Journal of Vascular Research
Research Paper
Selective Arterial Dilatation by Glyceryl Trinitrate Is Not Associated with Nitric Oxide Formation in vitroMiller M.R. · Grant S. · Wadsworth R.M.Department of Physiology and Pharmacology, University of Strathclyde, Glasgow, UK
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Article / Publication Details
Received: May 24, 2007
Accepted: November 21, 2007
Published online: March 20, 2008
Issue release date: August 2008
Number of Print Pages: 11
Number of Figures: 3
Number of Tables: 1
ISSN: 1018-1172 (Print)
eISSN: 1423-0135 (Online)
For additional information: https://www.karger.com/JVR
Abstract
Aims: Glyceryl trinitrate (GTN) is the most commonly used anti-anginal agent, yet its mechanism of action has still to be fully established. Release of nitric oxide (NO) and the selectivity of GTN in the venous system are believed to be crucial to this drug’s anti-anginal action. Methods: Rat superior mesenteric arteries and renal veins were mounted in a wire myograph with an intraluminal NO microsensor. Results: In the superior mesenteric arteries, GTN (1 nM to 10 µM) produced a dose-dependent vasodilatation without NO release, except at concentrations supramaximal for relaxation. GTN was found to be markedly less potent in a wide range of veins tested, and lowering the oxygen concentrations in the myograph to that of the venous system did not improve the venodilator activity of GTN. Conclusion: This is the first time that NO release from GTN has been monitored electrochemically in real time, simultaneously with vasodilatation. Unlike the endothelium-dependent vasodilator carbachol, NO could only be measured at concentrations of GTN that are supramaximal for relaxation. GTN was found to be arterioselective in vitro, even when oxygen levels were lowered to mimic those of the venous system in vivo.
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References
- Abrams J: Mechanisms of action of the organic nitrates in the treatment of myocardial ischemia. Am J Cardiol 1992;70:30B–42B.
- Ignarro LJ: After 130 years, the molecular mechanism of action of nitroglycerin is revealed. Proc Natl Acad Sci USA 2002;99:7816–7817.
- Bassenge E, Zanzinger J: Nitrates in different vascular beds, nitrate tolerance, and interactions with endothelial function. Am J Cardiol 1992;70:23B–29B.
- Bassenge E, Strein K: Dose-dependent effects of isosorbide-5-mononitrate on the venous, arterial and coronary arterial system of conscious dogs. Naunyn Schmiedebergs Arch Pharmacol 1986;334:100–104.
- Bauer JA, Fung HL: Differential hemodynamic effects and tolerance properties of nitroglycerin and an S-nitrosothiol in experimental heart failure. J Pharmacol Exp Ther 1991;256:249–254.
- Gruhn N, Boesgaard S, Eiberg J, Bang L, Thiis J, Schroeder TV, Aldershvile J: Effects of large conductance Ca2+-activated K+ channels on nitroglycerin-mediated vasorelaxation in humans. Eur J Pharmacol 2002;446:145–150.
- Sage PR, de la Lande IS, Stafford I, Bennett CL, Phillipov G, Stubberfield J, Horowitz JD: Nitroglycerin tolerance in human vessels: evidence for impaired nitroglycerin bioconversion. Circulation 2000;102:2810–2815.
- Sogo N, Campanella C, Webb DJ, Megson IL: S-nitrosothiols cause prolonged, nitric oxide-mediated relaxation in human saphenous vein and internal mammary artery: therapeutic potential in bypass surgery. Br J Pharmacol 2000;131:1236–1244.
- Uydes-Dogan BS, Nebigil M, Aslamaci S, Onuk E, Kanzik I, Akar F: The comparison of vascular reactivities of arterial and venous grafts to vasodilators: management of graft spasm. Int J Cardiol 1996;53:137–145.
- Edwards JC, Ignarro LJ, Hyman AL, Kadowitz PJ: Relaxation of intrapulmonary artery and vein by nitrogen oxide-containing vasodilators and cyclic GMP. J Pharmacol Exp Ther 1984;228:33–42.
- Rosen R, Konig E, Klaus W: Different sensitivities of arteries and veins to glyceryltrinitrate-induced relaxation and tolerance: an ‘in vitro’ study on isolated vessels from rabbits. Arch Int Pharmacodyn Ther 1987;285:226–237.
