Skip to main content
SpringerLink
Log in

Distinct effects of acute and chronic nicotine application on microvascular thrombus formation and endothelial function in male and female mice

  • Original Article
  • Published:
Langenbeck's Archives of Surgery Aims and scope Submit manuscript

Abstract

Background and aims

Cigarette smoking is linked to thromboembolic events; however, a relationship between nicotine exposition and thrombosis has not been established. Thus, we intended to study the effect of acute and chronic nicotine application in an in vivo mouse model.

Materials and methods

In microvessels of the dorsal skin fold chamber, light-dye-induced thrombus formation was analyzed using intravital fluorescence microscopy. Male and female C57BL/6J mice received nicotine chronically via the drinking water (100 μg/ml) for 8 weeks. An additional series of experiments was performed with acute iv nicotine treatment (3 mg/kg body weight).

Results

No significant differences in microvascular thrombus formation were detected after chronic nicotine application in male and female animals when compared with controls. Accordingly, flow cytometric analysis did not show significant effects on platelet activity. Chronic nicotine treatment resulted in a significantly reduced endothelial activation in male, but not in female mice. In contrast, acute iv application of nicotine revealed significantly shorter thrombosis times in arterioles of female mice and a significantly increased endothelial P-selectin expression in mice of both genders.

Conclusion

Chronic nicotine application does not promote microvascular thrombus formation in mice of either gender, whereas acute high-dose iv administration caused a significant increase of arteriolar thrombosis in female animals probably via a synergistic effect of increased endothelial P-selectin expression and female hormone levels. A gender-dependency of acute nicotine action can be presumed.

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.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

References

  1. US Department of Health and Human Services (1990) The health benefits of smoking cessation. US Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Washington, DC. DHHS Publication No. (CDC) 90–8416

  2. US Department of Health and Human Services (1983) The health consequences of smoking: cardiovascular disease: a report of the surgeon general. US Department of Health and Human Services, Public Health Service, Centers for Disease Control, Center for Chronic Disease Prevention and Health Promotion, Office on Smoking and Health, Washington, DC. DHHS Publication No: (PHS) 84–50204

  3. Zeiher AM, Schachinger V, Minners J (1995) Long-term cigarette smoking impairs endothelium-dependent coronary arterial vasodilator function. Circulation 92:1094–1100

    PubMed  CAS  Google Scholar 

  4. Fuster V, Chesebro JH, Frye RL, Elveback LR (1981) Platelet survival and the development of coronary artery disease in the young adult: effects of cigarette smoking, strong family history and medical therapy. Circulation 63:546–551

    PubMed  CAS  Google Scholar 

  5. Nair S, Kulkarni S, Camoens HM, Ghosh K, Mohanty D (2001) Changes in platelet glycoprotein receptors after smoking—a flow cytometric study. Platelets 12:20–26

    Article  PubMed  CAS  Google Scholar 

  6. Fitzgerald GA, Oates JA, Nowak J (1988) Cigarette smoking and hemostatic function. Am Heart J 115:267–271

    Article  PubMed  CAS  Google Scholar 

  7. Hioki H, Aoki N, Kawano K, Homori M, Hasumura Y, Yasumura T, Maki A, Yoshino H, Yanagisawa A, Ishikawa K (2001) Acute effects of cigarette smoking on platelet-dependent thrombin generation. Eur Heart J 22:56–61

    Article  PubMed  CAS  Google Scholar 

  8. Chalon S, Moreno H Jr, Benowitz NL, Hoffman BB, Blaschke TF (2000) Nicotine impairs endothelium-dependent dilatation in human veins in vivo. Clin Pharmacol Ther 67:391–397

    Article  PubMed  CAS  Google Scholar 

  9. Benowitz NL (1988) Pharmacologic aspects of cigarette smoking and nicotine addition. N Engl J Med 319:1318–1330

    Article  PubMed  CAS  Google Scholar 

  10. Benowitz NL (1997) Systemic absorption and effects of nicotine from smokeless tobacco. Adv Dent Res 11:336–341

    Article  PubMed  CAS  Google Scholar 

  11. Ramachandran J, Rubenstein D, Bluestein D, Jesty J (2004) Activation of platelets exposed to shear stress in the presence of smoke extracts of low-nicotine and zero-nicotine cigarettes: the protective effect of nicotine. Nicotine Tob Res 6:835–841

    Article  PubMed  CAS  Google Scholar 

  12. Joseph AM, Norman SM, Ferry LH, Prochazka AV, Westman EC, Steele BG, Sherman SE, Cleveland M, Antonnucio DO, Hartman N, McGovern PG (1996) The safety of transdermal nicotine as an aid to smoking cessation in patients with cardiac disease. N Engl J Med 335:1792–1798

    Article  PubMed  CAS  Google Scholar 

  13. Vaccarino V, Parsons L, Every NR, Barron HV, Krumholz HM (1999) Sex-based differences in early mortality after myocardial infarction. National registry of myocardial infarction 2 participants. N Engl J Med 341:217–225

