The effect of elevated homocysteine levels on adrenergic vasoconstriction of human resistance arteries: The role of the endothelium and reactive oxygen species

Purpose: This study investigated the effect of elevated homocysteine levels on adrenergic contraction of human resistance arteries and tested the hypo thesis that homocysteine-induced generation of reactive oxygen species cont ributes to vascular reactivity changes. Methods: Small (<200 mu m) subcutaneous arteries were cannulated and pressu rized in an arteriograph chamber that allowed the measurement of lumen diam eter. Two arteries from the same patient were obtained; one was perfused an d superfused (intraluminal pressure = 50 mm Hg) with physiologic saline sol ution (control, n = 6), and the other was perfused and superfused with phys iologic saline solution plus 200 mu mol/L homocysteine (HC, n = 6); the rea ctivity to adrenergic stimulation was assessed. Another group of arteries w as incubated in 200 mu mol/L homocpsteine plus 1200 U/mL, superoxide dismut ase and 120 U/mL catalase (HC + SC, n = 6), and the reactivity to norepinep hrine was determined. The vasoreactivity of homocysteine was further assess ed in intact (n = 6) and denuded (n = 6) arteries that mere precontracted w ith an intermediate concentration of norepinephrine and homocysteine (20-20 0 mu mol/L) added to the bath while the lumen diameter was continuously rec orded. Results: Sensitivity to norepinephrine was diminished in HC arteries, which increased the median effective concentration (EC50) from 0.24 +/- 0.06 mu mol/L in control arteries to 0.65 +/- 0.10 mu mol/L in HC arteries (P < .01 ). Homocysteine also caused concentration-dependent vasodilation of arterie s contracted with an intermediate concentration of norepinephrine that was greater in intact than denuded arteries, with the half-maximum responses oc curring at 61 +/- 6 mu mol/L (intact) and 90 +/- 11 mu mol/L (denuded; P < .05). There was no significant difference in sodium nitroprusside sensitivi ty between control and homocysteine arteries (EC50 = 61 +/- 3 nmol/L vs 50 +/- 19 nmol/L; P > .05) or in sensitivity to acetylcholine (EC50 = 19 +/- 7 nmol/L vs 12 +/- 3 mnol/L; P > .05). Arteries in the presence of superoxid e dismutase and catalase had similarly impaired reactivity to norepinephrin e as did homocysteine arteries (EC50, 0.58 +/- 0.15 mu mol/L; P > .05 vs HC , P < .01 vs control). Conclusion: An elevated homocysteine level in vitro diminishes adrenergic c ontraction, with a differential endothelial versus smooth muscle influence that appears unrelated to the generation of reactive oxygen species.