- Khan SA, Higdon NR, Meisheri KD: Coronary vasorelaxation by nitroglycerin: involvement of plasmalemmal calcium-activated K+ channels and intracellular Ca++ stores. J Pharmacol Exp Ther 1998;284:838–846.
- Tsai SC, Adamik R, Manganiello VC, Moss J: Effects of nitroprusside and nitroglycerin on cGMP content and PGI2 formation in aorta and vena cava. Biochem Pharmacol 1989;38:61–65.
- Sutton SC, Fung HL: Effect of dosage regimen on the development of tolerance to nitroglycerin in rats. J Cardiovasc Pharmacol 1983;5:1086–1092.
- Kreye VA, Stiefel A: In vivo and in vitro studies to elucidate the hemodynamic differences of sodium nitroprusside, nitroglycerin, and two isosorbide nitrates. Z Kardiol 1983;72(suppl 3):52–55.
- MacAllister RJ, Calver AL, Riezebos J, Collier J, Vallance P: Relative potency and arteriovenous selectivity of nitrovasodilators on human blood vessels: an insight into the targeting of nitric oxide delivery. J Pharmacol Exp Ther 1995;273:154–160.
- Chen Z, Foster MW, Zhang J, Mao L, Rockman HA, Kawamoto T, Kitagawa K, Nakayama KI, Hess DT, Stamler JS: An essential role for mitochondrial aldehyde dehydrogenase in nitroglycerin bioactivation. Proc Natl Acad Sci USA 2005;102:12159–12164.
- Kollau A, Hofer A, Russwurm M, Koesling D, Keung WM, Schmidt K, Brunner F, Mayer B: Contribution of aldehyde dehydrogenase to mitochondrial bioactivation of nitroglycerin: evidence for the activation of purified soluble guanylate cyclase through direct formation of nitric oxide. Biochem J 2005;385:769–777.
- Sydow K, Daiber A, Oelze M, Chen Z, August M, Wendt M, Ullrich V, Mulsch A, Schulz E, Keaney JF Jr, Stamler JS, Munzel T: Central role of mitochondrial aldehyde dehydrogenase and reactive oxygen species in nitroglycerin tolerance and cross-tolerance. J Clin Invest 2004;113:482–489.
- Wenzel P, Hink U, Oelze M, Seeling A, Isse T, Bruns K, Steinhoff L, Brandt M, Kleschyov AL, Schulz E, Lange K, Weiner H, Lehmann J, Lackner KJ, Kawamoto T, Munzel T, Daiber A: Number of nitrate groups determines reactivity and potency of organic nitrates: a proof of concept study in ALDH-2–/– mice. Br J Pharmacol 2007;150:526–533.
- Chen Z, Zhang J, Stamler JS: Identification of the enzymatic mechanism of nitroglycerin bioactivation. Proc Natl Acad Sci USA 2002;99:8306–8311.
- Brien JF, McLaughlin BE, Nakatsu K, Marks GS: Chemiluminescence headspace-gas analysis for determination of nitric oxide formation in biological systems. Methods Enzymol 1996;268:83–92.
- Kojima H, Urano Y, Kikuchi K, Higuchi T, Hirata Y, Nagano T: Fluorescent indicators for imaging nitric oxide production. Angew Chem Int Ed Engl 1999;38:3209–3212.
- Núñez C, Víctor VM, Tur R, Alvarez-Barrientos A, Moncada S, Esplugues JV, D’Ocón P: Discrepancies between nitroglycerin and NO-releasing drugs on mitochondrial oxygen consumption, vasoactivity, and the release of NO. Circ Res 2005;97:1063–1069.
- Kleschyov AL, Munzel T: Advanced spin trapping of vascular nitric oxide using colloid iron diethyldithiocarbamate. Methods Enzymol 2002;359:42–51.
- Wadsworth R, Stankevicius E, Simonsen U: Physiologically relevant measurements of nitric oxide in cardiovascular research using electrochemical microsensors. J Vasc Res 2006;43:70–85.
- Mulvany MJ, Halpern W: Contractile properties of small arterial resistance vessels in spontaneously hypertensive and normotensive rats. Circ Res 1977;41:19–26.
- Simonsen U, Wadsworth RM, Buus NH, Mulvany MJ: In vitro simultaneous measurements of relaxation and nitric oxide concentration in rat superior mesenteric artery. J Physiol 1999;516:271–282.
-
Guyton AC, Hall JE: Textbook of Medical Physiology, ed 10. Philadelphia, WB Saunders, 2000.