    Article  PubMed  CAS  Google Scholar 

  14. Roy S (1999) Effects of smoking on prostacyclin formation and platelet aggregation in users of oral contraceptives. Am J Obstet Gynecol 180:S364–368

    Article  PubMed  CAS  Google Scholar 

  15. Holschermann H, Terhalle HM, Zakel U, Maus U, Parviz B, Tillmanns H, Haberbosch W (1999) Monocyte tissue factor expression is enhanced in women who smoke and use oral contraceptives. Thromb Haemost 82:1614–1620

    PubMed  CAS  Google Scholar 

  16. Lehr HA, Leunig M, Menger MD, Nolte D, Messmer K (1993) Dorsal skinfold chamber technique for intravital microscopy in nude mice. Am J Pathol 143:1055–1062

    PubMed  CAS  Google Scholar 

  17. Thorlacius H, Vollmar B, Seyfert UT, Vestweber D, Menger MD (2000) The polysaccharide fucoidan inhibits microvascular thrombus formation independently from P-and L-selectin function in vivo. Eur J Clin Investig 30:804–810

    Article  CAS  Google Scholar 

  18. Vollmar B, Schmits R, Kunz D, Menger MD (2001) Lack of in vivo function of CD31 in vascular thrombosis. Thromb Haemost 85:160–164

    PubMed  CAS  Google Scholar 

  19. Roesken F, Ruecker M, Vollmar B, Boeckel N, Morgenstern E, Menger MD (1997) A new model for quantitative in vivo microscopic analysis of thrombus formation and vascular recanalisation: the ear of the hairless (hr/hr) mouse. Thromb Haemost 78:1408–1414

    PubMed  CAS  Google Scholar 

  20. Rumbaut RE, Randhawa JK, Smith CW, Burns AR (2004) Mouse cremaster venules are predisposed to light/dye-induced thrombosis independent of wall shear rate, CD18, ICAM-1, or P-selectin. Microcirculation 11:239–247

    Article  PubMed  CAS  Google Scholar 

  21. Baker M, Wayland H (1974) On-line volume flow rate and velocity profile measurements for blood in microvessels. Microvasc Res 7:131–143

    Article  PubMed  CAS  Google Scholar 

  22. Suner IJ, Espinosa-Heidmann DG, Marin-Castano ME, Hernandez EP, Pereira-Simon S, Cousins SW (2004) Nicotine increases size and severity of experimental choroidal neovascularization. Investig Ophthalmol Vis Sci 45:311–317

    Article  Google Scholar 

  23. Heeschen C, Jang JJ, Weis M, Pathak A, Kaji S, Hu RS, Tsao PS, Johnson FL (2001) Nicotine stimulates angiogenesis and promotes tumor growth and atherosclerosis. Nat Med 7:833–839

    Article  PubMed  CAS  Google Scholar 

  24. Nieswandt B, Schulte V, Bergmeier W (2004) Flow-cytometric analysis of mouse platelet function. Methods Mol Biol 272:255–268

    PubMed  CAS  Google Scholar 

  25. Rowell PP, Hurst HE, Marlowe C, Bennett BD (1983) Oral administration of nicotine: its uptake and distribution after chronic administration to mice. J Pharmacol Methods 9:249–261

    Article  PubMed  CAS  Google Scholar 

  26. McBride PE (1992) The health consequences of smoking. Cardiovascular diseases. Med Clin North Am 76:333–353

    PubMed  CAS  Google Scholar 

  27. Howard G, Wagenknecht LE, Burke GL, Diez-Roux A, Evans GW, McGovern P, Nieto FJ, Tell GS (1998) Cigarette smoking and progression of atherosclerosis: The Atherosclerosis Risk in Communities (ARIC) Study. JAMA 279:119–124

    Article  PubMed  CAS  Google Scholar 

  28. Barua RS, Ambrose JA, Eales-Reynolds LJ, DeVoe MC, Zervas JG, Saha DC (2001) Dysfunctional endothelial nitric oxide biosynthesis in healthy smokers with impaired endothelium-dependent vasodilatation. Circulation 104:1905–1910

    PubMed  CAS  Google Scholar 

  29. Lehr HA, Kress E, Menger MD, Friedl HP, Hubner C, Arfors KE, Messmer K (1993) Cigarette smoke elicits leukocyte adhesion to endothelium in hamsters: inhibition by CuZn-SOD. Free Radic Biol Med 14:573–581

    Article  PubMed  CAS  Google Scholar 

  30. Ludviksdottir D, Blondal T, Franzon M, Gudmundsson TV, Sawe UJ (1999) Effects of nicotine nasal spray on atherogenic and thrombogenic factors during smoking cessation. J Intern Med 246:61–66

