Thromb Haemost 1996; 76(01): 111-117
DOI: 10.1055/s-0038-1650532
Original Article
Schattauer GmbH Stuttgart

Effects of NO-Donors on Thrombus Formation and Microcirculation in Cerebral Vessels of the Rat

Yasuto Sasaki
The Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, Kobe
,
Junji Seki
1   The Department of Biomedical Engineering, National Cardiovascular Center Research Institute, Suita, Japan
,
John C Giddings
2   The Department of Haematology, University of Wales College of Medicine, Cardiff, UK
,
Junichiro Yamamoto
The Laboratory of Physiology, Faculty of Nutrition, Kobe Gakuin University, Kobe
› Author Affiliations
Further Information

Publication History

Received 06 October 1995

Accepted after revision 11 March 1996

Publication Date:
10 July 2018 (online)

Summary

Sodium nitroprusside (SNP) and 3-morpholinosydnonimine (SIN-1), are known to liberate nitric oxide (NO). In this study the effects of SNP and SIN-1 on thrombus formation in rat cerebral arterioles and venules in vivo were assessed using a helium-neon (He-Ne) laser. SNP infused at doses from 10 Μg/kg/h significantly inhibited thrombus formation in a dose dependent manner. This inhibition of thrombus formation was suppressed by methylene blue. SIN-1 at a dose of 100 Μg/kg/h also demonstrated a significant antithrombotic effect. Moreover, treatment with SNP increased vessel diameter in a dose dependent manner and enhanced the mean red cell velocity measured with a fiber-optic laser-Doppler anemometer microscope (FLDAM). Blood flow, calculated from the mean red cell velocity and vessel diameters was increased significantly during infusion. In contrast, mean wall shear rates in the arterioles and venules were not changed by SNP infusion. The results indicated that SNP and SIN-1 possessed potent antithrombotic activities, whilst SNP increased cerebral blood flow without changing wall shear rate. The findings suggest that the NO released by SNP and SIN-1 may be beneficial for the treatment and protection of cerebral infarction

