Skip to main content
SpringerLink
Log in

Drugs Modifying Nitric Oxide Metabolism Affect Plasma Cholesterol Levels, Coagulation Parameters, Blood Pressure Values and the Appearance of Plasma Myocardial Necrosis Markers in Rabbits: Opposite Effects of L-NAME and Nitroglycerine

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Various experiments have shown that decreased nitric oxide values alter plasma lipid levels or coagulation parameters or blood pressure values or cause myocardial necrosis phenomena, but it is not clear whether these alterations are reciprocally connected, or whether nitric oxide changes are involved in the appearance of some coronary disease risk factors (lipid, coagulation, blood pressure alterations) and myocardial necrosis.

Aims. We modified nitric oxide levels in rabbits using L-NAME (a NO synthase blocker) or nitroglycerine (a NO donor), and simultaneously evaluated variations in total and HDL cholesterol levels, some coagulation parameters, mean blood pressure values and myocardial necrosis patterns.

Results. L-NAME lowered plasma nitric oxide values, increased plasma total cholesterol and decreased HDL cholesterol levels, enhanced the amount of plasma fibrinogen, shortened prothrombin times, elevated the mean blood pressure values and caused the appearance of cardiac necrosis markers (c-troponin I, creatine kinase) in plasma and coagulative necrosis lesions in the myocardium. The administration of nitroglycerine to rabbits treated with L-NAME increased plasma nitric oxide levels and reversed the biochemical lesions caused by L-NAME.

Conclusions. Our data show that the studied alterations in cholesterol values, coagulation parameters, increased mean blood pressure values and myocardial necrosis markers are strictly related to modified plasma nitric oxide levels, and that the regulation of nitric oxide metabolism affects the presence or absence of some coronary disease risk factors (lipid, coagulation and blood pressure alterations) and plasma indicators of myocardial necrosis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Similar content being viewed by others

References

  1. Radomski MW, Moncada S. Regulation of vascular homeostasis by nitric oxide. Thrombosis and Haemostasis 1993;70:36-41.

    Google Scholar 

  2. Moncada S. The 1991 ULF von Euler lecture. The Larginine: Nitric oxide pathway. Acta Physiol Scandinavica 1992;145:201-227.

    Google Scholar 

  3. Kelm M, Schrader J. Control of coronary vascular tone by nitric oxide. Circulation Res 1990;66:1561-1575.

    Google Scholar 

  4. Celermajer DS, Sorensen KE, Bull C, Robinson J, Deanfield JE. Endothelium-dependent dilation in the systemic arteries of asymptomatic subjects relates to coronary risk factors and their interaction. J Am Coll Cardiol 1994;24:1468-1474.

    Google Scholar 

  5. MorenoJr M, Nathan LP, Metze K, et al. Non-specific inhibitors of nitric oxide synthase cause myocardial necrosis in the rats. Clin Exp Pharmacol & Physiol 1997;24:349-352.

    Google Scholar 

  6. Ono Y, Ono H, Matsuoka H, Fujimori T, Frohlich ED. Apoptosis, coronary arterial remodeling and myocardial infarction after nitric oxide inhibition in SHR. Hypertension 1999;34:609-616.

    Google Scholar 

  7. Radomski MW, Palmer RM, Moncada S. An L-arginine: Nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 1990;87:5193-5197.

    Google Scholar 

  8. Dambisya YM, Lee TL. A thromboelastograhy study on the in vitro effects of L-arginine and L-NG-nitroarginine methyl ester on human whole blood coagulation and fibrinolysis. Blood Coagulation & Fibrinolysis 1996;7: 678-683.

    Google Scholar 

  9. Khedara A, Kawai Y, Kayashita J, Kato N. Feedeing rats the nitric oxide synthase inhibitor, L-Nωnitroarginine, elevates serum triglyceride and cholesterol and lowers hepatic fatty acid oxidation. J Nutr 1996;126:2563-2567.

    Google Scholar 

  10. Cayatte AJ, Palacino JJ, Horten K, Cohen RA. Chronic inhibition of nitric oxide production [1] accelerates neointima formation and impairs endothelial function in hypercholesterolemic rabbits. Arteriosclerosis & Thrombosis 1994;14:753-759.

