Skip to main content
NCBI home page
British Journal of Pharmacology logoLink to British Journal of Pharmacology
. 1995 Apr;114(7):1371–1382. doi: 10.1111/j.1476-5381.1995.tb13358.x

Influence of chronic treatment with a nitric oxide donor on fatty streak development and reactivity of the rabbit aorta.

H Bult 1, G R De Meyer 1, A G Herman 1
PMCID: PMC1510274  PMID: 7606341

Abstract

1. The influence of chronic treatment with molsidomine, pro-drug of the nitric oxide (NO) donor, 3-morpholino-sydnonimine (SIN-1), on fatty streak development and release of NO and prostacyclin (PGI2) was studied in the aorta of normal and cholesterol-fed rabbits. 2. Groups of 10 rabbits received standard diet (150 g day-1), or diets with 0.3% cholesterol, with 0.02% molsidomine or with the combination of cholesterol and molsidomine for 16 weeks. Lesion area and thickness, maximum change in isometric force (Emax) and sensitivity (-log EC50 or pD2) to constricting and relaxing agonists were assessed in segments of arch, thoracic and abdominal aorta. Bioassay was used to assess NO release. 3. Cholesterol-induced fatty streaks tapered off towards the abdominal aorta. Area, thickness, weight and cholesterylester content of the lesions were augmented by the NO donor, whereas the hypercholesterolaemia remained unchanged. The exacerbation was attributed to co-release of superoxide anion from the sydnonimine. 4. As fatty streaks progressed, amplitude and pD2 of acetylcholine (ACh)-induced relaxations decreased, whereas cyclic GMP and cyclic AMP second messenger systems were not influenced, since Emax and sensitivity to SIN-1 and forskolin remained unchanged. However, extensive lesions apparently trapped some NO, as the pD2 of authentic NO decreased. 5. The fatty streaks curtailed the biosynthesis of PGI2 and the overflow of NO from the perfused thoracic aorta. The latter defect was not restored by L-arginine and appears to be consistent with a functional change of the endothelial muscarinic receptors. 6. The NO donor desensitized the aorta to cyclic GMP-mediated relaxations (ACh, SIN-1 and NO), without affecting cyclic AMP-mediated relaxation to forskolin or constrictor responses to phenylephrine and 5-hydroxytryptamine. 7. The drug also suppressed the ACh-induced overflow of NO, without changing PGI2 release. This selective reduction of endothelial NO release and the desensitization of cyclic GMP-mediated relaxations occurred independently of fatty streak formation. 8. The results indicate that chronic exposure to exogenous NO downregulates endothelial NO release and cyclic GMP-mediated relaxations, and provide evidence for the existence of negative feed-back regulations of the L-arginine NO pathway under in vivo conditions.

Full text

PDF
1371

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Ahlner J., Andersson R. G., Torfgård K., Axelsson K. L. Organic nitrate esters: clinical use and mechanisms of actions. Pharmacol Rev. 1991 Sep;43(3):351–423. [PubMed] [Google Scholar]
  2. Assreuy J., Cunha F. Q., Liew F. Y., Moncada S. Feedback inhibition of nitric oxide synthase activity by nitric oxide. Br J Pharmacol. 1993 Mar;108(3):833–837. doi: 10.1111/j.1476-5381.1993.tb12886.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Beetens J. R., Coene M. C., Verheyen A., Zonnekeyn L., Herman A. G. Biphasic response of intimal prostacyclin production during the development of experimental atherosclerosis. Prostaglandins. 1986 Sep;32(3):319–334. doi: 10.1016/0090-6980(86)90002-x. [DOI] [PubMed] [Google Scholar]
