Oral naftidrofuryl prevents platelet hyperreactivity ex vivo and inhibits functional desensitization to prostacyclin in hypercholesterolemic rabbits.
Among other mediators, platelet-derived serotonin (5-HT) may contribute to thromboembolic complications of atherosclerosis. We determined whether long-term oral treatment with the 5-HT2 antagonist naftidrofuryl (NAF, 50 mg/kg daily for 12 weeks) alters platelet function in cholesterol-fed (1%) rabbits. Hypercholesterolemia resulted in marked platelet hyperreactivity to collagen and ADP. This included increased aggregation, ATP secretion, and thromboxane formation; e.g., collagen-induced (1.2 micrograms/ml) platelet aggregation was stimulated to 210 +/- 10 mm/30 s in cholesterol-fed rabbits as compared with 108 +/- 9 mm/30 s in rabbits fed a standard diet (p < 0.05). Inhibition of ADP-stimulated platelet activation by the prostacyclin mimetic iloprost was significantly reduced. NAF did not reduce plasma cholesterol in hypercholesterolemia, but prevented enhanced platelet aggregation, thromboxane formation, and ATP secretion. NAF treatment significantly reduced collagen-induced (1.2 micrograms/ml) aggregation to 81 +/- 20 mm/30 s in these animals (p < 0.05). NAF also inhibited functional desensitization of platelets to iloprost, but did not alter the impaired binding of [3H]iloprost to platelet membranes in hypercholesterolemic animals. NAF also did not change any of these parameters in normocholesterolemic rabbits. These data suggest beneficial effects of NAF on platelet hyperreactivity in experimental hypercholesterolemia which may also be relevant for its clinical use.
Weber
A A
AA
Institut für Pharmakologie, Heinrich-Heine-Universität Düsseldorf, Germany.
Hohlfeld
T
T
Strobach
H
H
Schrör
K
K
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D001792:Blood Platelets / Q000187:drug effects*; D002784:Cholesterol / Q000097:blood; D003094:Collagen / Q000494:pharmacology; D004032:Diet; D011464:Epoprostenol / Q000494:pharmacology*; D006801:Humans; D006937:Hypercholesterolemia / Q000503:physiopathology*; D016285:Iloprost / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009257:Nafronyl / Q000494:pharmacology*; D010974:Platelet Aggregation / Q000187:drug effects; D010975:Platelet Aggregation Inhibitors / Q000494:pharmacology; D011817:Rabbits; D013931:Thromboxanes / Q000096:biosynthesis
D010975:Platelet Aggregation Inhibitors; D013931:Thromboxanes; D009257:Nafronyl; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D003094:Collagen; D002784:Cholesterol; D011464:Epoprostenol; D016285:Iloprost