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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.

An atheroma-like neo-intima was produced by positioning a flexible collar around the common carotid arteries of normocholesterolaemic rabbits. Vessel segments taken from the mid-region of the collared and control region of the same artery were studied 7 days after surgery. Placebo rabbits were provided ab libitum with regular tap water, and treated animals were supplied with water containing perindopril (0.3 mg/kg/day) for 14 days. Perindopril treatment reduced plasma angiotensin converting enzyme (ACE) activity by 88%, but did not significantly alter arterial blood pressure or heart rate. In control rings from placebo rabbits perindoprilat in vitro (0.1-1.0 microM) reduced the sensitivity to angiotension I up to 20-fold but did not affect that of angiotensin II. In placebo rabbits, the collared arterial segments were approximately five-fold more sensitive to the vasoconstrictor action of 5-HT (P < 0.05) than the corresponding control segments. Perindopril treatment did not prevent the supersensitivity of the collared vessels to 5-HT. Development of the lesion in placebo or perindopril-treated rabbits did not alter the vascular sensitivity to either angiotensin I (10(-9)-10(-5)M) or angiotensin II (10(-10)-10(-6)M). The vasorelaxant action of sodium nitroprusside was similar in collared and control rings, whereas the maximum endothelium-dependent vasorelaxant response to acetylcholine was reduced from 68 +/- 5% in control rings, to 44 +/- 8% (mean +/- S.E.M., n = 9, P < 0.05) in collared rings of placebo-treated rabbits. In the perindopril-treated animals, this impairment of relaxation was restored in collared vessels and was no longer significantly different from the control sections. In contrast, perindoprilat in vitro (1.0 microM) did not alter the vasorelaxant response to acetylcholine in control or collared rings in a separate series of placebo rabbits. Morphologically, vessel segments taken from the centre of the collared artery of all placebo rabbits showed a thickened intima filled with cells that had the appearance of synthetic-state smooth muscle. The intimal/medial cross-sectional area ratio was reduced from 0.11 +/- 0.02 (n = 10) in placebo rabbits to 0.05 +/- 0.01 (n = 9) in perindopril-treated rabbits, whereas cross-sectional area of media of the collared vessels was similar in the two groups. Thus ACE may have important roles in the initiation and progression of atheroma-like lesions. Inhibition of ACE with perindopril reduces intimal thickening and restores the defective vasodilatation induced by the endothelial-dependent vasodilator, acetylcholine.

Application of periarterial collars induced atheroma-like lesions in the carotid arteries of normocholesterolemic rabbits. Vessel segments taken from the mid-region of the collar (cuffed region) and control regions of the same artery were studied at 7 days after surgery. A group of placebo rabbits was provided ad libitum with regular tap water, and treated animals were supplied for 14 days (beginning 7 days before collar application) with water containing perindopril (daily intake of approximately 0.3 mg/kg). Perindopril treatment reduced plasma angiotensin-converting enzyme (ACE) activity by 88% but did not significantly alter arterial blood pressure or heart rate. The sensitivity of arterial rings to angiotensins I and II did not differ between control and cuffed arteries in either placebo or perindopril-treated rabbits, but in rings from both groups of rabbits the sensitivity to the vasoconstrictor action of serotonin was higher in the cuffed segments, as in previous studies. In addition, in placebo rabbits the endothelium-dependent vasorelaxant response to acetylcholine (which results from the release of nitric oxide) was weaker in cuffed arteries than in controls, whereas in the perindopril-treated animals, this impairment of relaxation was restored to the extent that, in cuffed vessels, it was no longer significantly different from the controls. Similar results were obtained in rabbits treated with another ACE inhibitor (ramipril). In contrast, acute treatment with the metabolite, perindoprilat, in vitro (1.0 microM) did not alter the response to acetylcholine in control or cuffed rings from placebo rabbits. Morphologically, vessel segments taken from the center of the cuffed artery of placebo rabbits showed a thickened intima with marked smooth muscle cell proliferation.(ABSTRACT TRUNCATED AT 250 WORDS)

1. The effects of the immunosuppressants cyclosporin A (CsA) and FK506 on nitric oxide (NO) synthesis induced by lipopolysaccharide (LPS) or cytokines were examined in rat vascular smooth muscle cells (VSMC) in culture. 2. CsA inhibited by up to 90% the accumulation of nitrite induced by LPS, but FK506 had a weaker effect on nitrite accumulation induced by LPS in these cells. Both CsA and FK506 (at 1 mumol/L) significantly inhibited nitrite production induced by recombinant murine interleukin-1 beta (rIL-1 beta). 3. Given their differing potency, it is likely that CsA and FK506 suppress induction of NO synthase through different intracellular mechanisms. This action could contribute to the side effects of CsA therapy.