  4. Bossaller C., Habib G. B., Yamamoto H., Williams C., Wells S., Henry P. D. Impaired muscarinic endothelium-dependent relaxation and cyclic guanosine 5'-monophosphate formation in atherosclerotic human coronary artery and rabbit aorta. J Clin Invest. 1987 Jan;79(1):170–174. doi: 10.1172/JCI112779. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Buga G. M., Griscavage J. M., Rogers N. E., Ignarro L. J. Negative feedback regulation of endothelial cell function by nitric oxide. Circ Res. 1993 Nov;73(5):808–812. doi: 10.1161/01.res.73.5.808. [DOI] [PubMed] [Google Scholar]
  6. Bult H., Fret H. R., Jordaens F. H., Herman A. G. Dipyridamole potentiates the anti-aggregating and vasodilator activity of nitric oxide. Eur J Pharmacol. 1991 Jun 18;199(1):1–8. doi: 10.1016/0014-2999(91)90629-5. [DOI] [PubMed] [Google Scholar]
  7. Bult H., Fret H. R., Van den Bossche R. M., Herman A. G. Platelet inhibition by endothelium-derived relaxing factor from the rabbit perfused aorta. Br J Pharmacol. 1988 Dec;95(4):1308–1314. doi: 10.1111/j.1476-5381.1988.tb11769.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cayatte A. J., Palacino J. J., Horten K., Cohen R. A. Chronic inhibition of nitric oxide production accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arterioscler Thromb. 1994 May;14(5):753–759. doi: 10.1161/01.atv.14.5.753. [DOI] [PubMed] [Google Scholar]
  9. Chin J. H., Azhar S., Hoffman B. B. Inactivation of endothelial derived relaxing factor by oxidized lipoproteins. J Clin Invest. 1992 Jan;89(1):10–18. doi: 10.1172/JCI115549. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Chobanian A. V., Haudenschild C. C., Nickerson C., Drago R. Antiatherogenic effect of captopril in the Watanabe heritable hyperlipidemic rabbit. Hypertension. 1990 Mar;15(3):327–331. doi: 10.1161/01.hyp.15.3.327. [DOI] [PubMed] [Google Scholar]
  11. Cooke J. P., Andon N. A., Girerd X. J., Hirsch A. T., Creager M. A. Arginine restores cholinergic relaxation of hypercholesterolemic rabbit thoracic aorta. Circulation. 1991 Mar;83(3):1057–1062. doi: 10.1161/01.cir.83.3.1057. [DOI] [PubMed] [Google Scholar]
  12. Cooke J. P., Singer A. H., Tsao P., Zera P., Rowan R. A., Billingham M. E. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest. 1992 Sep;90(3):1168–1172. doi: 10.1172/JCI115937. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Cowan C. L., Palacino J. J., Najibi S., Cohen R. A. Potassium channel-mediated relaxation to acetylcholine in rabbit arteries. J Pharmacol Exp Ther. 1993 Sep;266(3):1482–1489. [PubMed] [Google Scholar]
  14. Darley-Usmar V. M., Hogg N., O'Leary V. J., Wilson M. T., Moncada S. The simultaneous generation of superoxide and nitric oxide can initiate lipid peroxidation in human low density lipoprotein. Free Radic Res Commun. 1992;17(1):9–20. doi: 10.3109/10715769209061085. [DOI] [PubMed] [Google Scholar]
  15. Daugherty A., Schonfeld G., Sobel B. E., Lange L. G. Metabolism of very low density lipoproteins after cessation of cholesterol feeding in rabbits. A factor potentially contributing to the slow regression of atheromatous plaques. J Clin Invest. 1986 Apr;77(4):1108–1115. doi: 10.1172/JCI112409. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. De Meyer G. R., Bult H., Herman A. G. Early atherosclerosis is accompanied by a decreased rather than an increased accumulation of fatty acid hydroxyderivatives. Biochem Pharmacol. 1991 Jul 5;42(2):279–283. doi: 10.1016/0006-2952(91)90714-g. [DOI] [PubMed] [Google Scholar]
  17. De Meyer G. R., Bult H., Van Hoydonck A. E., Jordaens F. H., Buyssens N., Herman A. G. Neointima formation impairs endothelial muscarinic receptors while enhancing prostacyclin-mediated responses in the rabbit carotid artery. Circ Res. 1991 Jun;68(6):1669–1680. doi: 10.1161/01.res.68.6.1669. [DOI] [PubMed] [Google Scholar]
