigated. Subthreshold concentrations of insulin failed to evoke vasorelaxation in rat aortas. Strikingly, short-term endothelin A/B receptor blockade with bosentan (10 Ϫ2 mmol/L) uncovered insulin-mediated dilation; the percent maximum contraction and sensitivity of aortas to norepinephrine were attenuated (% maximum relaxation: bosentanϩinsulin 74Ϯ4%* versus bosentan 92Ϯ3%, insulin 107Ϯ5% PϽ0.002; pD 2 values: bosentanϩinsulin 6.87Ϯ0.14* versus bosentan 7.40Ϯ0.15, insulin 7.63Ϯ0.11, *PϽ0.002). This effect was mediated through endothelin A receptors because bosentan and BQ-123 (10 Ϫ2 mmol/L) attenuated norepinephrine-induced contraction to a similar degree. In addition, insulin evoked vasorelaxation in aortas isolated from rats after long-term bosentan treatment (100 mg ⅐ kg Ϫ1 ⅐ d Ϫ1 , 3 weeks). The component of insulin-mediated vasorelaxation uncovered by endothelin receptor blockade was tetrahydrobiopterindependent because it was reversed by diaminohydroxyprimidine. These data demonstrate, for the first time, the functional interaction between insulin, endothelin-1, and tetrahydrobiopterin in modulating vascular tone in rat aortas in vitro and in vivo. Key Words: insulin Ⅲ endothelin Ⅲ vasodilation Ⅲ insulin resistance Ⅲ hypertension Ⅲ rat aorta Ⅲ tetrahydrobiopterin Ⅲ bosentan T he vascular actions of insulin represent an area of much current interest as they relate to both whole-body glucose metabolism/insulin sensitivity and vascular tone/hypertension. 1,2 The balance of published information suggests that the vascular actions of insulin are mediated chiefly through the regulation of endothelium-derived factors. 2 In this regard, insulin can stimulate the production of tetrahydrobiopterin (BH 4 )-dependent nitric oxide (NO) formation while concurrently augmenting the production of the potent endotheliumderived vasoconstrictor endothelin-1 (ET-1) (Figure 1). 3,4 Although insulin-induced vasorelaxation occurs at physiological concentrations in humans, this effect appears to be mainly a pharmacol...