    Google Scholar 

  11. Naruse K, Shimizu K, Muramatsu M, et al. Long-term inhibition of NO synthesis promotes atherosclerosis in the hypercholesterolemic rabbit thoracic aorta. PGH2 does not contribute to impaired endothelium-dependent relaxation. Arteriosclerosis & Thrombosis 1994;14:746-752.

    Google Scholar 

  12. Moncada S, Higgs A. The L-arginine nitric oxide pathway. New Engl J Med 1993;329:2002-2012.

    Google Scholar 

  13. Rang HP, Dale MM, Ritter JM. Pharmacology, IV Edition. London: Churchill Livingston, 1999.

    Google Scholar 

  14. Pasquinelli F. Diagnostica e tecniche di laboratorio. Milano: Rosini, 1997.

    Google Scholar 

  15. Marzinzig M, Nussler AK, Stadler J, et al. Improved methods to measure end products of nitric oxide in biological fluids: Nitrite, nitrate and s-nitrosothiols. Nitric Oxide 1997;1:177-189.

    Google Scholar 

  16. O'Brien PJ, LandtY, Ladenson JH. Differential reactivity of cardiac and skeletal muscle from various species in a cardiac troponin I immunoassay. Clin Chem 1997;43:2333-2338.

    Google Scholar 

  17. Grand RJ, Wilkinson JM. The aminoacid sequence of rabbit cardiac troponin I. Biochem J 1976;159:633-641.

    Google Scholar 

  18. Vallins WJ, Brand NJ, Dabhade N, Buttler-Browne G, Yacoub MH. Molecular cloning of human cardiac Troponin I using polimerase chain reaction. FEBS Letters 1990;270:57-61.

    Google Scholar 

  19. Malouf NN, McMahon D, Oakeley AE, Anderson PA. A cardiac troponin T epitope conserved across phyla. J Biol Chem 1992;267:9269-9274.

    Google Scholar 

  20. Bodor GS, Porter S, Landt Y, Ladenson JH. The development of monoclonal antibodies and an assay for cardiac troponin-I with preliminary results in suspected myocardial infarction. Clin Chem 1992;11:2203-2214.

    Google Scholar 

  21. AFIP. Manual of Histologic Staining Methods of the Armed Forces Institute of Pathology, 3rd Edition. New York: McGraw-Hill Book Company, 1968.

    Google Scholar 

  22. Armitage P. In Statistica Medica, X Edizione. Milano: Feltrinelli, 1991.

    Google Scholar 

  23. Senna SM, Moraes RB, Bravo MF, et al. Effects of prostaglandins and nitric oxide on rat macrophage lipid metabolism in culture: Implications for arterial wallleukocyte interplay in atherosclerosis. Biochem & Mol Biol Int 1998;46:1007-1018.

    Google Scholar 

  24. Khedara A, Goto T, Kayashita J, Kato N. Hypercholesterolemic effect in rats of a dietary addition of the nitric oxide synthase inhibitor, L-N omega nitroarginine, by less synthesis of bile acids. Bioscience, Biotechnology &Biochemistry 1998;62:773-777.

    Google Scholar 

  25. Scalia R, Appel JZ 3rd, Lefer AM. Leukocyte-endothelium interaction during the early stages of hypercholesterolemia in the rabbit: Role of P-Selectin, ICAM-1, and VCAM-1. Arteriosclerosis, Thrombosis & Vascular Biology 1998;18:1093-1100.

    Google Scholar 

  26. Kuvin JT, Ramet ME, Patel AR, Pandian NG, Mendelsohn ME, Karas RH. A novel mechanism for the beneficial vascular effects of high-density lipoprotein cholesterol: Enhanced vasorelaxation and increased endothelial nitric oxide synthase expression. Am Heart J 2002;144:165-172.

    Google Scholar 

  27. Lippe IT, Sametz W, Sabin K, Holzer P. Inhibitory role of capsaicin-sensitive afferent neurons and nitric oxide in hemostasis. Am J Physiol 1993;265:H1864-H1868.

