Summary
Tolerance to the cyclic GMP-mediated vasodilator action of nitroglycerin develops with prolonged exposure and may be mediated either by formation of less nitric oxide from nitroglycerin or by desensitization of soluble guanylate cyclase to activation with nitric oxide. In the latter case, smooth muscle cells tolerant to nitroglycerin should show cross-tolerance to nitric oxide released from sydnonimines and endothelial cells (endothelium-derived relaxing factor).
Therefore cultured smooth muscle cells from rabbit aorta were pretreated for 1 h with vehicle or high concentrations (0.55 mM) of nitroglycerin or the sydnonimine SIN-1. The formation of cyclic GMP induced by subsequent small doses of nitroglycerin, sydnonimine SIN-1 and endothelium-derived relaxing factor (released from cultured endothelial cells) was compared with the changes in activation of soluble guanylate cyclase, cyclic GMP formation and vasodilation in response to the same stimuli in similarly pretreated segments from rabbit thoracic aortae.
Both cultured and native smooth muscle cells remained responsive to stimulation with sydnonimine SIN-1 and endothelium-derived relaxing factor after pretreatment with nitroglycerin, vehicle, or sydnonimine SIN-1, even though they were tolerant to nitroglycerin after pretreatment with nitroglycerin. In contrast, activation of soluble guanylate cyclase by nitroglycerin and sydnonimine SIN-1 was attenuated in homogenates of nitrate-tolerant aortae. The findings suggest that nitroglycerin tolerance in intact cells does not involve desensitization of soluble guanylate cyclase, because in intact cells nitrate tolerance can be overcome by direct activators of soluble guanylate cyclase.
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References
Axelsson KL, Anderson RGG (1983) Tolerance towards nitroglycerin, induced in vivo, is correlated to a reduced cGMP response and an alteration in cGMP turnover. Eur J Pharmacol 88:71–79
Axelsson KL, Ahlner J (1987) Nitrate tolerance from a biochemical point of view. Drugs 33 (Suppl 4):63–68
Bassenge E, Mülsch A, Stewart DJ (1988) Nitroglycerin tolerance and endothelium-dependent vasodilation. In: Halpern W, Pegram B, Brayden J, Mackey K, McLaughlin M, Osol G (eds) Resistance arteries. Perinatology Press, Ithaca, NY, pp 3–9
Bennett BM, Kobus SM, Brien JF, Nakatsu K, Marks GS (1986a) Requirement for reduced, unliganded hemoprotein for the hemoglobin- and myoglobin-mediated biotransformation of glyceryl trinitrate. J Pharmacol Exp Ther 237:629–635
Bennet BM, Hayward LD, Murad F (1986b) Effect of d- and l-stereoisomers of isoidide dinitrate on relaxation and cyclic GMP accumulation in rat aorta and comparison to glyceryl trinitrate. J Appl Cardiol 1:203–209
Böhme E, Grossmann G, Herz J, Mülsch A, Spies C, Schultz G (1984) Regulation of cyclic GMP formation by soluble guanylate cyclase: stimulation by NO-containing compounds. Adv Cycl Nucleotide Protein Phosphorylation Res 17:259–266
Brien JF, McLaughlin BE, Breedon TH, Bennett BM, Nakatsu K, Marks GS (1986) Biotransformation of glyceryl trinitrate occurs concurrently with relaxation of rabbit aorta. J Pharmacol Exp Ther 237:608–614
Busse R, Förstermann U, Matsuda H, Pohl U (1984) The role of prostaglandins in the endothelium-mediated vasodilatory response to hypoxia. Pflügers Arch 401:77–83
Feelisch M, Noack EA (1987) Correlation between nitric oxide formation during degradation of organic nitrates and activation of guanylate cyclase. Eur J Biochem 139:19–30
Förstermann U, Goppelt-Strübe M, Frölich JC, Busse R (1986) Inhibitors of acyl-Coenzyme A:lysolecithin acyltransferase activate the production of endothelium-derived vascular relaxing factor. J Pharmacol Exp Ther 238:352–359
Fung HL, Sutton SC, Kamiya A (1984) Blood vessel uptake and metabolism of organic nitrates in the rat. J Pharmacol Exp Ther 228:334–341
Furchgott RF (1988) Studies on relaxation of rabbit aorta by sodium nitrite: the basis for the proposal that the acid-activatable inhibitory factor from bovine retractor penis is inorganic nitrite and the endothelium-derived relaxing factor is nitric oxide. In: Vanhoutte PM (ed) Vasodilatation, vol 4. Raven Press, New York, pp 401–414
Ganz P, Davies PF, Leopold JA, Gimbrone MA, Alexander RW (1986) Short- and long-term interactions of endothelium and vascular smooth muscle in coculture: effects on cyclic GMP production. Proc Natl Acad Sci USA 83:3552–3556
Gruetter CA, Lemke SM (1985) Dissociation of cysteine and glutathione levels from nitroglycerin-induced relaxation. Eur J Pharmacol 111: 85–95
Gruetter CA, Lemke SM (1986) Effects of sulfhydryl reagents on nitroglycerin-induced relaxation of bovine coronary artery. Can J Physiol Pharmacol 64:1395–1401
Gruetter CA, Kadowitz PJ, Ignarro LJ (1981) Methylene blue inhibits coronary arterial relaxation and guanylate cyclase activation by nitroglycerin, sodium nitrite and amyl nitrite. Can J Physiol Pharmacol 59:150–156
Harris DW, Baker CA, Saneii HH, Johnson GA (1985) Stimulation of cyclic GMP formation in smooth muscle cells by atriopeptin II. Life Sci 37:591–597
