title: The effect of chronic treatment with NO donors during intimal thickening and fatty streak formation.
abstract: Intimal thickening in arteries is considered as a site of predilection for atherosclerosis. We investigated whether oral application of the nitric oxide (NO) donors SPM-5185 (N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethylester, 10 mg/kg body weight/b.i.d.) and molsidomine (pro-drug of 3-morpholino-sydnonimine (SIN-1), 10 mg/kg body weight/day) can retard intimal thickening and changes in vascular reactivity induced by a silicone collar positioned around the carotid artery of rabbits. Intimal thickening was significantly inhibited by SPM-5185 (cross-sectional area 18 +/- 6 vs. 44 +/- 10 x 10(-3) mm2; P < 0.05), but not by molsidomine (28 +/- 6 vs. 35 +/- 9 x 10(-3) mm2), which is a donor of both NO and superoxide anions. In organ chamber studies collaring was associated with a decreased sensitivity to acetylcholine (ACh). SPM-5185 evoked a tendency towards normalization of the pD2 of ACh in collared arteries. We also investigated whether chronic nitric oxide (NO) treatment affected vascular reactivity and fatty streak development in the rabbit aorta. During 16 weeks rabbits received 150 g/day of a standard diet, or diets with 0.3% cholesterol, with 0.02% molsidomine (10 mg/kg body weight/day) or with the combination. The NO donor enhanced the area of fatty streaks, without affecting hypercholesterolemia. Moreover, it desensitized the smooth muscle cells of the rabbit aorta to vasodilators acting via the cytoplasmic guanylate cyclase and suppressed the capacity of the endothelial cells to release NO in response to muscarinic receptor stimulation. This suggested that chronic exposure to large quantities of NO caused a negative feedback, with selective decreases of both the endothelial capacity to generate NO and the responsiveness to vasodilators operating via cyclic GMP. In conclusion, we demonstrated that exogenous NO can decrease intimal hyperplasia in vivo. However, prolonged in vivo treatment with a donor of NO enhanced atherosclerosis in hypercholesterolemic rabbits.
authors.affiliation: Division of Pharmacology, University of Antwerp, Belgium.
authors.forename: G R
authors.initials: GR
authors.lastname: De Meyer
authors.forename: H
authors.initials: H
authors.lastname: Bult
authors.forename: M M
authors.initials: MM
authors.lastname: Kockx
authors.forename: A G
authors.initials: AG
authors.lastname: Herman
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000502:physiology; D002339:Carotid Arteries / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D002784:Cholesterol / Q000097:blood; D002791:Cholesterol, Dietary; D004036:Diet, Atherogenic; D004151:Dipeptides / Q000494:pharmacology*; D004730:Endothelium, Vascular / Q000187:drug effects / Q000502:physiology; D006937:Hypercholesterolemia / Q000473:pathology / Q000503:physiopathology*; D066298:In Vitro Techniques; D008297:Male; D008981:Molsidomine / Q000494:pharmacology*; D009119:Muscle Contraction / Q000187:drug effects; D009569:Nitric Oxide / Q000502:physiology*; D010656:Phenylephrine / Q000494:pharmacology; D011355:Prodrugs / Q000494:pharmacology*; D011817:Rabbits; D017539:Tunica Intima / Q000187:drug effects* / Q000473:pathology / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D002791:Cholesterol, Dietary; D004151:Dipeptides; D011355:Prodrugs; D014665:Vasodilator Agents; C076992:N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteine ethyl ester; D010656:Phenylephrine; D009569:Nitric Oxide; D002784:Cholesterol; D008981:Molsidomine; D000109:Acetylcholine