  18. Drexler H., Zeiher A. M., Meinzer K., Just H. Correction of endothelial dysfunction in coronary microcirculation of hypercholesterolaemic patients by L-arginine. Lancet. 1991 Dec 21;338(8782-8783):1546–1550. doi: 10.1016/0140-6736(91)92372-9. [DOI] [PubMed] [Google Scholar]
  19. Dupuis J., Lalonde G., Lemieux R., Rouleau J. L. Tolerance to intravenous nitroglycerin in patients with congestive heart failure: role of increased intravascular volume, neurohumoral activation and lack of prevention with N-acetylcysteine. J Am Coll Cardiol. 1990 Oct;16(4):923–931. doi: 10.1016/s0735-1097(10)80342-0. [DOI] [PubMed] [Google Scholar]
  20. Freiman P. C., Mitchell G. G., Heistad D. D., Armstrong M. L., Harrison D. G. Atherosclerosis impairs endothelium-dependent vascular relaxation to acetylcholine and thrombin in primates. Circ Res. 1986 Jun;58(6):783–789. doi: 10.1161/01.res.58.6.783. [DOI] [PubMed] [Google Scholar]
  21. Galle J., Busse R., Bassenge E. Hypercholesterolemia and atherosclerosis change vascular reactivity in rabbits by different mechanisms. Arterioscler Thromb. 1991 Nov-Dec;11(6):1712–1718. doi: 10.1161/01.atv.11.6.1712. [DOI] [PubMed] [Google Scholar]
  22. Guerra R., Jr, Brotherton A. F., Goodwin P. J., Clark C. R., Armstrong M. L., Harrison D. G. Mechanisms of abnormal endothelium-dependent vascular relaxation in atherosclerosis: implications for altered autocrine and paracrine functions of EDRF. Blood Vessels. 1989;26(5):300–314. doi: 10.1159/000158779. [DOI] [PubMed] [Google Scholar]
  23. Habib J. B., Bossaller C., Wells S., Williams C., Morrisett J. D., Henry P. D. Preservation of endothelium-dependent vascular relaxation in cholesterol-fed rabbit by treatment with the calcium blocker PN 200110. Circ Res. 1986 Feb;58(2):305–309. doi: 10.1161/01.res.58.2.305. [DOI] [PubMed] [Google Scholar]
  24. Harrison D. G., Armstrong M. L., Freiman P. C., Heistad D. D. Restoration of endothelium-dependent relaxation by dietary treatment of atherosclerosis. J Clin Invest. 1987 Dec;80(6):1808–1811. doi: 10.1172/JCI113276. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Havel R. J. George Lyman Duff memorial lecture. Role of the liver in atherosclerosis. Arteriosclerosis. 1985 Nov-Dec;5(6):569–580. doi: 10.1161/01.atv.5.6.569. [DOI] [PubMed] [Google Scholar]
  26. Heistad D. D., Armstrong M. L., Marcus M. L., Piegors D. J., Mark A. L. Augmented responses to vasoconstrictor stimuli in hypercholesterolemic and atherosclerotic monkeys. Circ Res. 1984 Jun;54(6):711–718. doi: 10.1161/01.res.54.6.711. [DOI] [PubMed] [Google Scholar]
  27. Henry P. D., Yokoyama M. Supersensitivity of atherosclerotic rabbit aorta to ergonovine. Mediation by a serotonergic mechanism. J Clin Invest. 1980 Aug;66(2):306–313. doi: 10.1172/JCI109858. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Jacobs M., Plane F., Bruckdorfer K. R. Native and oxidized low-density lipoproteins have different inhibitory effects on endothelium-derived relaxing factor in the rabbit aorta. Br J Pharmacol. 1990 May;100(1):21–26. doi: 10.1111/j.1476-5381.1990.tb12045.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  29. Jayakody L., Senaratne M., Thomson A., Kappagoda T. Endothelium-dependent relaxation in experimental atherosclerosis in the rabbit. Circ Res. 1987 Feb;60(2):251–264. doi: 10.1161/01.res.60.2.251. [DOI] [PubMed] [Google Scholar]
  30. Kruth H. S. Subendothelial accumulation of unesterified cholesterol. An early event in atherosclerotic lesion development. Atherosclerosis. 1985 Nov;57(2-3):337–341. doi: 10.1016/0021-9150(85)90045-0. [DOI] [PubMed] [Google Scholar]
  31. Kukovetz W. R., Holzmann S. Mechanism of vasodilation by molsidomine. Am Heart J. 1985 Mar;109(3 Pt 2):637–640. doi: 10.1016/0002-8703(85)90669-6. [DOI] [PubMed] [Google Scholar]
