title: Effect of endothelin-1 on human platelet shape change: reversal of activation by naftidrofuryl.
abstract: 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 are elevated in patients with vascular disease. Platelet rich plasma (PRP) was prepared from healthy volunteers. NAF at concentrations similar to therapeutic levels (3.5-14 micromol/l), inhibited (P < 0.02) platelet activation (as indicated by a fall in median platelet volume, MPV) induced by ET-1 (0.4 micromol/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 micromol/l) in combination with ADP (0.05-0.15 micromol/l) or serotonin (0.03-0.13 micromol/ l). We assessed the effect of ET(A) (BQ123, 50 nmol/l) or ET(B) (BQ788, 50 nmol/l) receptor antagonists on PSC induced by ET-1 alone. Both antagonists significantly inhibited PSC. We conclude that ET-1 activates human platelets. Both ET(A) and ET(B) receptors probably contribute to this response by a complex mechanism that requires further elucidation. NAF antagonises the action of ET-1 on human platelets. These actions may contribute to the beneficial effects of NAF in PVD.
authors.affiliation: Department of Molecular Pathology and Clinical Biochemistry, Royal Free & University College Medical School, London, UK.
authors.forename: I A
authors.initials: IA
authors.lastname: Jagroop
authors.forename: D P
authors.initials: DP
authors.lastname: Mikhailidis
mesh_terms: D000244:Adenosine Diphosphate / Q000494:pharmacology; D000328:Adult; D001792:Blood Platelets / Q000166:cytology*; D048429:Cell Size / Q000187:drug effects; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000494:pharmacology*; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D009257:Nafronyl / Q000494:pharmacology; D015539:Platelet Activation / Q000187:drug effects; D012701:Serotonin / Q000494:pharmacology; D012702:Serotonin Antagonists / Q000494:pharmacology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D012702:Serotonin Antagonists; D014665:Vasodilator Agents; D012701:Serotonin; D009257:Nafronyl; D000244:Adenosine Diphosphate