ANTIATHEROSCLEROTIC EFFECTS OF ORAL NAFTIDROFURYL IN CHOLESTEROL-FED RABBITS INVOLVE INHIBITION OF NEUTROPHIL FUNCTION

We investigated the action of oral naftidrofuryl, a serotonin (5-HT2)a ntagonist, on atheromatous plaque formation, endothelial function, and neutrophil activity in cholesterol-fed (1% for 12 weeks) rabbits. Cho lesterol feeding caused almost complete (84 +/- 4%) coverage of the ao rtic surface with atheromas and a marked intimal thickening. The endot helium-dependent relaxation to acetylcholine (ACh 1 nM-10 mu M) and su bstance P (30 nM) was considerably reduced, whereas the relaxing effec t to the endothelium-independent nitric oxide donor linsidomine (SIN-1 ) (100 mu M) was unchanged. Treatment of hypercholesterolemic rabbits with naftidrofuryl (50 mg/kg body weight) resulted in a marked (54 +/- 6%, p < 0.05) reduction in aortic plaque formation. Endothelium-depen dent relaxation to ACh was significantly improved in rings of both tho racic aorta: 33 +/- 5 versus 14 +/- 5% (p < 0.05) and abdominal aorta 68 +/- 9 versus 37 +/- 10% (p ( 0.05). Similar results were obtained w ith substance P, but the responses to SIN-1 were unchanged. Zymosan-in duced, luminol-enhanced chemiluminescence of polymorphonuclear leukocy tes (PMN) was markedly stimulated in cholesterol-fed rabbits. Naftidro furyl reduced this hyperreactivity to that of control rabbits. There w as no change by naftidrofuryl in any of these parameters in control ra bbits, precluding a direct action of the compound in nonhypercholester olemic conditions. These data demonstrate significant endothelium-prot ective actions of long-term oral naftidrofuryl in cholesterol-fed rabb its that involve inhibition of cholesterol-induced neutrophil activati on.