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Arzneimittelforschung 2010; 60(4): 189-197
DOI: 10.1055/s-0031-1296272
Cardiac Drugs · Cardiac Stimulants · Coronary Drugs
Editio Cantor Verlag Aulendorf (Germany)

Comparison of vasorelaxant effect and tolerance profile of a novel isosorbide-5-mononitrate derivative with its stereoisomer and parent drug on rat mesenteric artery

Radica M Stepanović-Petrović
1   Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Serbia
,
Vladimir Savić
2   Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Serbia
,
Maja A. Tomić
1   Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Serbia
,
Zorana Tokic-Vujošević
2   Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Serbia
,
Milena Simić
2   Department of Organic Chemistry, Faculty of Pharmacy, University of Belgrade, Serbia
,
Jelena M. Stepanović
3   Department of Cardiology, Diagnostic and Catheterization Laboratories, Institute for Cardiovascular Diseases, Clinical Center of Serbia, Belgrade, Serbia
,
Milan Jokanović
4   Faculty of Medicine, University of Nish, Serbia
,
Ana Micov
1   Department of Pharmacology, Faculty of Pharmacy, University of Belgrade, Serbia
› Institutsangaben
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Publikationsverlauf

Publikationsdatum:
02. Dezember 2011 (online)

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Abstract

Background/Aims:

5-Ketoximeisosorbide-2-mononitrate (5O-IS-2-MN) was synthesized and its pharmacological and texicological characteristics were examined and compared with its parent drug, isosor-bide-5-mononitrate (IS-5-MN, CAS 16051-77-7), and its diastereoisomer 2-ketoximeisosorbide-5-mononitrate.

Methods:

Vasorelaxation was studied on phenylephrine-precontracted rat superior mesenteric artery rings in organ bath procedure. In some rings, the endothelium was mechanically removed. In vitro tolerance was induced by treating the precontracted rings with maximal concentrations of the parent drug and the ketoximes, and after washing out, the procedure was repeated for two times. Furthermore, rats were treated with a single oral dose (1000 mg/kg) of 5O-IS-2-MN and 2O-IS-5-MN.

Results:

After a phenylephrine-induced contraction, 5O-IS-2-MN (10−8–10−4 mol/l) caused a concentration-dependent relaxation of the rat superior mesenteric artery that was strongly potentiated after the removal of the vascular endothelium. In preparations with or without endothelium, 5O-IS-2-MN was a more potent relaxant than either the parent compound or its isomer. The mechanism of the relaxant effect of 5O-IS-2-MN involves the activated soluble guanylyl cyclase-cyclic GMP pathway. Hydralazine (10−5 mol/l), a strong antioxidant, ameliorated tolerance to IS-5-MN, but did not affect the absence of tolerance to either ketoxime. The minimum lethal dose in rat for 5O-IS-2-MN and 2O-IS-5-MN was greater than 1000 mg/kg.

Conclusion:

These results suggest that the modification of the configuration at the ester carbon of IS-5-MN contributes to more potent and tolerance-devoid activity on the rat superior mesenteric artery.

Key words

Endothelium - Hydralazine - 5-Ketoximeisosorbide-2-mononitrate - Nitrate tolerance - Organic nitrates
 

