RESPONSES TO ENDOTHELIUM-DEPENDENT AGONISTS IN SUBCUTANEOUS ARTERIES EXCISED FROM HYPERCHOLESTEROLEMIC MEN

1 Vasomotor function of the vascular endothelium was examined in human subcutaneous arteries excised from 8 hypercholesterolaemic and 7 norm olipidaemic subjects. 2 Left gluteal skin biopsies were performed unde r local anaesthesia. Subcutaneous arteries were isolated and two vesse ls from each subject mounted in separate myographs. A 20 ml fasting bl ood sample was taken at the time of the biopsy. 3 Hypercholesterolaemi c subjects had either never been treated with lipid lowering therapy o r therapy had been stopped at least two weeks before the study (n = 2) . At the time of the study total plasma cholesterol levels (control: 4 .6 +/- 0.3 vs hypercholesterolaemic: 8.3+/-0.6 mmol l(-1): P < 0.01) w ere significantly elevated in hypercholesterolaemic subjects when comp ared with controls. 4 Full concentration-response curves to the vasoco nstrictor noradrenaline and the vasodilators acetylcholine and substan ce P were constructed. A single point concentration-response to sodium nitroprusside (10 mu M) was also obtained. Dilator responses were obt ained in vessels pre-constricted with a submaximal concentration of no radrenaline. Vessels were then incubated for 30 min with either L-or D -arginine (10 mu M) and the concentration-response curves to the three dilator agonists repeated in the presence of the amino acid. 5 Maximu m relaxation responses to acetylcholine (control vs hypercholesterolae mic: 83.3 +/- 6.1% vs 47.4 +/- 13.5%; P < 0.05), but not to substance P or sodium nitroprusside, were dampened in the hypercholesterolaemic group when compared with controls. 6 Neither incubation with L-arginin e nor D-arginine had any effect on maximum relaxation responses to ace tylcholine in either the control group (pre L-arginine vs plus L-argin ine: 83.3 +/- 6.1 vs 82.3 +/- 5.5%, pre D-arginine vs plus D-arginine: 98.9 +/- 1.2 vs 98.2 +/- 1.1%) or the hypercholesterolaemic group (pr e L-arginine vs plus L-arginine: 47.4 +/- 13.5 vs 55.3 +/- 14.3%, pre D-arginine vs plus D-argenine: 43.3 +/- 13.6 vs 65.4 +/- 12.3%). 7 Whe n results from the two study groups were pooled, the strongest predict or of maximum relaxation obtained to acetylcholine was apolipoprotein A(1) (r = 0.67; P = 0.001). 8 In conclusion, relaxation responses medi ated by the endothelium-dependent agonist acetylcholine, but not by su bstance P, are impaired in hypercholesterolaemic patients. L-Arginine did not improve the impaired relaxation responses to acetylcholine. We suggest that impaired endothelium-dependent relaxation is specific to acetylcholine and not to an abnormal L-arginine-nitric oxide pathway in subcutaneous arteries excised from this study group.