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Nitric oxide: An endogenous cardioprotectant?

  • Chapter
Myocardial Ischemia: Mechanisms, Reperfusion, Protection

Part of the book series: EXS ((EXS,volume 76))

Abstract

Nitric oxide (NO) is one of a number of labile endogenous molecules, along with prostacyclin, adenosine and others, that have been proposed recently to function in the cardiovascular system as endogenous protective substances. In the case of NO, most of the evidence to support this proposal is provided by studies that identify exogenous NO as mediating protection in disease states. Some evidence, provided largely from the use of inhibitors of NO synthase (NOS), has supported the necessary prerequisite that reduction of ambient NO production exacerbates the disease state. This is an exciting field in which the possibility exists for the development of a pathophysiological principle, namely that disease outcome may be determined by the antagonism (largely uncompetitive) between a variety of chemical mediators of disease and their protectant counterparts. However, the position is far from clear. Establishment that NO (and/or other substances) function as endogenous protectants under experimental conditions does not necessarily mean that mimicry of the NO or enhancement of its presence (by inducing its synthesis or blocking its degration) will give rise to new therapeutic agents. This may be because local levels of NO in the clinical setting are in excess of the required amount for eliciting a maximal protective response, yet this response is inadequate for protection to be manifest because the tendency to protection is overwhelmed by the pathogenic components of the disease milieu.

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References

  1. Ross R. The pathogenesis of atherosclerosis: an update. N Engl J Med 1986; 314: 488–500.

    Article  PubMed  CAS  Google Scholar 

  2. Minor RL Jr, Myers PR, Guerra R Jr, Bates JN, Harrison DG. Diet-induced atherosclerosis increases the release of nitrogen oxides from rabbit aorta. J Clin Invest 1990; 86: 2109–2116.

    Article  PubMed  CAS  Google Scholar 

  3. Radomski MW, Palmer RMJ, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci USA 1990; 87: 5193–5197.

    Article  PubMed  CAS  Google Scholar 

  4. Garg UC, Hassid A. Nitric oxide-generating vasodilators and 8-bromo-cyclic guanosine monophosphate inhibit mitogenesis and proliferation of cultured rat vascular smooth muscle cells. J Clin Invest 1989; 83: 1774–1777.

    Article  PubMed  CAS  Google Scholar 

  5. Bath PMW. The effect of nitric oxide-donating vasodilators on monocyte chemotaxis and intracellular cGMP concentrations in vitro. Eur J Clin Pharmacol 1993; 45: 53–58.

    Article  PubMed  CAS  Google Scholar 

  6. Cooke JP, Singer AH, Tsao P, Zera P, Rowan RA, Billingham ME. Antiatherogenic effects of L-arginine in the hypercholesterolemic rabbit. J Clin Invest 1992; 90: 1168–1172.

    Article  PubMed  CAS  Google Scholar 

  7. Tanner FC, Noll G, Boulanger CM, Luscher TF. Oxidized low density lipoproteins inhibit relaxations of porcine coronary arteries. Role of scavenger receptor and endothelium-derived nitric oxide. Circulation 1991; 83: 2012–2020.

    PubMed  CAS  Google Scholar 

  8. Creager MA, Gallagher SJ, Girerd XJ, Coleman SM, Dzau VJ, Cooke JP. L-Arginine improves endothelium-dependent vasodilation in hypercholesterolemic humans. J Clin Invest 1992; 90: 1248–1253.

    Article  PubMed  CAS  Google Scholar 

  9. Cohen RA, Zitnay KM, Haudenschild CC, Cunningham LD. Loss of selective endothelial cell vasoactive functions in pig coronary arteries caused by hypercholesterolemia. Circ Res 1988; 63: 903–910.

    PubMed  CAS  Google Scholar 

  10. Andrews HE, Bruckdorfer KR, Dunn RC, Jacobs M. Low-density lipoproteins inhibit endothelium-dependent relaxation in rabbit aorta. Nature 1987; 327: 237–239.

    Article  PubMed  CAS  Google Scholar 

  11. Tsao PS, McEvoy LM, Drexler H, Butcher EC, Cooke JP. Enhanced endothelial adhesiveness in hypercholesterolemia is attenuated by L-arginine. Circulation 1994; 89: 2176 - 2182.

    PubMed  CAS  Google Scholar 

  12. McNamara DB, Bedi H, Aurora L, Tena L, Ignarro LJ, Kadowitz PJ, Akers DL. L-Arginine inhibits balloon catheter-induced intimal hyperplasia. Biochem Biophys Res Commun 1993; 193: 291–296.