  • Literature

  • 1 Müller S, Laber U, Müllenheim J, Meyer W, Kojda G. Preserved endothelial function after long-term eccentric iso-sorbide mononitrate despite moderate nitrate tolerance. J Am Coll Cardiol. 2003; 41: 1994-2000
    CrossrefPubMedGoogle Scholar
  • 2 Daiber A, Oelze M, Coldewey M, Bachschmid M, Wenzel P, Sydow K et al Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaery-thritol tetranitrate with other organic nitrates. Mol Pharmacol. 2004; 66: 1372-82
    CrossrefPubMedGoogle Scholar
  • 3 Thomas GR, DiFabio JM, Gori T, Parker JD. Once daily therapy with isosorbide-5-mononitrate causes endothelial dysfunction in humans: evidence of a free-radical-mediated mechanism. J Am Coll Cardiol. 2007; 49: 1289-95
    CrossrefPubMedGoogle Scholar
  • 4 Gutterman DD. Combating nitrate tolerance: a novel endogenous mechanism. Arterioscler Thromb Vasc Biol. 2007; 27: 1673-6
    CrossrefPubMedGoogle Scholar
  • 5 Stepanović-Petrović RM, Vujošević ZT, Milovanović S, Čeković Ž, Bokonjić D, Dobrić S. Pharmacological evaluation of a novel oxime derived from isosorbide-5-mononitrate on isolated rat superior mesenteric artery. Pharmazie. 2002; 57: 507-8
    PubMedGoogle Scholar
  • 6 Stepanović-Petrović RM, Tokić-Vujošević Z, Milovanović S, Čeković Ž, Tomić MA. Comparison of the relaxant effects of a new oxime-nitrate derived from isosorbide-5-mononi-trate and the parent drug. Arzneimittelforschung. 2004; 54 (4) 195-202
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 7 Murad F. Cellular signaling with nitric oxide and cyclic GMP. Braz J Med Biol Res. 1999; 32: 1317-27
    PubMedGoogle Scholar
  • 8 Ignarro LJ. Nitric oxide: a unique endogenous signaling molecule in vascular biology (Nobel lecture). Angew Chem Int Ed. 1999; 38: 1882-92
    CrossrefPubMedGoogle Scholar
  • 9 Eur Pat Application 57 847 (1981, inventor); Chem Abstr 98, 54 395 1983
    PubMed
  • 10 Tokić-Vujošević Z, Čeković Z. Synthesis of new stereoiso-meric nitrate esters derived from isosorbide-mononitrate II: bicyclic d-lactams and tetrahydrofuran derivatives. Synthesis. 2001; 13: 2028-34
    Artikel in Thieme ConnectPubMedGoogle Scholar
  • 11 Katušić ZS, Shepherd JT, Vanhoutte PM. Vasopressin causes endothelium-dependent relaxations of the canine basilar artery. Circ Res. 1984; 55: 575-9
    CrossrefPubMedGoogle Scholar
  • 12 Krstić MK, Stepanović RM, Krstić SK, Katušić ZS. Endothelium-dependent relaxation of the rat renal artery caused by activation of histamine H1-receptors. Pharmacology. 1989; 38: 113-20
    CrossrefPubMedGoogle Scholar
  • 13 Furchgott RF, Zawadzki JV. The obligatory role of endothelial cells in the relaxation of arterial smooth muscle by acetylcholine. Nature. 1980; 288: 373-6
    CrossrefPubMedGoogle Scholar
  • 14 Tallarida RJ, Murray RB. Manual of Pharmacologic Calculations with Computer Programs. 2nd ed. New York: Springer Verlag; 1986
    CrossrefGoogle Scholar
  • 15 Lüscher TF, Richard V, Yang ZH. Interaction between en-dothelium-derived nitric oxide and SIN-1 in human and porcine blood vessels. J Cardiovasc Pharmacol. 1989; 14: S76-S80
    PubMedGoogle Scholar
  • 16 Koenig A, Lange K, Konter J, Daiber A, Stalleicken D, Glusa E et al Potency and in vitro tolerance of organic nitrates: partially denitrated metabolites contribute to the tolerance-devoid activity of pentaerythrityl tetranitrate. Cardiovasc Pharmacol. 2007; 50: 68-74
    CrossrefPubMedGoogle Scholar
  • 17 Morrow DA, Gersh BJ. Chronic coronary artery disease. In: Libby P, Bonow RO, Mann DL, Zipes DP. editors. Braun-wald’s Heart Disease A textbook of cardiovascular medicine. 8th ed. Philadelphia (USA): Elsevier Saunders; 2008: 1353-1417
    Google Scholar
  • 18 Axelsson KL, Andersson RG. Tolerance towards nitroglycerin, induced in vivo, is correlated to a reduced cGMP response and an alteration in cGMP turnover. Eur J Pharmacol. 1983; 88: 71-9
    CrossrefPubMedGoogle Scholar
  • 19 Kojda G, Beck JK, Meyer W, Noack E. Nitrovasodilator-in-duced relaxation and tolerance development in porcine vena cordis magna: dependence on intact endothelium. Br J Pharmacol. 1994; 112: 533-40