- Karamsetty MR, Wadsworth RM, Kane KA: Effect of K+ channel blocking drugs and nitric oxide synthase inhibition on the response to hypoxia in rat pulmonary artery rings. J Auton Pharmacol 1998;18:49–56.
- MacKenzie A, Wadsworth RM: Extracellular L-arginine is required for optimal NO synthesis by eNOS and iNOS in the rat mesenteric artery wall. Br J Pharmacol 2003;139:1487–1497.
- Mathewson AM, Wadsworth RM: Induction of iNOS restricts functional activity of both eNOS and nNOS in pig cerebral artery. Nitric Oxide 2004;11:331–339.
- Bennett BM, Leitman DC, Schroder H, Kawamoto JH, Nakatsu K, Murad F: Relationship between biotransformation of glyceryl trinitrate and cyclic GMP accumulation in various cultured cell lines. J Pharmacol Exp Ther 1989;250:316–323.
- Chung SJ, Fung HL: Identification of the subcellular site for nitroglycerin metabolism to nitric oxide in bovine coronary smooth muscle cells. J Pharmacol Exp Ther 1990;253:614–619.
- Schror K, Forster S, Woditsch I: On-line measurement of nitric oxide release from organic nitrates in the intact coronary circulation. Naunyn Schmiedebergs Arch Pharmacol 1991;344:240–246.
- Hanspal IS, Magid KS, Webb DJ, Megson IL: The effect of oxidative stress on endothelium-dependent and nitric oxide donor-induced relaxation: implications for nitrate tolerance. Nitric Oxide 2002;6:263–270.
- Miller MR, Okubo K, Roseberry MJ, Webb DJ, Megson IL: Extracellular nitric oxide release mediates soluble guanylate cyclase-independent vasodilator action of spermine NONOate: comparison with other nitric oxide donors in isolated rat femoral arteries. J Cardiovasc Pharmacol 2004;43:440–451.
- Daiber A, Oelze M, Coldewey M, Bachschmid M, Wenzel P, Sydow K, Wendt M, Kleschyov AL, Stalleicken D, Ullrich V, Mulsch A, Munzel T: Oxidative stress and mitochondrial aldehyde dehydrogenase activity: a comparison of pentaerythritol tetranitrate with other organic nitrates. Mol Pharmacol 2004;66:1372–1382.
- Mollnau H, Wenzel P, Oelze M, Treiber N, Pautz A, Schulz E, Schuhmacher S, Reifenberg K, Stalleicken D, Scharffetter-Kochanek S, Kleinert H, Munzel T, Daiber A: Mitochondrial oxidative stress and nitrate tolerance – comparison of nitroglycerin and pentaerithrityl tetranitrate in Mn-SOD+/– mice. BMC Cardiovasc Disord 2006;6:44.
- Kleschyov AL, Oelze M, Daiber A, Huang Y, Mollnau H, Schulz E, Sydow K, Fichtlscherer B, Mulsch A, Munzel T: Does nitric oxide mediate the vasodilator activity of nitroglycerin? Circ Res 2003;93:e104–e112.
- Janero DR, Bryan NS, Saijo F, Dhawan V, Schwalb DJ, Warren MC, Feelisch M: Differential nitros(yl)ation of blood and tissue constituents during glyceryl trinitrate biotransformation in vivo. Proc Natl Acad Sci USA 2004;101:16958–16963.
- Malinski T, Taha Z: Nitric oxide release from a single cell measured in situ by a porphyrinic-based microsensor. Nature 1992;358:676–678.
- Kojima H, Hirotani M, Nakatsubo N, Kikuchi K, Urano Y, Higuchi T, Hirata Y, Nagano T: Bioimaging of nitric oxide with fluorescent indicators based on the rhodamine chromophore. Anal Chem 2001;73:1967–1973.
- Dikalov S, Fink B, Skatchkov M, Stalleicken D, Bassenge E: Formation of reactive oxygen species by pentaerithrityltetranitrate and glyceryl trinitrate in vitro and development of nitrate tolerance. J Pharmacol Exp Ther 1998;286:938–944.
- Keimer R, Stutzer FK, Tsikas D, Troost R, Gutzki FM, Frolich JC: Lack of oxidative stress during sustained therapy with isosorbide dinitrate and pentaerythrityl tetranitrate in healthy humans: a randomized, double-blind crossover study. J Cardiovasc Pharmacol 2003;41:284–292.
