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 to the decreased vessel tone observed in primary varicosis. 2. We determined the intracellular accumulation of guanosine 3':5'-cyclic monophosphate cyclic GMP; a measure of nitric oxide production and the release of endothelin and prostacyclin (measured as its stable metabolite 6-keto-prostaglandin F1alpha) from cultured cells derived from the long saphenous veins of patients with primary varicosis (Varicose saphena group, n = 27) or from patients undergoing coronary artery bypass surgery (Healthy saphena group, n = 22). In addition, levels of endothelin, angiotensin II, bradykinin, cyclic GMP and cyclic AMP in plasma from patients with primary varicosis and healthy volunteers (n = 8-11 in each group) were determined. 3. Although basal cyclic GMP levels were similar, more cyclic GMP accumulated in response to histamine (1-100 micromol 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 well). Furthermore, the relaxant potency of nitroprusside (1 nmol l(-1) - 300 micromol l[-1]) in vitro was higher for varicose veins (mean EC50 = 5.9 micromol l(-1); n = 8) than healthy veins (mean EC50 = 20.0 micromol l(-1); n = 7). 4. The production of prostacyclin was significantly less in cells from varicose than healthy saphenous veins (66 +/- 8.7 and 121 +/- 20.1 nmol g(-1) protein), but the production of endothelin was similar in both groups. Prostacyclin (3 nmol l(-1) 30 micromol l[-1]) consistently contracted rings of varicose saphenous vein in vitro with a mean EC50 value of 10-20 micromol l(-1) (n = 7); the maximum tension generated was approximately 50% of that of a completely depolarizing solution of K+ (120 mmol l[-1]). 5. In plasma from patients with varicose veins, levels of cyclic GMP were higher than in healthy controls (9.2 +/- 0.03 and 7.2 +/- 0.02 nmol l[-1]), levels of angiotensin II were lower (81 +/- 11.5 and 147 +/- 21.7 pmol l[-1]), and levels of endothelin, cyclic AMP, and bradykinin were not different. 6. It is concluded that endothelial cells from diseased saphenous veins secrete less constrictor mediators than cells from healthy veins and that in diseased veins the nitric oxide/cyclic GMP system is up-regulated which may shift the balance of vasoactive factors towards vasodilatation and contribute to the development of primary varicosis.