IMBALANCE BETWEEN THE ENDOTHELIAL CELL-DERIVED CONTRACTING FACTORS PROSTACYCLIN AND ANGIOTENSIN-II AND NITRIC-OXIDE CYCLIC-GMP IN HUMAN PRIMARY VARICOSIS

1 The role of the endothelium in the vasomotor control of human veins in the lower extremity is little understood. We tested the hypothesis that the production of relaxing and contracting factors is altered in endothelial cells from varicose saphenous veins which may predispose t o the decreased vessel lone observed in primary varicosis. 2 We determ ined the intracellular accumulation of guanosine 3':5'-cyclic monophos phate cyclic GMP; a measure of nitric oxide production) and the releas e of endothelin and prostacyclin (measured as its stable metabolite 6- keto-prostaglandin F-1 alpha) from cultured cells derived from the lon g saphenous veins of patients with primary varicosis (Varicose saphena group, n=27) or from patients undergoing coronary artery bypass surge ry (Healthy saphena group, n=22). In addition, levels of endothelin, a ngiotensin II, bradykinin, cyclic GMP and cyclic AMP in plasma from pa tients with primary varicosis and healthy volunteers (n=8-11 in each g roup) were determined. 3 Although basal cyclic GMP levels were similar , more cyclic GMP accumulated in response to histamine (1-100 mu mol l (-1)) in cells from varicose saphenous veins (0.75+/-0.1 pmol per well ) than in cells from veins without varicosis (0.27+/-0.05 pmol per wel l). Furthermore, the relaxant potency of nitroprusside (1 nmol l(-1)-3 00 mu mol l(-1)) in vitro was higher for varicose veins (mean EC50=5.9 mu mol l(-1); n=8) than healthy veins (mean EC50=20.0 mu mol l(-1); n =7). 4 The production of prostacyclin was significantly less in cells from varicose than healthy saphenous veins (66+/-8.7 and 12.1+/-20.1 n mol g(-1) protein), but the production of endothelin was similar in bo th groups. Prostacyclin (3 nmol l(-1)-30 mu mol l(-1)) consistently co ntracted rings of varicose saphenous vein in vitro with a mean EC50 va lue of 10-20 mu mol l(-1) (n=7); the maximum tension generated was sim ilar to 50% of that of a completely depolarizing solution of K+ (120 m mol l(-1)). 5 In plasma from patients with varicose veins, levels of c yclic GMP were higher than in healthy controls (9.2+/-0.03 and 7.2+/-0 .02 nmol l(-1)), levels of angiotensin IT were lower (81+/-11.5 and 14 7+/-21.7 pmol l(-1)), and levels of endothelin, cyclic AMP, and bradyk inin were not different. 6 It is concluded that endothelial cells from diseased saphenous veins secrete less constrictor mediators than cell s from healthy veins and that in diseased veins the nitric oxide/cycli c GMP system is upregulated which may shift the balance of vasoactive factors towards vasodilatation and contribute to the development of pr imary varicosis.