- Collier JG, Lorge RE, Robinson BF: Comparison of effects of tolmesoxide (RX71107), diazoxide, hydrallazine, prazosin, glyceryl trinitrate and sodium nitroprusside on forearm arteries and dorsal hand veins of man. Br J Clin Pharmacol 1978;5:35–44.
- Mackenzie JE, Parratt JR: Comparative effects of glyceryl trinitrate on venous and arterial smooth muscle in vitro; relevance to antianginal activity. Br J Pharmacol 1977;60:155–160.
- Miller RR, Vismara LA, Williams DO, Amsterdam EA, Mason DT: Pharmacological mechanisms for left ventricular unloading in clinical congestive heart failure: differential effects of nitroprusside, phentolamine, and nitroglycerin on cardiac function and peripheral circulation. Circ Res 1976;39:127–133.
- Stiefel A, Kreye VA: On the haemodynamic differences between sodium nitroprusside, nitroglycerin, and isosorbide nitrates: comparison of their vasorelaxant effects in vitro and of their inactivation in vivo. Naunyn Schmiedebergs Arch Pharmacol 1984;325:270–274.
- Luscher TF, Yang Z, Tschudi M, von Segesser L, Stulz P, Boulanger C, Siebenmann R, Turina M, Buhler FR: Interaction between endothelin-1 and endothelium-derived relaxing factor in human arteries and veins. Circ Res 1990;66:1088–1094.
- Yang ZH, Buhler FR, Diederich D, Luscher TF: Different effects of endothelin-1 on cAMP- and cGMP-mediated vascular relaxation in human arteries and veins: comparison with norepinephrine. J Cardiovasc Pharmacol 1989;13(suppl 5):S129–S131.
- Agvald P, Adding LC, Artlich A, Persson MG, Gustafsson LE: Mechanisms of nitric oxide generation from nitroglycerin and endogenous sources during hypoxia in vivo. Br J Pharmacol 2002;135:373–382.
- Bennett BM, McDonald BJ, St James MJ: Hepatic cytochrome P-450-mediated activation of rat aortic guanylyl cyclase by glyceryl trinitrate. J Pharmacol Exp Ther 1992;261:716–723.
- Marks GS, McLaughlin BE, Nakatsu K, Brien JF: Direct evidence for nitric oxide formation from glyceryl trinitrate during incubation with intact bovine pulmonary artery. Can J Physiol Pharmacol 1992;70:308–311.
- Thatcher GR, Nicolescu AC, Bennett BM, Toader V: Nitrates and NO release: contemporary aspects in biological and medicinal chemistry. Free Radic Biol Med 2004;37:1122–1143.
- Lamping KG, Bloom EN: Comparison of coronary microvascular response to nipradilol and nitroglycerin. Pharmacology 1995;51:315–322.
- Ogilvie RI: Effect of nitroglycerin on peripheral blood flow distribution and venous return. J Pharmacol Exp Ther 1978;207:372–380.
- Imhof PR, Ott B, Frankhauser P, Chu LC, Hodler J: Difference in nitroglycerin dose-response in the venous and arterial beds. Eur J Clin Pharmacol 1980;18:455–460.
- Bassenge E, Stewart DJ: Effects of nitrates in various vascular sections and regions. Z Kardiol 1986;75(suppl 3):1–7.
- Vatner SF, Pagani M, Rutherford JD, Millard RW, Manders WT: Effects of nitroglycerin on cardiac function and regional blood flow distribution in conscious dogs. Am J Physiol 1978;234:H244–H252.
- Franciosa JA, Blank RC, Cohn JN: Nitrate effects on cardiac output and left ventricular outflow resistance in chronic congestive heart failure. Am J Med 1978;64:207–213.
- Packer M: Mechanisms of nitrate action in patients with severe left ventricular failure: conceptual problems with the theory of venosequestration. Am Heart J 1985;110:259–264.
-
Petrovich LJ, Smith GB, Quinones MA, Adyanthaya AV, Alexander JK: Hemodynamic effects of nitroglycerin vs pure preload reduction: masked arteriolar dilatory effect. Circulation 1978;59(suppl II):273.
Article / Publication Details
Received: May 24, 2007
Accepted: November 21, 2007
Published online: March 20, 2008
Issue release date: August 2008
Number of Print Pages: 11
Number of Figures: 3
Number of Tables: 1
ISSN: 1018-1172 (Print)
eISSN: 1423-0135 (Online)
For additional information: https://www.karger.com/JVR
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