 
  • References

  • 1 Palmer RMJ, Ferrige AG, Moncada S. Nitric oxide release accounts for the biological activity of endothelium-derived relaxing factor. Nature 1987; 327: 524-526
  • 2 Rosenblum WI. Endothelium-derived relaxing factor in brain blood vessels is not nitric oxide. Stroke 1992; 23: 1527-1532
  • 3 Moncada S, Palmer RMJ, Higgs EA. Nitric oxide: physiology, pathophysiology, and pharmacology. Pharmacol Rev 1991; 43: 109-142
  • 4 Moncada S. The 1991 Ulf von Euler lecture. The L-arginine: nitric oxide pathway. Acta Physiol Scand 1992; 145: 201-227
  • 5 Radomski MW, Palmer RMJ, Moncada S. The role of nitric oxide and cGMP in platelet adhesion to vascular endothelium. Biochem Biophys Res Commu 1987; 148: 1482-1489
  • 6 Radomski MW, Palmer RMJ, Moncada S. The antiaggregating properties of vascular endothelium: interactions between prostacyclin and nitric oxide. BrJ Pharmacol 1987; 92: 639-646
  • 7 Bruhwyler J, Chleide E, Liegeois JF, Carreer F. Nitric oxide: a new messenger in the brain. Neurosci Behavior Rev 1993; 17: 373-384
  • 8 Liew FY, Cox FEG. Nonspecific defense mechanism: the role of nitric oxide. Immunoparasitol Today 1991; 7: A17-21
  • 9 Traystman RJ, Moore LE, Helfaer MA, Davis S, Banasiak K, Williams M, Hum PD. Nitro-L-arginine analogues. Dose- and time- related nitric oxide synthase inhibition in brain. Stroke 1995; 26: 864-869
  • 10 Iadecola C, Pelligrino DA, Moskowitz MA, Lassen NA. Nitric oxide synthase inhibition and cerebrovascular regulation. J Cereb Blood Flow Metab 1994; 14: 175-192
  • 11 Deana R, Ruzzene M, Doni MG, Zoccarato F, Alexandre A. Cyclic GMP and nitroprusside inhibit the activation of human platelets by fluoroalumi-nate. Biochim Biophys Acta 1989; 1014: 203-206
  • 12 Azuma H, Ishikawa M, Sekizaki S. Endothelium-dependent inhibition of platelet aggregation. Br J Pharmacol 1986; 88: 411-415
  • 13 Salvemini D, Radziszewski W, Korbut R, Vane J. The use of oxyhaemo-globin to explore the events underlying inhibition of platelet aggregation , induced by NO or NO-donors. Br J Pharmacol 1990; 101: 991-995
  • 14 Chirkov YY, Belushkina NN, Tyshchuk IA, Severina IS, Horowitz JD. Increase in reactivity of human platelet guanylate cyclase during aggregation potentiates the disaggregating capacity of sodium nitroprusside. Clin Exp Pharm Physiol 1991; 18: 517-524
  • 15 Nishimura H, Rosenblum WI, Nelson GH, Boynton S. Agents that modify EDRF formation alter antiplatelet properties of brain arteriolar endothelium in vivo. Am J Physiol 1991; 261: H15-21
  • 16 Golino P, Cappelli-Bigazzi M, Ambrosio G, Ragni M, Russolillo E, Condo-relli M, Chiariello M. Endothelium-derived relaxing factor modulates platelet aggregation in an in vivo model of recurrent platelet activation. Circ Res 1992; 71: 1447-1456
  • 17 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
  • 18 Spiecker M, Darius H, Meyer J. Synergistic platelet antiaggregatory effects of the adenylate cyclase activator iloprost and the guanylate cyclase activating agent SIN-1 in vivo. Thromb Res 1993; 70: 405-415
  • 19 De Caterina R, Giannessi D, Crea F, Chierchia S, Bemini W, Gazzetti P, L’Abbate A. Inhibition of platelet function by injectable isosorbide dinitrate. Am J Cardiol 1984; 53: 1683-1687
  • 20 Hogan JC, Lewis MJ, Henderson AH. In vivo EDRF activity influences platelet function. BrJ Pharmacol 1988; 94: 1020-1022
  • 21 Bhardwaj R, Page CP, May GR, Moore PK. Endothelium-derived relaxing factor inhibits platelets aggregation in human whole blood in vitro and in the rat in vivo. Eur J Pharmacol 1988; 157: 83-91
  • 22 Diodati J, Theroux P, Latour JG, Lacoste L, Lam JYT, Waters D. Effects of nitroglycerin at therapeutic doses on platelet aggregation in unstable angina pectoris and acute myocardial infarction. Am J Cardiol 1990; 66: 683-688
  • 23 Plotkine M, Allix M, Guillou J, Boulu R. Oral administration of isosorbide dinitrate inhibits arterial thrombosis in rats. Eur J Pharmacol 1991; 201: 115-116