    Article  PubMed  CAS  Google Scholar 

  31. Palmer RM, Stapleton JA, Sutherland G, Coward PY, Wilson RF, Scott DA (2002) Effect of nicotine replacement and quitting smoking on circulating adhesion molecule profiles (sICAM-1, sCD44v5, sCD44v6). Eur J Clin Investig 32:852–857

    Article  CAS  Google Scholar 

  32. Wang L, Kittaka M, Sun N, Schreiber SS, Zlokovic BV (1997) Chronic nicotine treatment enhances focal ischemic brain injury and depletes free pool of brain microvascular tissue plasminogen activator in rats. J Cereb Blood Flow Metab 17:136–146

    Article  PubMed  CAS  Google Scholar 

  33. Zidovetzki R, Chen P, Fisher M, Hofman FM, Faraci FM (1999) Nicotine increases plasminogen activator inhibitor-1 production by human brain endothelial cells via protein kinase C-associated pathway. Stroke 30:651–655

    PubMed  CAS  Google Scholar 

  34. Sikora L, Rao SP, Sriramarao P (2003) Selectin-dependent rolling and adhesion of leukocytes in nicotine-exposed microvessels of lung allografts. Am J Physiol Lung Cell Mol Physiol 285:L654–L663

    PubMed  CAS  Google Scholar 

  35. Rubenstein D, Jesty J, Bluestein D (2004) Differences between mainstream and sidestream cigarette smoke extracts and nicotine in the activation of platelets under static and flow conditions. Circulation 109:78–83

    Article  PubMed  CAS  Google Scholar 

  36. Tutka P, Mosiewicz J, Wielosz M (2005) Pharmacokinetics and metabolism of nicotine. Pharmacol Rep 57:143–153

    PubMed  CAS  Google Scholar 

  37. Ueno H, Pradhan S, Schlessel D, Hirasawa H, Sumpio BE (2006) Nicotine enhances human vascular endothelial cell expression of ICAM-1 and VCAM-1 via protein kinase C, p38 mitogen-activated protein kinase, NF-kappaB, and AP-1. Cardiovasc Toxicol 6:39–50

    Article  PubMed  CAS  Google Scholar 

  38. Lilienberg G, Venge P (1998) Platelet adhesion in patients prone to arterial and venous thrombosis: the impact of gender, smoking and heredity. Scand J Clin Lab Invest 58:279–286

    Article  PubMed  CAS  Google Scholar 

  39. Helmerhorst FM, Bloemenkamp KW, Rosendaal FR, Vandenbroucke JP (1997) Oral contraceptives and thrombotic disease: risk of venous thromboembolism. Thromb Haemost 78:327–333

    PubMed  CAS  Google Scholar 

  40. Tanis BC, Rosendaal FR (2003) Venous and arterial thrombosis during oral contraceptive use: risks and risk factors. Semin Vasc Med 3:69–84

    Article  PubMed  Google Scholar 

  41. Chasan-Taber L, Stampfer MJ (1998) Epidemiology of oral contraceptives and cardiovascular disease. Ann Intern Med 128:467–477

    PubMed  CAS  Google Scholar 

  42. Merten M, Thiagarajan P (2000) P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation 102:1931–1936

    PubMed  CAS  Google Scholar 

Download references

Acknowledgments

The authors kindly thank Berit Blendow, Doris Butzlaff, Dorothea Frenz, Maren Nerowski, and Kathrin Sievert, Institute for Experimental Surgery, University of Rostock for their excellent technical assistance. This study is supported by a grant from the Deutsche Forschungsgemeinschaft, Bonn-Bad Godesberg, Germany (Vo 450/8-1).

Author information

Authors and Affiliations

  1. Institute for Experimental Surgery, University of Rostock, Schillingallee 70, 18055, Rostock, Germany

    Nicole Lindenblatt, Uwe Platz & Brigitte Vollmar

  2. Department of General Surgery, University of Rostock, Schillingallee 35, 18055, Rostock, Germany

    Nicole Lindenblatt & Ernst Klar

  3. Institute for Toxicology, University of Rostock, Schillingallee 70, 18055, Rostock, Germany

    Jörn Hameister

  4. Institute for Clinical and Experimental Surgery, University of Saarland, Kirrberger Strasse, 66424, Homburg-Saar, Germany

    Michael D. Menger

Authors
  1. Nicole Lindenblatt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Uwe Platz
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jörn Hameister
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ernst Klar
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Michael D. Menger
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Brigitte Vollmar
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Nicole Lindenblatt.

Additional information

Best abstracts — Surgical Forum 2007

Rights and permissions

Reprints and permissions

About this article

Cite this article

Lindenblatt, N., Platz, U., Hameister, J. et al. Distinct effects of acute and chronic nicotine application on microvascular thrombus formation and endothelial function in male and female mice. Langenbecks Arch Surg 392, 285–295 (2007). https://doi.org/10.1007/s00423-007-0173-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00423-007-0173-6

Keywords

Search

Navigation