    Article  PubMed  CAS  Google Scholar 

  13. Groves PH, Lewis MJ, Cheadle HA, Penny WJ. SIN-1 reduces platelet adhesion and platelet thrombus formation in a porcine model of balloon angioplasty. Circulation 1993; 87: 590–597.

    PubMed  CAS  Google Scholar 

  14. Groves PH, Penny WJ, Cheadle HA, Lewis MJ. Exogenous nitric oxide inhibits in vivo platelet adhesion following balloon angioplasty. Cardiovasc Res 1992; 26: 615 - 619.

    Article  PubMed  CAS  Google Scholar 

  15. Guo J-p, Siegfried MR, Lefer AM. Endothelial preserving actions of a nitric oxide donor in carotid arterial intimai injury. Meth Find Exp Clin Pharmacol 1994; 14: 347–354.

    Google Scholar 

  16. Hearse DJ, Bolli R. Reperfusion-induced injury. Manifestations, mechanisms and clinical relevance. Trends Cardiovasc Med 1991; 1: 233–240.

    Article  PubMed  CAS  Google Scholar 

  17. Lucchesi BR. Modulation of leukocyte-mediated myocardial reperfusion injury. Ann Rev Physiol 1990; 52: 561–576.

    Article  CAS  Google Scholar 

  18. Lawrence MB, Springer TA. Leukocytes roll on a selectin at physiologic flow rates: distinction from and prerequisite for adhesion through integrins. Cell 1991; 65: 859–873.

    Article  PubMed  CAS  Google Scholar 

  19. Ma X-I, Tsao PS, Viehmann GE, Lefer AM. Neutrophil-mediated vasoconstriction and endothelial dysfunction in low-flow perfusion-reperfused cat coronary artery. Circ Res 1991; 69: 95–106.

    PubMed  CAS  Google Scholar 

  20. Ma X-I, Weyrich AS, Lefer DJ, Lefer AM. Diminished basal nitric oxide release after myocardial ischemia and reperfusion promotes neutrophil adherence to coronary endothelium. Circ Res 1993; 72: 403–412.

    PubMed  CAS  Google Scholar 

  21. Lefer AM, Tsao PS, Lefer DJ, Ma X-I. Role of endothelial dysfunction in the pathogenesis of reperfusion injury after myocardial ischemia. FASEB J 1991; 5: 2029–2034.

    PubMed  CAS  Google Scholar 

  22. Tsao PS, Aoki N, Lefer DJ, Johnson III G, Lefer AM. Time course of endothelial dysfunction and myocardial injury during myocardial ischemia and reperfusion in the cat. Circulation 1990; 82: 1402–1412.

    Article  PubMed  CAS  Google Scholar 

  23. Engler R, Schmid-Schonbein GW, Pavelec RS. Leukocyte capillary plugging in myocardial ischemia and reperfusion in the dog. Am J Path 1983; 111: 98–111.

    PubMed  CAS  Google Scholar 

  24. Kubes P, Suzuki M, Granger DN. Nitric oxide: An endogenous modulator of leukocyte adhesion. Proc Natl Acad Sci USA 1991; 88: 4651–4655.

    Article  PubMed  CAS  Google Scholar 

  25. Gaboury J, Woodman RC, Granger DN, Reinhardt P, Kubes P. Nitric oxide prevents leukocyte adherence: role of superoxide. Am J Physiol 1993; 265: H862–H867.

    PubMed  CAS  Google Scholar 

  26. Kubes P, Kanwar S, Niu X-F, Gaboury JP. Nitric oxide synthesis inhibition induces leukocyte adhesion via superoxide and mast cells. FASEB J 1993; 7: 1293–1299.

    PubMed  CAS  Google Scholar 

  27. Kurose I, Kubes P, Wolf R, Anderson DC, Paulson J, Miyasaka M, Granger DN. Inhibition of nitric oxide production: mechanism of vascular albumin leakage. Circ Res 1993; 73: 164–171.

    PubMed  CAS  Google Scholar 

  28. Gauthier TW, Davenpeck KL, Lefer AM. Nitric oxide attenuates leukocyte-endothelial interaction via P-selectin in splanchnic ischemia-reperfusion. Am J Physiol 1994; 267: G562–G568.

    PubMed  CAS  Google Scholar 

  29. Gryglewski RJ, Palmer RMJ, Moncada S. Superoxide anion is involved in the breakdown of endothelium-derived vascular relaxing factor. Nature 1986; 320: 454–456.

