INFLUENCE OF CHRONIC TREATMENT WITH A NITRIC-OXIDE DONOR ON FATTY STREAK DEVELOPMENT AND REACTIVITY OF THE RABBIT AORTA

1 The influence of chronic treatment with molsidomine, pro-drug of the nitric oxide (NO) donor, 3-morpholino-sydnonimine (SIN-1), on fatty s treak development and release of NO and prostacyclin (PGI(2)) was stud ied in the aorta of normal and cholesterol-fed rabbits. 2 Groups of 10 rabbits received standard diet (150 g day(-1)), or diets with 0.3% ch olesterol, with 0.02% molsidomine or with the combination of cholester ol and molsidomine for 16 weeks. Lesion area and thickness, maximum ch ange in isometric force (E(max)) and sensitivity (-log EC(50) or pD(2) ) to constricting and relaxing agonists were assessed in segments of a rch, thoracic and abdominal aorta. Bioassay was used to assess NO rele ase. 3 Cholesterol-induced fatty streaks tapered off towards the abdom inal aorta. Area, thickness, weight and cholesterylester content of th e lesions were augmented by the NO donor, whereas the hypercholesterol aemia remained unchanged. The exacerbation was attributed to co-releas e of superoxide anion from the sydnonimine. 4 As fatty streaks progres sed, amplitude and pD(2) of acetylcholine (ACh)-induced relaxations de creased, whereas cyclic GMP and cyclic AMP second messenger systems we re not influenced, since E(max) and sensitivity to SIN-1 and forskolin remained unchanged. However, extensive lesions apparently trapped som e NO, as the pD(2) of authentic NO decreased. 5 The fatty streaks curt ailed the biosynthesis of PGI(2) and the overflow of NO from the perfu sed thoracic aorta. The latter defect was not restored by L-arginine a nd appears to be consistent with a functional change of the endothieli al muscarinic receptors. 6 The NO donor desensitized the aorta to cycl ic GMP-mediated relaxations (ACh, SIN-1 and NO), without affecting cyc lic AMP-mediated relaxation to forskolin or constrictor responses to p henylephrine and 5-hydroxytryptamine. 7 The drug also suppressed the A Ch-induced overflow of NO, without changing PGI(2) release. This selec tive reduction of endothelial NO release and the desensitization of cy clic GMP-mediated relaxations occurred independently of fatty streak f ormation. 8 The results indicate that chronic exposure to exogenous NO downregulates endothelial NO release and cyclic GMP-mediated relaxati ons, and provide evidence for the existence of negative feed-back regu lations of the L-arginine NO pathway under in vivo conditions.