Platelet Activation by Superoxide Anion and Hydroxyl Radicals Intrinsically Generated by Platelets That Had Undergone Anoxia and Then Reoxygenated

Leo, Roberto; Praticò, Domenico; Iuliano, Luigi; Pulcinelli, Fabio M.; Ghiselli, Andrea; Pignatelli, Pasquale; Colavita, Angela Rita; FitzGerald, Garret A.; Violi, Francesco

doi:10.1161/01.cir.95.4.885

Cited by 134 publications

(105 citation statements)

References 37 publications

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“…However, NO also has been associated with damaging effects. The protective effects of NO seem to be associated with eNOS-derived NO, which causes vasodilation and inhibits leukocyte adhesion and platelet aggregation (31), whereas the damaging and proinflammatory effects have been associated with iNOS-derived NO, which forms the peroxynitrite anion from the interaction of NO and superoxide (32). The plasma levels of nitrite (used as an indicator of NO formation) measured at the end of the 6-h reperfusion period indicate I/R-induced elevated NO production as demonstrated previously (10).…”

Section: Discussionmentioning

confidence: 99%

Nitrite-Derived Nitric Oxide Protects the Rat Kidney against Ischemia/Reperfusion Injury In Vivo

Tripatara¹,

Patel²,

Webb³

et al. 2007

Journal of the American Society of Nephrology

213

159

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In normal conditions, nitric oxide (NO) is oxidized to the anion nitrite, but in hypoxia, this nitrite may be reduced back to NO by the nitrite reductase action of deoxygenated hemoglobin, acidic disproportionation, or xanthine oxidoreductase (XOR). Herein, is investigated the effects of topical sodium nitrite administration in a rat model of renal ischemia/reperfusion (I/R) injury. Rats were subjected to 60 min of bilateral renal ischemia and 6 h of reperfusion in the absence or presence of sodium nitrite (30 nmol) administered topically 1 min before reperfusion. Serum creatinine, serum aspartate aminotransferase, creatinine clearance, fractional excretion of Na ؉ , and plasma nitrite/nitrate concentrations were measured. The nitrite-derived NO-generating capacity of renal tissue was determined under acidic and hypoxic conditions by ozone chemiluminescence in homogenates of kidneys that were subjected to sham, ischemia-only, and I/R conditions. Nitrite significantly attenuated renal dysfunction and injury, an effect that was abolished by previous treatment of rats with the NO scavenger 2-(4-carboxyphenyl)-4,4,5,5-tetramethylimidazole-1-oxyl-3-oxide (2.5 mol intravenously 5 min before ischemia and 50 nmol topically 6 min before reperfusion). Renal tissue homogenates produced significant amounts of NO from nitrite, an effect that was attenuated significantly by the xanthine oxidoreductase inhibitor allopurinol. Taken together, these findings demonstrate that topically administered sodium nitrite protects the rat kidney against I/R injury and dysfunction in vivo via the generation, in part, of xanthine oxidoreductase-catalyzed NO production. These observations suggest that nitrite therapy might prove beneficial in protecting kidney function and integrity during periods of I/R such as those encountered in renal transplantation. U ntil recently, the nitrite anion was regarded merely as an inactive metabolite of nitric oxide (NO) oxidation produced under normal physiologic conditions, accounting for approximately 70% of the endogenous nitrite pool (1). However, we (2) and others (3) recently demonstrated that, far from being inactive, nitrite has marked protective effects in ischemia/reperfusion (I/R) injury of both the heart and the liver. Moreover, these studies demonstrate that the beneficial effects of nitrite are related to its reduction to NO, under ischemic conditions. J Am Soc NephrolThe generation of NO is attributed conventionally to the enzyme NO synthase (NOS), of which there are three isoforms. Endothelial NOS (eNOS)-derived NO plays an important role in determining and maintaining aspects of normal renal function, for instance proximal tubule sodium reabsorption (4,5), but in elevated concentrations, NO also contributes to renal pathophysiology (6), such as in proximal tubule ischemic injury (4). This dual nature of NO perhaps is an oversimplification, because NO either ameliorates or exacerbates renal injury, depending on the site and the rate of NO production and the chemical fate of NO (7,8). Further...

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Section: Discussionmentioning

confidence: 99%

Nitrite-Derived Nitric Oxide Protects the Rat Kidney against Ischemia/Reperfusion Injury In Vivo

Tripatara¹,

Patel²,

Webb³

et al. 2007

Journal of the American Society of Nephrology

213

159

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“…During reperfusion, both endothelial cells and leukocytes are known to release considerable amounts of reactive oxygen species (8,17). Reactive oxygen species are capable of causing platelet activation and P-selectin expression (18,20). Furthermore, activated platelets per se are also a source of reactive oxygen species (18,19).…”

Section: Discussionmentioning

confidence: 99%

“…Reactive oxygen species are capable of causing platelet activation and P-selectin expression (18,20). Furthermore, activated platelets per se are also a source of reactive oxygen species (18,19). The platelet agonists platelet-activating factor and thrombin are also known to mediate I/R-induced leukocyte adhesion (14,27).…”

Section: Discussionmentioning

confidence: 99%

Time-dependent platelet-vessel wall interactions induced by intestinal ischemia-reperfusion