    Article  PubMed  CAS  Google Scholar 

  30. Kurose I, Wolf R, Grisham MB, Granger DN. Modulation of ischemia/reperfusion-induced microvascular dysfunction by nitric oxide. Circ Res 1994; 74: 376–382.

    PubMed  CAS  Google Scholar 

  31. Siegfried MR, Erhardt J, Rider T, Ma X-I, Lefer AM. Cardioprotection and attenuation of endothelial dysfunction by organic nitric oxide donors in myocardial ischemia-reperfusion. J Pharmacol Exp Ther 1992; 260: 668–675.

    PubMed  CAS  Google Scholar 

  32. Lefer DJ, Nakanishi K, Johnston WE, Vinten-Johansen J. Antineutrophil and myocardial protecting actions of a novel nitric oxide donor after acute myocardial ischemia and reperfusion in dogs. Circulation 1993; 88: 2337–2350.

    PubMed  CAS  Google Scholar 

  33. Pabla R, Buda AJ, Flynn DM, Salzberg DB, Lefer DJ. Intracoronary nitric oxide improves postischemic coronary blood flow and myocardial contractile function following ischemia and reperfusion. Am J Physiol 1995; 269: HI 113–1121.

    Google Scholar 

  34. Bohn H, Brendel J, Martorana PA, Schonafinger K. Cardiovascular actions of the furoxan CAS 1609, a novel donor of nitric oxide. Br J Pharmacol 1995; 114: 1605–1612.

    PubMed  CAS  Google Scholar 

  35. Patel VC, Yellon DM, Singh KJ, Neild GH, Woolfson RG. Inhibition of nitric oxide limits infarct size in the in situ rabbit heart. Biochem Biophys Res Commun 1993; 194: 234–238.

    Article  PubMed  CAS  Google Scholar 

  36. Woolfson RG, Patel VC, Neild GH, Yellon DM. Inhibition of nitric oxide synthesis reduces infarct size by an adenosine-dependent mechanism. Circulation 1995; 91: 1545–1551.

    PubMed  CAS  Google Scholar 

  37. Kloner RA, Ganote CE, Jennings RB. The “no-reflow” phenomenon after temporary coronary occlusion in the dog. J Clin Invest 1974; 54: 1496–1508.

    Article  PubMed  CAS  Google Scholar 

  38. Forman MB, Virmani R, Puett DW. Mechanisms and therapy of myocardial reperfusion injury. Circulation 1990; 81(IV): IV-69–78.

    Google Scholar 

  39. Bolli R, Jeroudi MO, Patel BS, Aruoma Ol, Halliwell B, Lai EK, McCay PB. Marked reduction of free radical generation and contractile dysfunction by antioxidant therapy begun at the time of reperfusion. Circ Res 1989; 65: 607–622.

    PubMed  CAS  Google Scholar 

  40. Weyrich AS, Ma X-I, Buerke M, Murohara T, Armstead VE, Lefer AM, Nicolas JM, Thomas AP, Lefer DJ, Vinten-Johansen J. Physiological concentrations of nitric oxide do not elicit an acute negative inotropic effect in unstimulated cardiac muscle. Circ Res 1994; 75: 692–700.

    PubMed  CAS  Google Scholar 

  41. Amrani M, O’Shea J, Allen NJ, Harding SE, Jayakumar J, Pepper JR, Moncada S, Yacoub MH. Role of basal release of nitric oxide on coronary flow and mechanical performance of the isolated rat heart. J Physiol 1992; 456: 681–687.

    PubMed  CAS  Google Scholar 

  42. Brady AJB, Warren JB, Poole-Wilson PA, Williams TJ, Harding SE. Nitric oxide attenuates cardiac myocyte contraction. Am J Physiol 1993; 265: HI76–HI82.

    Google Scholar 

  43. Brutsaert DL, Meulemans AL, Sipido KR, Sys SU. Effects of damaging the endocardial surface on the mechanical performance of isolated cardiac muscle. Circ Res 1988; 62: 358–366.

    PubMed  CAS  Google Scholar 

  44. Evans HG, Lewis MJ, Shah AM. Modulation of myocardial relaxation by basal release of endothelin from endocardial endothelium. Card Res 1994; 28: 1694–1699.

    Article  CAS  Google Scholar 

  45. Finkel MS, Oddis CV, Jacob TD, Watkins SC, Hauler BG, Simmons RL. Negative inotropic effects of cytokines on the heart mediated by nitric oxide. Science 1992; 257: 387–397.

