Abstract
A new class of nitroderivatives of non-steroidal anti-inflammatory drugs has recently been synthesized (Nicox Ltd., London, UK). In order to improve gastric tolerance of the parent compound, a side-chain, able to release nitric oxide, has been added to the core structure of the molecule. We studied in vitro the effects of nitrofenac and two NO-aspirins (NCX 4215 and NCX 4016) on platelets and isolated arteries to identify any possible effect due to the release of nitric oxide or to the inhibition of cyclo-oxygenase activity. Nitrofenac induced a dose-dependent relaxation both with intact (46% with 1 × 10-3 mol/L) and endothelium-denuded (75% with 1 × 10-3 mol/L) rings of rat aorta precontracted with epinephrine, while diclofenac did not affect this contraction (0% relaxation in intact and 22% in rubbed arteries). Pretreatment with diclofenac 1 × 10-3 mol/L significantly increased the vasorelaxant effects of nitrofenac at each drug concentration, both in intact (86% with 1 × 10-3 mol/L) and rubbed preparations (89%). NO-aspirins, unlike acetylsalicylic acid, were able to relax both intact and endothelium-denuded rings of rat aorta (100% relaxation). Methylene blue and oxyhaemoglobin completely reversed the relaxation induced by nitrofenac and NO-aspirins, both in rubbed and intact aortic rings.
Both NO-aspirins exhibited antiaggregating properties in archididonic acid-stimulated human platelets, measured using a turbidimetric method (NCX 4215, 1 × 10-3 mol/L: 70% inhibition; NCX 4016, 1 × 10-4 mol/L: 100%), NCX 4016 proving as effective as acetylsalicylic acid 1 × 10-5 mol/L. Thrombin-induced platelet aggregation was inhibited in acetylsalicylic acid-treated platelets (NCX 4215, 1 x 10-3 mol/L: 50%, NCX 4016, 1 × 10-4 mol/L: 92%). NCX 4016 was also able to prevent thrombin-induced intracellular free calcium increase, effect not observed with acetylsalicylic acid. In vitro thromboxane A2 production in human platelets, assayed by RIA as thromboxane B2 serum concentration, was reduced by NCX 4215, 1 × 10-3 mol/L (76%) and virtually abolished by NCX 4016 5 × 10-5 mol/L (95% inhibition).
These results demonstrate in vitro the antiaggregating activity of NO-aspirins, NCX 4016 being more active than NCX 4215, and the vasorelaxant effects of all the tested molecules. The mechanism involved is two-fold: release of nitric oxide and inhibition of cyclo-oxygenase.
Access this chapter
Tax calculation will be finalised at checkout
Purchases are for personal use only
Preview
Unable to display preview. Download preview PDF.
References
Conforti A, Donini M, Brocco G, Del Soldato P, Benoni G, Cuzzolin L. Acute anti-inflammatory activity and gastro-intestinal tolerability of diclofenac and nitrofenac. Agents Actions. 1993;40:176–80.
Vane J. Towards a better aspirin. Nature. 1994;367:215–16.
Ignarro IJ, Ross G, Tillisch J. Pharmacology of endothelium-derived nitric oxide and nitrovasodilators. West J Med. 1991;154:51–62.
Shafer AI, Alexander RV, Andin RI. Inhibition of platelet function by organic nitrate vasodilators. Blood. 1980;55:649–54.
Gerzer R, Karrenbrock W, Siess W, Heim JM. Direct comparison of the effects of nitroprusside, SIN 1, and various nitrates on platelet aggregation and soluble guanylate-cyclase activity. Thromb Res. 1988;52:11–21.
Gyires K. Some of the factors that may mediate or modify the gastrointestinal mucosal damage induced by non-steroidal anti-inflammatory drugs. Agents Action. 1994;41:73–9.
Wallace JL, Reuter B, Cicala C, McKnight W, Grisham NB, Cirino G. Novel NSAID derivatives with markedly reduced ulcerogenic properties in the rat. Gastroenterology. 1994;107:173–9.