  32. Laurenza A., Sutkowski E. M., Seamon K. B. Forskolin: a specific stimulator of adenylyl cyclase or a diterpene with multiple sites of action? Trends Pharmacol Sci. 1989 Nov;10(11):442–447. doi: 10.1016/S0165-6147(89)80008-2. [DOI] [PubMed] [Google Scholar]
  33. Lipton S. A., Choi Y. B., Pan Z. H., Lei S. Z., Chen H. S., Sucher N. J., Loscalzo J., Singel D. J., Stamler J. S. A redox-based mechanism for the neuroprotective and neurodestructive effects of nitric oxide and related nitroso-compounds. Nature. 1993 Aug 12;364(6438):626–632. doi: 10.1038/364626a0. [DOI] [PubMed] [Google Scholar]
  34. Manderson J. A., Cocks T. M., Campbell G. R. Balloon catheter injury to rabbit carotid artery. II. Selective increase in reactivity to some vasoconstrictor drugs. Arteriosclerosis. 1989 May-Jun;9(3):299–307. doi: 10.1161/01.atv.9.3.299. [DOI] [PubMed] [Google Scholar]
  35. Minor R. L., Jr, Myers P. R., Guerra R., Jr, Bates J. N., Harrison D. G. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta. J Clin Invest. 1990 Dec;86(6):2109–2116. doi: 10.1172/JCI114949. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Moncada S., Gryglewski R., Bunting S., Vane J. R. An enzyme isolated from arteries transforms prostaglandin endoperoxides to an unstable substance that inhibits platelet aggregation. Nature. 1976 Oct 21;263(5579):663–665. doi: 10.1038/263663a0. [DOI] [PubMed] [Google Scholar]
  37. Moncada S., Palmer R. M., Higgs E. A. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev. 1991 Jun;43(2):109–142. [PubMed] [Google Scholar]
  38. Moore S. Dietary atherosclerosis and arterial wall injury. Lab Invest. 1989 Jun;60(6):733–736. [PubMed] [Google Scholar]
  39. Mügge A., Elwell J. H., Peterson T. E., Hofmeyer T. G., Heistad D. D., Harrison D. G. Chronic treatment with polyethylene-glycolated superoxide dismutase partially restores endothelium-dependent vascular relaxations in cholesterol-fed rabbits. Circ Res. 1991 Nov;69(5):1293–1300. doi: 10.1161/01.res.69.5.1293. [DOI] [PubMed] [Google Scholar]
  40. Mülsch A., Busse R., Winter I., Bassenge E. Endothelium- and sydnonimine-induced responses of native and cultured aortic smooth muscle cells are not impaired by nitroglycerin tolerance. Naunyn Schmiedebergs Arch Pharmacol. 1989 May;339(5):568–574. doi: 10.1007/BF00167263. [DOI] [PubMed] [Google Scholar]
  41. Naruse K., Shimizu K., Muramatsu M., Toki Y., Miyazaki Y., Okumura K., Hashimoto H., Ito T. Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation. Arterioscler Thromb. 1994 May;14(5):746–752. doi: 10.1161/01.atv.14.5.746. [DOI] [PubMed] [Google Scholar]
  42. Omodeo Salè F., Marchesini S., Fishman P. H., Berra B. A sensitive enzymatic assay for determination of cholesterol in lipid extracts. Anal Biochem. 1984 Nov 1;142(2):347–350. doi: 10.1016/0003-2697(84)90475-5. [DOI] [PubMed] [Google Scholar]
  43. Packer M. What causes tolerance to nitroglycerin? The 100 year old mystery continues. J Am Coll Cardiol. 1990 Oct;16(4):932–935. doi: 10.1016/s0735-1097(10)80343-2. [DOI] [PubMed] [Google Scholar]
  44. Schröder H., Leitman D. C., Bennett B. M., Waldman S. A., Murad F. Glyceryl trinitrate-induced desensitization of guanylate cyclase in cultured rat lung fibroblasts. J Pharmacol Exp Ther. 1988 May;245(2):413–418. [PubMed] [Google Scholar]
  45. Senaratne M. P., Thomson A. B., Kappagoda C. T. Lovastatin prevents the impairment of endothelium dependent relaxation and inhibits accumulation of cholesterol in the aorta in experimental atherosclerosis in rabbits. Cardiovasc Res. 1991 Jul;25(7):568–578. doi: 10.1093/cvr/25.7.568. [DOI] [PubMed] [Google Scholar]