    Google Scholar 

  28. Catani MV, Bernassola F, Rossi A, Melino G. Inhibition of clotting factor XIII activity by nitric oxide. Biochem Biophys Res Comm 1998;249:275-278.

    Google Scholar 

  29. Kawabata A. Evidence that endogenous nitric oxide modulates plasma fibrinogen levels in the rat. Br J Pharmacol 1996;117:236-237.

    Google Scholar 

  30. Irokawa M, Nishinaga M, Ikeda U, et al. Endothelial-derived nitric oxide preserves anticoagulant heparan sulfate expression in cultured porcine aortic endothelial cells. Atherosclerosis 1997;135:9-17.

    Google Scholar 

  31. Cella G, Sbarai A, Mazzaro G, et al. Plasma markers of endothelial dysfunction in chronic obstructive pulmonary disease. Clinical & Applied Thrombosis/Hemostasis 2001;7:205-208.

    Google Scholar 

  32. Moriguchi S, Ohzuru N, Koga N, et al. Central administration of a nitric oxide synthase inhibitor causes pressor responses via the sympathetic nervous system and the reninangiotensin system in Wistar rats. Neuroscience Letters 1998;245:109-112.

    Google Scholar 

  33. Kasuya A, Satoh S, Yoshida M, Hisa H, Suzuki-Kusaba M, Satoh S. Inhibitory effect of nitric oxide on the reninangiotensin system in Dahl salt-sensitive rats. Clinical & Experimental Pharmacology &Physiology 1999;26:914-919.

    Google Scholar 

  34. Mathew V, Cannan CR, Miller VM, et al. Enhanced endothelin-mediated coronary vasoconstriction and attenuated basal nitric oxide activity in experimental hypercholesterolemia. Circulation 1997;96:1930-1936.

    Google Scholar 

  35. Buxton IL, Cheek DJ, Eckman D, Westfall DP, Sanders KM, Keef KD. NG-nitro L-arginine methyl ester and other alkyl esters of arginine are muscarinic receptor antagonists. Circulation Res 1993;72:387-395.

    Google Scholar 

  36. Cohen RI, Chen L, Scharf SM. The effects of high dose NG-nitro-L-arginine-methyl ester on myocardial blood flow and left ventricular function in dogs. J Critical Care 1996;11:206-213.

    Google Scholar 

  37. De Caterina R, Libby P, Peng HB, et al. Nitric oxide decreases cytokine-induced endothelial activation. Nitric oxide selectively reduces endothelial expression of adhesion molecules and proinflammatory cytokines. J Clin Invest 1995;96:60-68.

    Google Scholar 

  38. Nagata M, Sedgwick JB, Bates ME, Kita H, Busse WW. Eosinophil adhesion to vascular cell adhesion molecule-1 activates superoxide anion generation. J Immunol 1995;155:2194-2202.

    Google Scholar 

  39. Nagata M, Sedgwick JB, Busse WW. Differential effects of granulocyte-macrophage colony-stimulating factor on eosinophil and neutrophil superoxide anion generation. J Immunol 1995;155:4948-4954.

    Google Scholar 

  40. Lefer AM, Ma XL. Decreased basal nitric oxide release in hypercholesterolemia increases neutrophil adherence to rabbit coronary artery endothelium. Arteriosclerosis & Thrombosis 1993;13:771-776.

    Google Scholar 

  41. Boger RH, Bode-Boger SM, Kienke S, Stan AC, Nafe R, Frolich JC. Dietary L-arginine decreases myointimal cell proliferation and vascular monocyte accumulation in cholesterol-fed rabbits. Atherosclerosis 1998;136:67-77.

    Google Scholar 

  42. Osterud B, Elvevoll EO, Brox J, et al. Haemostatic parameters related to lipids and adhesion molecules. Blood Coagulation &Fibrinolysis 1999;10:465-470.

    Google Scholar 

  43. Lindahl B, Andren B, Ohlsson J, Venge P, Wallentin L. Non-invasive risk stratification in unstable coronary artery disease: Exercise test and biochemical markers. FRISC study group. Am J Cardiol 1997;80:40E-44E.

