A platelet-activating factor antagonist (WEB 2170) preserves endothelium-dependent vasodilatation and prevents development of a neo-intima induced by a periarterial collar in rabbit carotid arteries.
Platelet-activating factor (PAF) may be involved in adhesion of leucocytes and migration of cells during vascular remodelling for it is expressed in leucocytes after cytokine priming and is required for cell adhesion. We studied the effects of WEB 2170, a potent PAF antagonist, on the development of an atheroma-like neo-intima induced by a peri-arterial collar in rabbits. Either WEB 2170 (3 mg/kg/day) or vehicle was given by subcutaneous injection once a day for 4 or 9 days, and on day 3 peri-arterial collars were applied to both carotid arteries in all animals. Two or 7 days after implanting the collars vasodilator responses to the endothelium-dependent vasodilator, acetylcholine and the endothelium-independent vasodilator, sodium nitroprusside were studied in isolated artery rings from both groups of rabbits. Neo-intima formation after 7 days (day 10 of treatment) was measured by light microscopy as the ratio of cross-sectional areas of intima and media, and expression of inducible nitric oxide synthase (iNOS) was studied by immunohistochemistry. PAF-induced platelet aggregation ex vivo was inhibited specifically in WEB 2170-treated rabbits. At day 5, acetylcholine-induced vasorelaxation in collared artery rings was markedly impaired as compared to control sections from both vehicle- and WEB 2170-treated rabbits. At day 10, acetylcholine-induced vasorelaxation in collared artery rings from vehicle rabbits was markedly less than in controls, but in WEB 2170-treated rabbits, the acetylcholine response in collared arteries was similar to control sections. Intimal thickening was much reduced in WEB 2170-treated rabbits, ratios of intima/media areas being vehicle: 0.21 +/- 0.02 (n = 5) and WEB 2170: 0.07 +/- 0.01 (n = 7; p < 0.01). Immunofluorescence showed expression of iNOS only in the neo-intima of vehicle-treated, collared arteries, but not in the residual neo-intima of WEB 2170-treated, collared arteries. These results suggest that WEB 2170 is effective in preserving endothelial function, prevents the development of neo-intima and blocks iNOS expression in the neo-intima in this model.
Yin
Z L
ZL
Department of Physiology, University of Melbourne, Parkville, Victoria, Australia.
Hickey
H
H
Dusting
G J
GJ
D000818:Animals; D001011:Aorta / Q000187:drug effects / Q000503:physiopathology; D001381:Azepines / Q000008:administration & dosage / Q000494:pharmacology*; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D005260:Female; D007150:Immunohistochemistry; D066298:In Vitro Techniques; D007279:Injections, Subcutaneous; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000276:immunology; D052247:Nitric Oxide Synthase Type II; D010975:Platelet Aggregation Inhibitors / Q000008:administration & dosage / Q000494:pharmacology*; D011817:Rabbits; D014230:Triazoles / Q000008:administration & dosage / Q000494:pharmacology*; D017539:Tunica Intima / Q000737:chemistry / Q000187:drug effects* / Q000503:physiopathology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology
D001381:Azepines; D010975:Platelet Aggregation Inhibitors; D014230:Triazoles; C063964:bepafant; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II