  46. Shimokawa H., Vanhoutte P. M. Impaired endothelium-dependent relaxation to aggregating platelets and related vasoactive substances in porcine coronary arteries in hypercholesterolemia and atherosclerosis. Circ Res. 1989 May;64(5):900–914. doi: 10.1161/01.res.64.5.900. [DOI] [PubMed] [Google Scholar]
  47. Sparrow C. P., Doebber T. W., Olszewski J., Wu M. S., Ventre J., Stevens K. A., Chao Y. S. Low density lipoprotein is protected from oxidation and the progression of atherosclerosis is slowed in cholesterol-fed rabbits by the antioxidant N,N'-diphenyl-phenylenediamine. J Clin Invest. 1992 Jun;89(6):1885–1891. doi: 10.1172/JCI115793. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Stewart D. J., Holtz J., Bassenge E. Long-term nitroglycerin treatment: effect on direct and endothelium-mediated large coronary artery dilation in conscious dogs. Circulation. 1987 Apr;75(4):847–856. doi: 10.1161/01.cir.75.4.847. [DOI] [PubMed] [Google Scholar]
  49. Sugano M., Nakashima Y., Matsushima T., Takahara K., Takasugi M., Kuroiwa A., Koide O. Suppression of atherosclerosis in cholesterol-fed rabbits by diltiazem injection. Arteriosclerosis. 1986 Mar-Apr;6(2):237–241. doi: 10.1161/01.atv.6.2.237. [DOI] [PubMed] [Google Scholar]
  50. Verbeuren T. J., Bonhomme E., Laubie M., Simonet S. Evidence for induction of nonendothelial NO synthase in aortas of cholesterol-fed rabbits. J Cardiovasc Pharmacol. 1993 May;21(5):841–845. doi: 10.1097/00005344-199305000-00023. [DOI] [PubMed] [Google Scholar]
  51. Verbeuren T. J., Coene M. C., Jordaens F. H., Van Hove C. E., Zonnekeyn L. L., Herman A. G. Effect of hypercholesterolemia on vascular reactivity in the rabbit. II. Influence of treatment with dipyridamole on endothelium-dependent and endothelium-independent responses in isolated aortas of control and hypercholesterolemic rabbits. Circ Res. 1986 Nov;59(5):496–504. doi: 10.1161/01.res.59.5.496. [DOI] [PubMed] [Google Scholar]
  52. Verbeuren T. J., Jordaens F. H., Bult H., Herman A. G. The endothelium inhibits the penetration of serotonin and norepinephrine in the isolated canine saphenous vein. J Pharmacol Exp Ther. 1988 Jan;244(1):276–282. [PubMed] [Google Scholar]
  53. Verbeuren T. J., Jordaens F. H., Van Hove C. E., Van Hoydonck A. E., Herman A. G. Release and vascular activity of endothelium-derived relaxing factor in atherosclerotic rabbit aorta. Eur J Pharmacol. 1990 Nov 27;191(2):173–184. doi: 10.1016/0014-2999(90)94145-n. [DOI] [PubMed] [Google Scholar]
  54. Verbeuren T. J., Jordaens F. H., Zonnekeyn L. L., Van Hove C. E., Coene M. C., Herman A. G. Effect of hypercholesterolemia on vascular reactivity in the rabbit. I. Endothelium-dependent and endothelium-independent contractions and relaxations in isolated arteries of control and hypercholesterolemic rabbits. Circ Res. 1986 Apr;58(4):552–564. doi: 10.1161/01.res.58.4.552. [DOI] [PubMed] [Google Scholar]
  55. Wines P. A., Schmitz J. M., Pfister S. L., Clubb F. J., Jr, Buja L. M., Willerson J. T., Campbell W. B. Augmented vasoconstrictor responses to serotonin precede development of atherosclerosis in aorta of WHHL rabbit. Arteriosclerosis. 1989 Mar-Apr;9(2):195–202. doi: 10.1161/01.atv.9.2.195. [DOI] [PubMed] [Google Scholar]
  56. Ylä-Herttuala S., Palinski W., Rosenfeld M. E., Parthasarathy S., Carew T. E., Butler S., Witztum J. L., Steinberg D. Evidence for the presence of oxidatively modified low density lipoprotein in atherosclerotic lesions of rabbit and man. J Clin Invest. 1989 Oct;84(4):1086–1095. doi: 10.1172/JCI114271. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from British Journal of Pharmacology are provided here courtesy of The British Pharmacological Society

RESOURCES