  • 24 Drummer C, Valta-Seufzer U, Karrenbrock B, Heim JM, Gerzer R. Comparison of anti-platelet properties of molsidomine, isosorbide-5-mononitrate and placebo in healthy volunteers. Eur Heart J 1991; 12: 541-549
  • 25 Sinzinger H, Virgolini I, O’Grady J, Rauscha F, Fitscha P. Modification of platelet function by isosorbide dinitrate in patients with coronary artery disease. Thromb Res 1992; 65: 323-335
  • 26 Wallen NH, Larsson PT, Broijersen A, Andersson A, Hjelmdahl P. Effects of an oral dose of isosorbide dinitrate on platelet function and fibrinolysis in healthy volunteers. Br J Clin Pharmacol 1993; 35: 143-151
  • 27 Turitto VT, Baumgartner HR. Platelet interaction with subendothelium in flowing rabbit blood: effect of blood shear rate. Microvasc Res 1979; 17: 38-54
  • 28 Turitto VT, Baumgartner HR. Platelet-surface interactions. In: Hemostasis and Thrombosis. Basic Principles and Clinical Practice Colman RW, Hirsh J, Marder VJ, Salzman EW. eds. J.B. Lippincott Company; Philadelphia PA: 1987: 555-571
  • 29 Ikeda Y, Handa M, Kawano K, Kamata T, Murata M, Araki Y, Anbo H, Kawai Y, Watanabe K, Itagaki I, Sakai K, Ruggeri ZM. The role of von Willebrand factor and fibrinogen in platelet aggregation under, varying shear stress. J Clin Invest 1991; 87: 1234-1240
  • 30 Sixma JJ, de Groot PG. Regulation of platelet adhesion to the vessel wall. In: Platelet-dependent vascular occlusion. Fitzgerald GA, Jennings LK, Patrono C, eds. Anal New York Acad Sci 1994; 714: 190-199
  • 31 Rubanyi GM, Romero JC, Vanhoutte PM. Flow-induced release of endothelium-derived relaxing factor. Am J Physiol 1986; 250 HI 145-149
  • 32 Ohno M, Gibbons GH, Dzau VJ, Cooke JP. Shear stress elevates endothelial cGMP. Role of a potassium channel and G protein coupling. Circulation 1993; 88: 193-197
  • 33 Hecker M, Miilsch A, Bassenge E, Busse R. Vasoconstriction and increased flow: two principal mechanisms of shear stress-dependent endothelial auta-coid release. Am J Physiol 1993; 265: H828-833
  • 34 Korenaga R, Ando J, Tsuboi H, Yang W, Sakuma I, Toyo-oka T, Kamiya A. Laminar flow stimulates ATP-and shear stress-dependent nitric oxide production in cultured bovine endothelial cells. Biochem Biophys Res Commu 1994; 198: 213-219
  • 35 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
  • 36 Salvemini D, de Nucci G, Gryglewski RJ, Vane JR. Human neutrophils and mononuclear cells inhibit platelet aggregation by releasing a nitric oxide-like factor. Proc Natl Acad Sci USA 1989; 86: 6328-6332
  • 37 Dikshit M, Kumari R, Srimal RC. Pulmonary thromboembolism-induced alterations in nitric oxide release from rat circulating neutrophils. J Pharmacol Exp Ther 1993; 265: 1369-1373
  • 38 Schattner MA, Finiasz MR, Notrica JA, Lazzari MA. Platelet aggregation inhibition by mononuclear leukocytes. Thromb Res 1994; 73: 205-214
  • 39 De Graaf JC, Banga JD, Moncada S, Palmer RMJ, de Groot PG, Sixma JJ. Nitric oxide functions as an inhibitor of platelet adhesion under flow conditions. Circulation 1992; 85: 2284-2290
  • 40 Morikawa E, Rosenblatt S, Moskowitz MA. L-arginine dilates rat pial arterioles by nitric oxide-dependent mechanisms and increases blood flow during focal cerebral ischaemia. Br J Pharmacol 1992; 107: 905-907
  • 41 Morikawa E, Huang Z, Moskowitz MA. L-arginine decreases infarct size caused by middle cerebral arterial occlusion in SHR. Am J Physiol 1992; 263: H1632-1635
  • 42 Zhang F, Iadecola C. Nitroprusside improves blood flow and reduces brain damage after focal ischemia. NeuroReport 1993; 4: 559-562
  • 43 Dalkara T, Moskowitz MA. The complex role of nitric oxide in the pathophysiology of focal cerebral ischemia. Brain Pathol 1994; 4: 49-57
  • 44 Morikawa E, Moskowitz MA, Huang Z, Yoshida T, Irikura K, Dalkara T. L-arginine infusion promotes nitric oxide-dependent vasodilation, increases regional cerebral blood flow, and reduces infarction volume in the rat. Stroke 1994; 25: 429-435
  • 45 Zhang F, White JG, Iadecola C. Nitric oxide donors increase blood flow and reduce brain damage in focal ischemia: evidence that nitric oxide is beneficial in the early stages of cerebral ischemia. J Cereb Blood Flow and Metab 1994; 14: 217-226