Keith RA, Burkman AM, Sokoloski TD, Fertel RH (1982) Vascular tolerance to nitroglycerin and cyclic GMP generation in rat aortic smooth muscle. J Pharmacol Exp Ther 221:525–531
Kowaluk EA, Fung HL (1988) Effect of nitroglycerin (NTG) tolerance on nitrovasodilator-induced and endothelium-dependent relaxation of isolated rat aorta. FASEB J 2: A496
Kukovetz WR, Holzmann S (1986a) Cyclic GMP as the mediator of molsidomine-induced vasodilatation. Eur J Pharmacol 122:103–109
Kukovetz WR, Holzmann S (1986b) Mode of action of nitrates with regard to vasodilatation and tolerance. Z Kardiol 75 (Suppl 3):8–11
Kuropteva ZV, Pastushenko ON (1985) Change in paramagnetic blood and liver complexes in animals under the influence of nitroglycerin. Dokl Akad Nauk SSSR 281:189–192
Ljusegren ME, Ahlner J, Axelsson KL (1988) Studies on vascular smooth muscle tolerance to different cGMP-mediated vasodilators and cross-tolerance to glyceryl trinitrate. Pharmacol Toxicol 62:302–307
Lowry OH, Rosebrough NJ, Farr AL, Randall RJ (1951) Protein measurement with the Folin phenol reagent. J Biol Chem 193:265–275
Lückhoff A, Busse R, Winter I, Bassenge E (1987) Characterization of vascular relaxant factor released from cultured endothelial cells. Hypertension 9:295–303
Mittal CK, Murad F (1982) Guanylate cyclase: regulation of cGMP metabolism. In: Nathanson JA, Kebabian JW (eds) Cyclic nucleotides 1. Springer, New York, pp 225–260
Molina CR, Andresen JW, Rapoport RM, Waldman S, Murad F (1987) Effect of in vivo nitroglycerin therapy on endothelium-dependent vascular relaxation and cyclic GMP accumulation in rat aorta. J Cardiovasc Pharmacol 10:371–378
Mülsch A, Böhme E, Busse R (1987) Stimulation of soluble guanylate cyclase by endothelium-derived relaxing factor from cultured endothelial cells. Eur J Pharmacol 135:247–250
Palmer RMJ, Ferrige AG, Moncada S (1987) Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 327:524–526
Pohl U, Busse R (1987) Endothelium-derived relaxant factor inhibits the effect of nitrocompounds in isolated arteries. Am J Physiol 252: H307-H313
Rapoport RM, Murad F (1983) Agonist-induced endothelium-dependent relaxation in rat thoracic aorta may be mediated through cGMP. Circ Res 52:352–357
Rapoport RM, Waldman SA, Ginsburg R, Molina C, Murad F (1987) Effects of glyceryl trinitrate on endothelium-dependent and -independent relaxation and cyclic GMP levels in rat aorta and human coronary artery. J Cardiovasc Pharmacol 10:82–89
Schenk DB, Johnson LK, Schwartz K, Sista H, Scarborough RM, Lewicki JA (1985) Distinct atrial natriuretic factor receptor sites on cultured bovine aortic smooth muscle and endothelial cells. Biochem Biophys Res Commun 127:433–442
Schröder H, Noack E, Müller R (1985) Evidence for a correlation between nitric oxide formation by cleavage of organic nitrates and activation of guanylate cyclase. J Mol Cell Cardiol 17:931–934
Schröder H, Leitman DC, Hayward LD, Bennet BM, Waldman SA, Murad F (1987) Cultured rat lung fibroblasts as a model for organic nitrate-induced cyclic GMP accumulation and activation of guanylate cyclase. J Appl Cardiol 2:301–311
Schröder H, Leitman DC, Bennett BM, Waldman SA, Murad F (1988) Glyceryl trinitrate-induced desensitization of guanylate cyclase in cultured rat lung fbroblasts. J Pharmacol Exp Ther 1–31
Schultz G, Böhme E (1984) Guanylate cyclase. In: Bergmeyer HU (ed) Methods of enzymatic analysis, vol 3. Verlag Chemie, Weinheim, pp 379–389
Steiner AL, Parker CW, Kipnis DM (1972) Radioimmunoassay for cyclic nucleotides. J Biol Chem 247:1106–1113
Stewart DJ, Elsner D, Sommer O, Holtz J, Bassenge E (1986) Altered spectrum of nitroglycerin action in longterm treatment: nitroglycerin-specific venous tolerance with maintenance of arterial vasodepressor potency. Circulation 74:573–582
Stewart DJ, Holtz J, Bassenge E (1987) Long-term nitroglycerin treatment: effect on direct and endothelium-mediated large coronary artery dilation in conscious dogs. Circulation 75:847–856
Van de Voorde J, Leusen I, Vanheel B (1987) Influence of vascular tolerance to nitroglycerin on endothelium-dependent relaxation. Arch Int Pharmacodyn Ther 290:215–221
Vanin AF, Mordvintsev PJ, Kleshchev AL (1984) Nitric oxide appearance in animal tissues in vivo. Stud Biophys 102:135–143
Waldman SA, Rapoport RM, Ginsburg R, Murad F (1986) Desensitization to nitroglycerin in vascular smooth muscle from rat and human. Biochem Pharmacol 35:3525–3531
Wallenstein S, Zucker CL, Fleiss JL (1980) Some statistical methods useful in circulation research. Circ Res 47:1–9
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Mülsch, A., Busse, R., Winter, I. et al. Endothelium- and sydnonimine-induced responses of native and cultured aortic smooth muscle cells are not impaired by nitroglycerin tolerance. Naunyn-Schmiedeberg's Arch Pharmacol 339, 568–574 (1989). https://doi.org/10.1007/BF00167263
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DOI: https://doi.org/10.1007/BF00167263