l-Arginine Reverses the Impairment of Nitric Oxide-Dependent Collateral Perfusion in Dietary-Induced Hypercholesterolaemia in the Rabbit

Abstract

1. We have used an isolated, buffer-perfused, rabbit ear model of acute arterial occlusion to investigate the effects of exogenous l-arginine on the severe impairment of collateral perfusion associated with dietary-induced hypercholesterolaemia. The effects of l-arginine on hypercholesterolaemia-related impairment of endothelium-dependent relaxations to acetylcholine were also investigated in unligated, isolated rabbit ears perfused with buffer. 2. Cholesterol feeding for 8 weeks (blood cholesterol level 66.5 ± 5.3 versus 1.4 ± 0.2 mmol/l, P < 0.001) was associated with almost complete impairment of collateral perfusion, an effect previously observed after inhibition of nitric oxide synthesis. The impairment of collateral perfusion found in hypercholesterolaemia was completely reversed by the addition of 10 mmol/l l-arginine to the perfusion fluid. In control preparations from rabbits fed a normal diet, the addition of 10 mmol/l l-arginine did not influence collateral perfusion. 3. Endothelium-dependent relaxation to acetylcholine was impaired in preparations from the rabbits fed the high cholesterol diet for 8 weeks: the maximum relaxation of tone was 24.6 ± 0.8% and was significantly (P < 0.01) less than that in the controls (70.3 ± 2.4%). Addition of l-arginine to the perfusion fluid caused a modest improvement in the endothelium-dependent relaxations to acetylcholine, with a maximum response of 43.2 ± 1.3%. 4. We conclude that nitric oxide-dependent collateral perfusion is severely impaired in hypercholesterolaemia and that the addition of exogenous l-arginine fully reverses these changes. Endothelium-dependent relaxations to acetylcholine are similarly impaired by hypercholesterolaemia; however, this deficit was only partially reversed by l-arginine. In the context of collateral perfusion, l-arginine treatment may represent a therapeutic strategy to limit the deleterious effects of hypercholesterolaemia on acute arterial occlusion.