Effect of endothelin-1 on human platelet shape change: reversal of activation by naftidrofuryl

Naftidrofuryl (Praxilene; NAF) significantly improves claudication distance in patients with peripheral vascular disease (PVD). Endothelin-1 (ET-1) is a powerful endogenous vasoconstrictor and the circulating levels of ET-1 a re elevated in patients with vascular disease. Platelet rich plasma (PRP) w as prepared from healthy volunteers. NAF at concentrations similar to thera peutic levels (3.5-14 mu mol/l), inhibited (P < 0.02) platelet activation ( as indicated by a fall in median platelet volume, MPV) induced by ET-1 (0.4 mmol/l) alone. NAF also inhibited (P <0.0001) shape change (PSC; an early phase of platelet activation, characterised by an increase in MPV) induced by ET-1 (0.4 mu mol/l) in combination with ADP (0.05-0.15 mu mol/l) or sero tonin (0.03-0.13 mu mol/ l). We assessed the effect of ETA (BQ123, 50 nmol/ l) or ETB (BQ788, 50 nmol/l) receptor antagonists on PSC induced by ET-1 a lone. Both antagonists significantly inhibited PSC. We conclude that ET-1 a ctivates human platelets. Both ETA and ETB receptors probably contribute to this response by a complex mechanism that requires further elucidation. NA F antagonises the action of ET-1 on human platelets. These actions may cont ribute to the beneficial effects of NAF in PVD.