• Vincenzo Mollace, Carolina Muscoli, Concetta Dagostino, Luigino Antonio Giancotti, Micaela Gliozzi, Iolanda Sacco, Valeria Visalli, Santo Gratteri, Ernesto Palma, Natalia Malara, Vincenzo Musolino, Cristina Carresi, Saverio Muscoli, Cristiana Vitale, Daniela Salvemini, and Francesco Romeo.
• Interregional Research Center for Food Safety & Health (IRC-FSH), Department of Health Science, University "Magna Graecia" of Catanzaro, Complesso "Ninì Barbieri", 88021 Roccelletta di Borgia, Italy(1); IRCCS San Raffaele Pisana, Via di Val Cannuta, 247, 00166 Rome, Italy(2). Electronic address: mollace@libero.it.
• Pharmacol. Res. 2014 Nov 1; 89: 29-35.

AbstractBioconversion of glyceryl trinitrate (GTN) into nitric oxide (NO) by aldehyde dehydrogenase-2 (ALDH-2) is a crucial mechanism which drives vasodilatory and antiplatelet effect of organic nitrates in vitro and in vivo. Oxidative stress generated by overproduction of free radical species, mostly superoxide anions and NO-derived peroxynitrite, has been suggested to play a pivotal role in the development of nitrate tolerance, though the mechanism still remains unclear. Here we studied the free radical-dependent impairment of ALDH-2 in platelets as well as vascular tissues undergoing organic nitrate ester tolerance and potential benefit when using the selective peroxynitrite decomposition catalyst Mn(III) tetrakis (4-Benzoic acid) porphyrin (MnTBAP). Washed human platelets were made tolerant to nitrates via incubation with GTN for 4h. This was expressed by attenuation of platelet aggregation induced by thrombin (40U/mL), an effect accompanied by GTN-related induction of cGMP levels in platelets undergoing thrombin-induced aggregation. Both effects were associated to attenuated GTN-induced nitrite formation in platelets supernatants and to prominent nitration of ALDH-2, the GTN to NO metabolizing enzyme, suggesting that GTN tolerance was associated to reduced NO formation via impairment of ALDH-2. These effects were all antagonized by co-incubation of platelets with MnTBAP, which restored GTN-induced responses in tolerant platelets. Comparable effect was found under in in vivo settings. Indeed, MnTBAP (10mg/kg, i.p.) significantly restored the hypotensive effect of bolus injection of GTN in rats made tolerants to organic nitrates via chronic administration of isosorbide-5-mononitrate (IS-5-MN), thus confirming the role of peroxynitrite overproduction in the development of tolerance to vascular responses induced by organic nitrates. In conclusion, oxidative stress subsequent to prolonged use of organic nitrates, which occurs via nitration of ALDH-2, represents a key event in GTN tolerance, an effect counteracted both in vitro and in vivo by novel peroxynitrite decomposition catalyst. Copyright © 2014 Elsevier Ltd. All rights reserved.

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