    Google Scholar 

  44. Topol E. Patient stratification and its predictive value for cardiac events. Eur Heart J Suppl 1998;19:K5-K7.

    Google Scholar 

  45. Hamm CW. Risk stratifying acute coronary syndromes: Gradient of risk and benefit. Am Heart J 1999;138:S6-S11.

    Google Scholar 

  46. Bertinchant JP, Robert E, Polge A, et al. Comparison of the diagnostic value of cardiac troponin I and T determination for detecting early myocardial damage and the relationship with histological findings after isoprenaline-induced cardiac injury in rats. Clin Chim Acta 2000;298:13-28.

    Google Scholar 

  47. Bertsch T, Bleuel H, Deschl U, Rebel W. A new sensitive cardiac troponin T rapid test (TROPT) for the detection of experimental acute myocardial damage in rats. Exp Toxicol Pathol 1999;51:565-569.

    Google Scholar 

  48. Kaesemeyer WH, Caldwell RB, Huang J, Caldwell RW. Pravastatin sodium activates endothelial nitric oxide synthase independent of its cholesterol-lowering actions. J Am Coll Cardiol 1999;33:234-241.

    Google Scholar 

  49. Pruefer D, Scalia R, Lefer AM. Simvastatin inhibits leukocyte-endothelial cell interactions and protects against inflammatory processes in normocholesterolemic rats. Arterosclerosis Thrombosis & Vascular Biology 1999;19:2894-2900

    Google Scholar 

  50. Tannous M, Cheung R, Vignini A, Mutus B. Atorvastatin increases ecNOS levels in human platelets of hyperlipidemic subjects. Thrombosis & Haemostasis 1999;82:1390-1394.

    Google Scholar 

  51. Di Napoli P, Antonio Taccardi A, Grilli A, et al. Simvastatin reduces reperfusion injury by modulating nitric oxide synthase expression: An ex vivo study in isolated working rat hearts. Cardiovascular Res 2001;51:283-293.

    Google Scholar 

  52. Ni W, Egashira K, Kataoka C, et al. Antiinflammatory and antiarteriosclerotic actions of HMG-CoA reductase inhibitors in a rat model of chronic inhibition of nitric oxide synthesis. Circulation Res 2001;89:415-421.

    Google Scholar 

  53. Kayanoki Y, Kawata S, Yamasaki E, et al. Reduced nitric oxide production by L-arginine deficiency in lysinuric protein intolerance exacerbates intravascular coagulation. Metabolism: Clinical & Experimental 1999;48:1136-1140.

    Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Pharmacology, Chemotherapy and Medical Toxicology, Milan, Italy

    Arnaldo Pinelli, Silvio Trivulzio, Livio Tomasoni & Boris Bertolini

  2. Laboratory of Clinical Chemistry, Ospedale Niguarda Ca' Granda, Milan, Italy

    Sergio Brenna

  3. Institute of Pathology, Ospedale Niguarda Ca' Granda, Milan, Italy

    Edgardo Bonacina

  4. Institute of Clinical Physiology CNR, Ospedale Niguarda Ca' Granda, Milan, Italy

    Roberto Accinni

Authors
  1. Arnaldo Pinelli
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Silvio Trivulzio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Livio Tomasoni
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Boris Bertolini
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Sergio Brenna
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Edgardo Bonacina
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Roberto Accinni
    View author publications

    You can also search for this author in PubMed Google Scholar

Rights and permissions

Reprints and permissions

About this article

Cite this article

Pinelli, A., Trivulzio, S., Tomasoni, L. et al. Drugs Modifying Nitric Oxide Metabolism Affect Plasma Cholesterol Levels, Coagulation Parameters, Blood Pressure Values and the Appearance of Plasma Myocardial Necrosis Markers in Rabbits: Opposite Effects of L-NAME and Nitroglycerine. Cardiovasc Drugs Ther 17, 15–23 (2003). https://doi.org/10.1023/A:1024299523852

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1023/A:1024299523852

Search

Navigation