Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta

Abstract

1 The influence of chronic treatment with molsidomine, pro-drug of the nitric oxide (NO) donor, 3-morpholino-sydnonimine (SIN-1), on fatty streak development and release of NO and prostacyclin (PGI2) was studied in the aorta of normal and cholesterol-fed rabbits. 2 Groups of 10 rabbits received standard diet (150g day-'), or diets with 0.3% cholesterol, with 0.02% molsidomine or with the combination of cholesterol and molsidomine for 16 weeks. Lesion area and thickness, maximum change in isometric force (E.,,.) and sensitivity (-log EC3. or pD2) to constricting and relaxing agonists were assessed in segments of arch, thoracic and abdominal aorta. Bioassay was used to assess NO release. 3 Cholesterol-induced fatty streaks tapered off towards the abdominal aorta. Area, thickness, weight and cholesterylester content of the lesions were augmented by the NO donor, whereas the hypercholesterolaemia remained unchanged. The exacerbation was attributed to co-release of superoxide anion from the sydnonimine. 4 As fatty streaks progressed, amplitude and pD2 of acetylcholine (ACh)-induced relaxations decreased, whereas cyclic GMP and cyclic AMP second messenger systems were not influenced, since Em., and sensitivity to SIN-1 and forskolin remained unchanged. However, extensive lesions apparently trapped some NO, as the pD2 of authentic NO decreased. 5The fatty streaks curtailed the biosynthesis of PGI2 and the overflow of NO from the perfused thoracic aorta. The latter defect was not restored by L-arginine and appears to be consistent with a functional change of the endothelial muscarinic receptors. 6 The NO donor desensitized the aorta to cyclic GMP-mediated -relaxations (ACh, SIN-1 and NO), without affecting cyclic AMP-mediated relaxation to forskolin or constrictor responses to phenylephrine and 5-hydroxytryptamine. 7 The drug also suppressed the ACh-induced overflow of NO, without changing PGI2 release. This selective reduction of endothelial NO release and the desensitization of cyclic GMP-mediated relaxations occurred independently of fatty streak formation. 8 The results indicate that chronic exposure to exogenous NO downregulates endothelial NO release and cyclic GMP-mediated relaxations, and provide evidence for the existence of negative feed-back regulations of the L-arginine NO pathway under in vivo conditions.

The nitric oxide donor pentaerythritol tetranitrate can preserve endothelial function in established atherosclerosis

“…These ®ndings are in contrast to another study investigating the eect of molsidomine, a structurally dierent NO-donor (Bult et al, 1995), while another more experimentally used NODonor ((N-nitratopivaloyl-S-(N'-acetylalanyl)-cysteineethylester, SPM5185) showed bene®cial eects in rat carotid artery intimal injury (Guo et al, 1994). Thus, it seems questionable that prolonged in vivo treatment with NO-donors can initiate a protective eect in atherosclerosis.…”

“…NO is three times faster than that between superoxide and superoxide dismutase (Kojda & Harrison, 1999). Thus, the negative outcome of the study by Bult et al (1995) might re¯ect a proatherosclerotic eect of peroxynitrite rather than .…”

“…In contrast, a study with molsidomine showed that area, thickness, weight and cholesterylester content of the lesions were augmented by the . NO donor molsidomine (Bult et al, 1995). It seems possible that these eects might have been induced by peroxynitrite rather than .…”

Oxadiazoles

“…The pharmacological activity is correlated to the formation of a metabolite, the N-morpholino-N-nitrosoaminoacetonitrile, which acts as a nitric oxide donor (Scheme 13.36) [110]. Accordingly, to achieve site-specific delivery of nitric oxide (NO), a new class of glycosidase activated NO donors has been developed, in which glucose, galactose, and N-acetylneuraminic acid were covalently coupled to 3-morphorlinosydnonimine, via a carbamate linkage at the anomeric position [111].…”

The Subcellular Compartmentalization of Arginine Metabolizing Enzymes and Their Role in Endothelial Dysfunction

“…The reasons for this are not well understood and likely to be numerous. Chronic exposure to high levels of NO can desensitize NO signaling, impair l -arginine import and increase vascular lesions and mortality (66–69). In contrast, inhibition of endogenous NO can increase sensitivity to NO donors and collectively this suggests that there is pushback when “pushing” NO signaling.…”