  • 46 Hladvec J. Antithrombotic drugs in thrombosis models. CRC press; Florida: 1989
  • 47 Kovacs IB, Tigyi-Sebes A, Trombitas K, Gbrog P. Evans blue: an ideal energy-absorbing material to produce intravascular microinjury by He-Ne gas laser. Microvasc Res 1975; 10: 107-124
  • 48 Weichert W, Breddin HK, Staubesand J. Application of a laser-induced endothelial injury model in the screening of antithrombotic drugs. Semin Thromb Hemost 1988; 14: 106-114
  • 49 Sasaki Y, Morii S, Yamashita T, Yamamoto J. Antithrombotic effect of argatroban on the pial vessels of the rat: a study with He-Ne laser-induced thrombus formation. Haemostasis 1993; 23: 104-111
  • 50 Povlishock JT, Rosenblum WI. Injury of brain microvessels with a helium-neon laser and Evans blue can elicit local platelet aggregation without endothelial denudation. Acta Pathol Lab Med 1987; 111: 415-421
  • 51 Rosenblum WI, Nelson GH, Povlishock JT. Laser-induced endothelial damage inhibits endothelium-dependent relaxation in the cerebral microcirculation of the mouse. Circulation Res 1987; 60: 169-176
  • 52 Rosenblum WI, Nishimura H, Nelson GH. Endothelium-dependent L-arg- and L-NMMA-sensitive mechanisms regulate tone of brain microvessels. Am J Physiol 1990; 259: H1396-1401
  • 53 Feelisch M. The biochemical pathways of nitric oxide formation from nitro-vasodilators: appropriate choice of exogenous NO donors and aspects of preparation and handling of aqueous NO solutions. J Cardiovasc Pharmacol 1991; 17 (Suppl. 03) S25-33
  • 54 Morii S, Ngai AC, Winn HR. Reactivity of rat pial arterioles and venules to adenosine and carbon dioxide:with detailed description of the closed cranial window technique in rat. J Cereb Blood Flow Metab 1986; 6: 34-41
  • 55 Seki J. Fiber-optic laser-Doppler anemometer microscope developed for the measurement of microvascular red cell velocity. Microvasc Res 1990; 40: 302-316
  • 56 Seki J. Flow pulsation and network structure in mesenteric microvasculature of rats. Am J Physiol 1994; 266: H811-821
  • 57 Ma YP, Koo A, Kwan HC, Cheng KK. On-line measurement of the dynamic velocity of erythrocytes in the cerebral microvessels in the rat. Microvasc Res 1974; 8: 1-13
  • 58 Rosenblum WI, El-Sabban F, Hirsh PO. Angiotensin delays platelet aggregation after injury of cerebral arterioles. Stroke 1986; 17: 1203-1205
  • 59 Roller A, Raley G. Endothelial regulation of wall shear stress and blood flow in skeletal muscle microcirculation. Am J Physiol 1991; 260: H862-868
  • 60 Robari M, Gotoh F, Fukuuchi Y, Tanaka R, Suzuki N, Uematsu D. Blood flow velocity in the pial arteries of cats, with particular reference to the vessel diameter. J Cereb Blood Flow Metab 1984; 4: 110-114
  • 61 Mayrovitz HN, Roy J. Microvascular blood flow: evidence indicating a cubic dependence on arteriolar diameter. Am J Physiol 1983; 245: H1031-1038
  • 62 Melkumyants AM, Balashov SA, Rhayutin VM. Endothelium dependent control of arterial diameter by blood viscosity. Cardiovasc Res 1989; 23: 741-747
  • 63 Roller A, Raley G. Prostaglandins mediate arteriolar dilation to increased blood flow velocity in skeletal muscle microcirculation. Circ Res 1990; 67: 529-534
  • 64 Griffith TM, Edwards DH, Davies RL, Harrison TJ, Evans RT. EDRF coordinates the behaviour of vascular resistance vessels. Nature 1987; 329: 442-445
  • 65 Tagami M, Ikeda R, Nara Y, Fujino H, Rubota A, Numano F, Yamori Y. Detailed examination of vascular lesions triggered by an inhibitor of endothelium-derived relaxing factor. Laboratory Invest 1995; 72: 174-182
  • 66 Sessa WC, Pritchard R, Seyedi N, Wang J, Hintze TH. Chronic exercise in dogs increases coronary vascular nitric oxide production and endothelial cell nitric oxide synthase gene expression. Circ Res 1994; 74: 349-353
  • 67 Sasaki Y, Morimoto A, Ishii I, Morita S, Tsukahara M, Yamamoto J. Preventive effect of long-term aerobic exercise on thrombus formation in rat cerebral vessels. Haemostasis 1995; 25: 212-217