Cooper

Chitman

Williams

et al. 2003

American Journal of Physiology-Gastrointestinal and Liver Physi

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roll and adhere in venules exposed to ischemia-reperfusion (I/R). This platelet-endothelial adhesion may influence leukocyte trafficking because platelet depletion decreases I/Rinduced leukocyte emigration. The objectives of this study were 1) to assess the time course of platelet adhesion in the small bowel after I/R and 2) to determine the roles of endothelial and/or platelet P-selectin and P-selectin glycoprotein ligand-1 (PSGL-1) in this adhesion. The adhesion of fluorescently labeled platelets was monitored by intravital microscopy in postcapillary venules exposed to 45 min of ischemia and up to 8 h of reperfusion. Peak platelet adhesion was observed at 4 h of reperfusion. To assess the contributions of platelet and endothelial cell P-selectin, platelets from Pselectin-deficient and wild-type mice were infused into wildtype and P-selectin-deficient mice, respectively. Platelets deficient in P-selectin exhibited low levels of adhesion comparable to that in sham-treated animals. In the absence of endothelial P-selectin, platelet adhesion was reduced by 65%. Treatment with a blocking antibody against PSGL-1 reduced adhesion by 57%. These results indicate that I/R induces a time-dependent platelet-endothelial adhesion response in postcapillary venules via a mechanism that involves PSGL-1 and both platelet and endothelial P-selectin, with platelet P-selectin playing a greater role.

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“…The position of the imidazole and the carboxylic acid on the aromatic ring and the distance between these functional groups are important for the activity of TXA 2 synthetase inhibitors. [9][10][11][12][13] Among the indoline-based derivatives, the position of two functional groups and the distance between them in compound 2 may be more favorable for interaction with TXA 2 synthetase than those in the other four compounds (3)(4)(5)(6). Compound 4 showed potent free radical scavenging activity comparable to those of ascorbic acid and a-tocopherol.…”

Section: Resultsmentioning

confidence: 99%

A Novel Series of Thromboxane A2 Synthetase Inhibitors with Free Radical Scavenging and Anti-peroxidative Activities.

Kamiya

Shirahase

Nakamura

et al. 2001

CHEMICAL & PHARMACEUTICAL BULLETIN

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A novel series of indoline derivatives with imidazole and carboxyl moieties were synthesized and evaluated for their thromboxane A 2 (TXA 2 ) synthetase inhibiting, radical scavenging and anti-peroxidative activities. Among the compounds synthesized, 3-{5-substituted-3-[2-(imidazol-1-yl)ethyl]indolin-1-yl}propionic acids showed free radical scavenging activity and inhibitory effects on lipid-peroxidation of rat brain homogenate and on arachidonate-induced TXA 2 -dependent aggregation of rabbit platelets. The anti-platelet and anti-peroxidative activities were related to the lipophilicity of the 5-substituent. The 5-hexyloxy derivative (13) showed about 35-fold higher inhibitory activity on TXA 2 synthesis than that of ozagrel and about 100-fold higher activity on lipid peroxidation than that of a a-tocopherol. Compound 13 showed in vivo anti-thrombotic effect in mice and ex vivo anti-peroxidative activity in rats.Key words indoline derivative; thromboxane A 2 synthetase inhibitor; radical scavenger; anti-peroxidation duced with sodium cyanoborohydride (NaBH 3 CN) to corresponding indolines followed by protection with di-tert-butyl dicarbonate ((Boc) 2 O) to afford N-protected indoline derivatives (IV). Bromination of IV with CBr 4 and Ph 3 P followed by condensation with imidazole and deprotection with HCl to afford V. Target compounds (2, 7-9, 12-27) were obtained by condensation with ethyl acrylate or ethyl 3-bromopropionate followed by hydrolysis of ester precursors (VI) with NaOH.Compounds 10 and 11 were prepared from the 5-hydroxyindoline derivative (VII). Deprotection of VI (nϭ1, mϭ2, RϭOCH 2 C 6 H 5 ) was performed with trifluoroacetic acid (TFA) in anisole to afford the corresponding phenol (VII), which was condensed with the appropriate bromides followed by hydrolysis of ester precursors with NaOH to give 10 and 11.Chart 2 shows the synthetic route of 3. 5-Bromoindoline derivative (28) was reacted with CuCN in N-methylpyrrolidone to afford 5-cyanoindoline derivative (29). Hydrolysis of 29 with conc. HCl gave the corresponding carboxylic acid (30), 19) which was protected with ester and (Boc) 2 O to give 31. Bromination of 31 with CBr 4 and Ph 3 P followed by condensation with imidazole gave 32, which was deprotected with NaOH and HCl to afford 3.Chart 3 shows the synthetic route of the other indoline derivatives (4-6). The 4-substituted derivative (34a) was prepared from 33a by condensation with ethylene bromohydrin. The 5-or 6-substituted derivatives (34b, c) were obtained by reduction of the appropriate indoline carboxylate (33b, c) 19) with diisobutylaluminum hydride (DIBAL-H) or LiAlH 4 and protection with (Boc) 2 O. Bromination of 34a-c with CBr 4 and Ph 3 P followed by condensation with imidazole gave 35a-c, which were deprotected with HCl followed by condensation with ethyl bromoacetate or ethyl acrylate followed by hydrolysis of ester precursors with NaOH to afford target compounds 4-6. Results and DiscussionIn the present study, we synthesized a series of indoline derivatives and examined their...

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Platelet Activation by Superoxide Anion and Hydroxyl Radicals Intrinsically Generated by Platelets That Had Undergone Anoxia and Then Reoxygenated

Cited by 134 publications

References 37 publications

Nitrite-Derived Nitric Oxide Protects the Rat Kidney against Ischemia/Reperfusion Injury In Vivo

Nitrite-Derived Nitric Oxide Protects the Rat Kidney against Ischemia/Reperfusion Injury In Vivo

Time-dependent platelet-vessel wall interactions induced by intestinal ischemia-reperfusion

A Novel Series of Thromboxane A2 Synthetase Inhibitors with Free Radical Scavenging and Anti-peroxidative Activities.

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