Cuzzolin L, Conforti A, Adami A et al. Anti-inflammatory potency and gastrointestinal toxicity of a new compound, nitronaproxen. Pharm Res. 1995;31:61–5.
Spokas EG, Folco G, Quilley J, Chandler P, McGiff JC. Endothelial mechanism in the vascular action of hydralazine. Hypertension. 1983;5(Suppl 1):107–11.
Kojda G, Noack E. Nitric oxide liberating, soluble guanylate cyclase stimulating and vasorelaxing properties of a new nitrate-compound SPM 3672. J Cardiovasc Pharmacol. 1993;22:103–11.
Gruetter CA, Kadowitz PJ, Ignarro LJ. Methylene blue inhibits coronary arterial relaxation and guanylate cyclase activation by nitroglycerin, sodium nitrite and amyl nitrite. Can J Physiol Pharmacol. 1980;59:150–6.
Salvemini D, Radziewski W, Korbut R, Vane J. The use of oxyhaemoglobin to explore the events underlying inhibition of platelet aggregation induced by NO or NO-donors. Br J Pharmacol. 1990;101:991–5.
Stamler JS, Loscalzo J. The antiplatelet effects of organic nitrates and related compounds in vitro and in vivo and their relevance to cardiovascular disorders. J Am Coll Cardiol. 1991;81:529–36.
Buechler WA, Ivanova K, Wolfram G, Drummer C, Heim JM, Gerzer R. Soluble guanylyl cyclase and platelet function. Ann NY Acad Sci. 1994;714:151–7.
Minuz P, Lechi C, Tommasoli R et al. Antiaggregating and vasodilating effects of a new nitroderivative of acetylsalicylic acid. Thromb Res. 1995;80:367–76.
Hallam TJ, Thompson NT, Scrutton MC, Rink TJ. The role of cytoplasmic free calcium in the response of Quin 2-loaded human platelets to vasopressin. Biochem J. 1984;221:897–901.
Lechi C, Andrioli G, Gaino S et al. Antiplatelet effects of a new nitroderivative of acetylsalicylic acid; in vitro study of inhibition on early phase of platelet activation and on TXA2 production. Thromb Haemost. [in press].
Patron C, Ciabattoni G, Pinca E et al. Low dose aspirin and inhibition of thromboxane B2 production in healthy subjects. Thromb Res. 1980;17:317–27.
Pollock WK, Rink TJ, Irvine RF. Liberation of [3H]arachidonic acid and changes in cytosolic free calcium in fura-2-loaded human platelets stimulated by ionomycin and collagen. Biochemical J. 1986;235:869–77.
Vanhoutte PM, Katusic ZS. Endothelium-derived contracting factor: endothelium and/or superoxide anion? Trends Pharm Sci. 1988;9:229–30.
Sils D, Rodgers SE, Lloyd JV, Wilson KM, Siebert DM, Bochner F. Inhibition of platelet aggregation and thromboxane production by low concentrations of aspirin in vitro. Clin Sci. 1988;74:491–7.
Ahlner J, Axelsson KL, Karlsson JOG, Andersson RGG. Glyceryl trinitrate inhibits phosphatidyl inositol hydrolysis and protein kinase C activity in bovine mesenteric artery. Life Sci. 1988;43:1241–8.
Author information
Authors and Affiliations
Editor information
Editors and Affiliations
Rights and permissions
Copyright information
© 1997 Springer Science+Business Media Dordrecht
About this chapter
Cite this chapter
Minuz, P. et al. (1997). Effects of a New Class of No-Releasing NSAIDs on Platelets and Isolated Arteries. In: Rainsford, K.D. (eds) Side Effects of Anti-Inflammatory Drugs IV. Springer, Dordrecht. https://doi.org/10.1007/978-94-011-5394-2_27
Download citation
DOI: https://doi.org/10.1007/978-94-011-5394-2_27
Publisher Name: Springer, Dordrecht
Print ISBN: 978-94-010-6269-5
Online ISBN: 978-94-011-5394-2
eBook Packages: Springer Book Archive