Endothelium-derived relaxant factor inhibits platelet activation.
Experiments were designed to investigate whether platelet activation is modulated by endothelium-derived relaxant factor (EDRF) which has been shown to induce vascular smooth muscle relaxation by direct stimulation of soluble guanylate cyclase. EDRF was released from cultured bovine endothelial cells, grown on microcarrier beads, by stimulation with thimerosal in the presence of indomethacin. EDRF had no effect on the intracellular free calcium concentration (Cai2+, measured with the fluorescent indicator indo-1) of resting washed human platelets but significantly attenuated the thrombin-induced rise of Cai2+ from 896 +/- 99 (SEM) to 509 +/- 48 nmol/l. EDRF significantly increased platelet cyclic GMP levels from 0.25 +/- 0.04 to 2.5 +/- 0.4 pmol/10(8) platelets and reduced the thrombin-induced aggregation to 23 +/- 3% of control. EDRF had no effect on Cai2+, cyclic GMP or aggregation after a 3 min storage interval, but superoxide dismutase (shown to increase stability of the labile factor) significantly augmented the EDRF effects on Cai2+. The antiaggregatory potency of EDRF was completely abolished in the presence of hemoglobin. The results characterize EDRF as a potent cyclic GMP-dependent antiaggregatory factor which may act synergistically in vivo with the cyclic AMP-dependent inhibitory effect of prostacyclin.
Busse
R
R
Department of Applied Physiology, University of Freiburg, Federal Republic of Germany.
Lückhoff
A
A
Bassenge
E
E
D000818:Animals; D001013:Aorta, Thoracic; D001688:Biological Products / Q000302:isolation & purification / Q000494:pharmacology*; D001792:Blood Platelets / Q000378:metabolism; D002118:Calcium / Q000097:blood; D002417:Cattle; D002478:Cells, Cultured; D006152:Cyclic GMP / Q000097:blood; D004730:Endothelium, Vascular / Q000378:metabolism; D011464:Epoprostenol / Q000378:metabolism; D009569:Nitric Oxide; D009599:Nitroprusside / Q000494:pharmacology; D010974:Platelet Aggregation / Q000187:drug effects*; D013917:Thrombin / Q000494:pharmacology
D001688:Biological Products; D009599:Nitroprusside; D009569:Nitric Oxide; D011464:Epoprostenol; D013917:Thrombin; D006152:Cyclic GMP; D002118:Calcium