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Polymer nanocomposites enhance S-nitrosoglutathione intestinal absorption and promote the formation of releasable nitric oxide stores in rat aorta

Abstract : Alginate/chitosan nanocomposite particles (GSNO-acNCPs), i.e. S-nitrosoglutathione (GSNO) loaded polymeric nanoparticles incorporated into an alginate and chitosan matrix, were developed to increase the effective GSNO loading capacity, a nitric oxide (NO) donor, and to sustain its release from the intestine following oral administration. Compared with free GSNO and GSNO loaded nanoparticles, GSNO-acNCPs promoted 2.7-fold GSNO permeation through a model of intestinal barrier (Caco-2 cells). After oral administration to Wistar rats, GSNO-acNCPs promoted NO storage into the aorta during at least 17 h, as highlighted by (i) a long-lasting hyporeactivity to phenylephrine (decrease in maximum vasoconstrictive effect of aortic rings) and (ii) N-acetylcysteine (a thiol which can displace NO from tissues)-induced vasodilation of aortic rings preconstricted with phenylephrine. In conclusion, GSNO-acNCPs enhance GSNO intestinal absorption and promote the formation of releasable NO stores into the rat aorta. GSNO-acNCPs are promising carriers for chronic oral application devoted to the treatment of cardiovascular diseases. In the cardiovascular system, deficiency of endogenous nitric oxide (NO) is the consequence of either insufficient synthesis (endothelium dysfunction) 1,2 or excessive NO degradation 3,4 (increased oxidative or nitrosative stresses, decreased antioxidant enzyme activity). NO depletion is one of the key factors in the initiation and progress of many diseases, such as atherosclerosis, 5 pulmonary hypertension, 6 thrombosis, 7 ischemia 8 and cardiac arrhythmia. 9 To maintain an appropriate level of NO and treat NO deficiency, several NO-related therapeutics have been developed such as nitrosamines, organic nitrates, metal–NO complexes, N-diazeniumdiolates. However, all act at very short term and lead to tolerance phenomena. S-nitrosothiols (RSNOs) present the advantage of a longer half-life, with no tolerance nor oxidative stress induction. Under physiological conditions, S-nitrosoglutathione (GSNO), a major endogenous RSNO, is one of the main storage forms of NO in tissues. 10 GSNO has been investigated for its powerful antiplatelet activity, 11,12 arterio/venous selective vasodilator effects, 13,14 antimicrobial 15 and antithrombotic effects. 16 Despite such therapeutic potencies, GSNO pharmaceutical forms are still lacking. This may be related to the fast and often unpredictable rate of decomposition of GSNO. In vitro, because of pH-, light-and temperature-dependent sensitivities , GSNO is susceptible to many degradation processes
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Wen Wu, Caroline Perrin-Sarrado, Hui Ming, Isabelle Lartaud, Philippe Maincent, et al.. Polymer nanocomposites enhance S-nitrosoglutathione intestinal absorption and promote the formation of releasable nitric oxide stores in rat aorta. Nanomedicine: Nanotechnology, Biology and Medicine, Elsevier, 2016, 12 (7), pp.1795-1803. ⟨10.1016/j.nano.2016.05.006⟩. ⟨hal-01493332⟩



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