    CrossrefPubMedGoogle Scholar
  • 20 Feelisch M, Noack EA. Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Pharmacol. 1987; 139: 19-30
    CrossrefPubMedGoogle Scholar
  • 21 Koenig A, Roegler C, Lange K, Daiber A, Glusa E, Lehmann J. NO donors. Part 16: investigations on structure-activity relationships of organic mononitrates reveal 2-nitrooxy-ethylammoniumnitrate as a high potent vasodilator. Bioorg Med Chem Lett. 2007; 17: 5881-5
    CrossrefPubMedGoogle Scholar
  • 22 Michel T. Treatment of myocardial ischemia. In: Brunton LL, Lazo JS, Parker KL. editors Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 11th ed. New York: McGraw-Hill Medical Publishing Division; 2006: 823-844
    Google Scholar
  • 23 Rang HP, Dale MM, Ritter JM. The heart. In: Rang and Dale’s Pharmacology. 6th ed. Oxford: Churchill Livingstone; 2007: 277-297
    CrossrefGoogle Scholar
  • 24 Bang L, Boesgaard S, Nielsen-Kudsk JE, Vejlstrup NG, Al-dershvile J. Nitroglycerin-mediated vasorelaxation is modulated by endothelial calcium-activated potassium channels. Cardiovas Res. 1999; 43: 772-8
    CrossrefPubMedGoogle Scholar
  • 25 Gruhn N, Boesgaard S, Eiberg J, Bang L, Thiis J, Schroeder TV et al Effects of large conductance Ca2+-activated K+ channels on nitroglycerin-mediated vasorelaxation in humans. Eur J Pharmacol. 2002; 446: 145-50
    CrossrefPubMedGoogle Scholar
  • 26 Núñez C, Víctor VM, Tur R, Alvarez-Barrientos A, Moncada S, Esplugues JV et al Discrepancies between nitroglycerin and NO-releasing drugs on mitochondrial oxygen consumption, vasoactivity, and the release of NO. Circ Res. 2005; 97: 1063-9
    CrossrefPubMedGoogle Scholar
  • 27 Alzawahra WF, Talukder MA, Lui X, Samouilov A, Zweier JL. Heme proteins mediate the conversion of nitrite to nitric oxide in the vascular wall. Am J Physiol Heart Circ Physiol. 2008; 295: H499-H508
    CrossrefPubMedGoogle Scholar
  • 28 Münzel T, Kurz S, Heitzer T, Harrison DG. New insights into mechanisms underlying nitrate tolerance. Am J Cardiol. 1996; 77: C24-C30
    CrossrefPubMedGoogle Scholar
  • 29 Münzel T, Daiber A, Mulsch A. Explaining the phenomenon of nitrate tolerance. Circ Res. 2005; 97: 618-28
    CrossrefPubMedGoogle Scholar
  • 30 Daiber A, Oelze M, Wenzel P, Wickramanayake JM, Schuhmacher S, Jansen T et al Nitrate tolerance as a model of vascular dysfunction: roles for mitochondrial aldehyde dehydrogenase and mitochondrial oxidative stress. Pharmacol Rep. 2009; 61: 33-48
    PubMedGoogle Scholar
  • 31 Gori T, Parker JD. Nitrate tolerance: a unifying hypothesis. Circulation. 2002; 106: 2510-3
    CrossrefPubMedGoogle Scholar
  • 32 Klemenska E, Beresewicz A. Bioactivation of organic nitrates and the mechanism of nitrate tolerance. Cardiol J. 2009; 16: 11-9
    PubMedGoogle Scholar
  • 33 Unger P, Berkenboom G, Fontaine J. Interaction between hydralazine and nitrovasodilators in vascular smooth muscle. J Cardiovasc Pharmacol. 1993; 21: 478-83
    CrossrefPubMedGoogle Scholar
  • 34 Münzel T, Kurz S, Rajagopalan S, Thoenes M, Berrington WR, Thompson JA et al Hydralazine prevents nitroglycerin tolerance by inhibiting activation of a membrane-bound NADH oxidase. A new action for an old drug. J Clin Invest. 1996; 98: 1465-70
    CrossrefPubMedGoogle Scholar
  • 35 Elkayam U, Canetti M, Wani OR, Karaalp IS, Tummala PP. Hydralazine-induced prevention of nitrate tolerance: experimental and clinical evidence and potential mechanisms. Am J Cardiol. 1998; 81: 44A-48A
    CrossrefPubMedGoogle Scholar
  • 36 Taylor AL, Ziesche S, Yancy C, Carson P, D’Agostino Jr R, Ferdinand K et al Combination of isosorbide dinitrate and hydralazine in Blacks with heart failure. N Engl J Med. 2004; 351: 2049-57
    CrossrefPubMedGoogle Scholar
  • 37 Daiber A, Oelze M, Coldewey M, Kaiser K, Huth C Schildknecht et al Hydralazine is a powerful inhibitor of peroxy-nitrite formation as a possible explanation for its beneficial effects on prognosis in patients with congestive heart failure. Biochem Biophys Res Commun. 2005; 338: 1865-74
    CrossrefPubMedGoogle Scholar