    Article  PubMed  CAS  Google Scholar 

  46. Brady AJ, Poole-Wilson PA, Harding SE, Warren JB. Nitric oxide production within cardiac myocytes reduces their contractility in endotoxemia. Am J Physiol 1992; 263: H1963–H1966.

    PubMed  CAS  Google Scholar 

  47. Klabunde RE, Kimber ND, Kuk JE, Helgren MC, Förstermann U. NG-Methyl-L-arginine decreases contractility, cGMP and cAMP in isoproterenol-stimulated rat hearts in vitro. Eur J Pharmacol 1992; 223: 1–7.

    Article  PubMed  CAS  Google Scholar 

  48. Hasebe N, Shen YT, Vatner SF. Inhibition of endothelium-derived relaxing factor enhances myocardial stunning in conscious dog. Circulation 1993; 88: 2862–2871.

    PubMed  CAS  Google Scholar 

  49. Nakanishi K, Vinten-Johansen J, Lefer DJ, Zhao Z, Fowler WC, McGee DS, Johnston WE. Intracoronary L-arginine during reperfusion improves endothelial function and reduces infarct size. Am J Physiol 1992; 263: H1650–H1658.

    PubMed  CAS  Google Scholar 

  50. Manning AS, Hearse DJ. Reperfusion-induced arrhythmias: Mechanisms and prevention. J Mol Cell Cardiol 1984; 16: 497–518.

    Article  PubMed  CAS  Google Scholar 

  51. Parratt JR. Endogenous myocardial protective (antiarrhythmic) substances. Cardiovasc Res 1993; 27: 693–702.

    Article  PubMed  CAS  Google Scholar 

  52. Pabla R, Curtis MJ. Effects of nitric oxide modulation on cardiac arrhythmias in the rat isolated heart. Circ Res 1995; 77: 984–992.

    PubMed  CAS  Google Scholar 

  53. Pabla R, Curtis MJ. Effects of 7-nitro indazole on ventricular fibrillation, haemodynamics and nitric oxide levels in the isolated rat heart. Br J Pharmacol 1995; 114: 135 P.

    Google Scholar 

  54. Moore PK, Babbedge RC, Wallace P, Gaffen Z, Hart SL. 7-Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti-nociceptive activity in the mouse without increasing blood pressure. Br J Pharmacol 1993; 108: 296–297.

    PubMed  CAS  Google Scholar 

  55. Blough NV, Zafirion OC. Reaction of superoxide with nitric oxide to form peroxynitrite in alkaline aqueous solution. Inorg Chem 1985; 24: 3502–3504.

    Article  CAS  Google Scholar 

  56. Klimaschewski L, Klummer W, Mayer B, Couraud JY, Priessler U, Philippin B, Heym C. Nitric oxide synthase in cardiac nerve fibers and neurons of rat and guinea pig heart. Circ Res 1992; 71: 1533–1537.

    PubMed  CAS  Google Scholar 

  57. Pabla R, Curtis MJ. Cardioprotective effects of endothelial versus neuronal nitric oxide in rabbit. J Mol Cell Cardiol 1995; 27: A158.

    Google Scholar 

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Authors and Affiliations

  1. Cardiovascular Research Laboratories, Department of Pharmacology, Division of Biomedical Sciences, King—s College, University of London, SW3 6LX, London, UK

    R. Pabla & M. J. Curtis

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  1. R. Pabla
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  2. M. J. Curtis
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Editors and Affiliations

  1. Department of Pharmacology and Toxicology, University of Western Ontario, Medical Sciences Building, N6A 5C1, London, Ontario, Canada

    Morris Karmazyn PhD (Professor and Career Investigator of the Heart and Stroke Foundation of Ontario) (Professor and Career Investigator of the Heart and Stroke Foundation of Ontario)

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© 1996 Birkhäuser Verlag Basel/Switzerland

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Pabla, R., Curtis, M.J. (1996). Nitric oxide: An endogenous cardioprotectant?. In: Karmazyn, M. (eds) Myocardial Ischemia: Mechanisms, Reperfusion, Protection. EXS, vol 76. Birkhäuser Basel. https://doi.org/10.1007/978-3-0348-8988-9_5

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  • DOI: https://doi.org/10.1007/978-3-0348-8988-9_5

  • Publisher Name: Birkhäuser Basel

  • Print ISBN: 978-3-0348-9857-7

  • Online ISBN: 978-3-0348-8988-9

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