Skip to main content

Advertisement

SpringerLink
Log in

Effects of Nicotine on Cardiovascular Remodeling in a Mouse Model of Systemic Hypertension

  • Published:
Cardiovascular Toxicology Aims and scope Submit manuscript

Abstract

Usage of nicotine-only formulations, such as transdermal patches, nicotine gum, or electronic nicotine delivery systems is increasing, as they are perceived as healthier alternatives to traditional cigarettes. Unfortunately, there is little data available on the effect of isolated nicotine on myocardial and aortic remodeling, especially in the setting of cardiovascular disease risk factors, such as hypertension. We hypothesized that nicotine would exacerbate cardiovascular remodeling induced by angiotensin-II (Ang II) treatment. Subcutaneous osmotic minipumps were implanted to administer Ang II, Nic, nicotine plus Ang II or saline to C57Bl/6 mice for 4 weeks. Heart weights were increased by all treatments, with control < nicotine < Ang II < nicotine + Ang II. Activity levels of matrix metalloproteinase-2 mirrored these changes and demonstrated clear additivity between nicotine and Ang II. Histopathological analysis of aortas revealed that mice receiving combined nicotine and Ang II treatment induced significant hypertrophy compared to all other groups. This study reveals possible cardiotoxic interactions between nicotine and a common model of systemic hypertension. Safety testing of novel nicotine delivery devices should consider that hypertension is a common impetus to begin smoking cessation therapy, and potential interactions should be more thoroughly studied.

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

Abbreviations

Ang II:

Angiotensin II

AAA:

Abdominal aortic aneurysm

ACE:

Angiotensin-converting enzyme

CO:

Carbon monoxide

MMP:

Matrix metalloproteinase

NRT:

Nicotine replacement therapy

RAS:

Renin–angiotensin system

ROS:

Reactive oxygen species

References

  1. CDC Vital Signs: Current cigarette smoking among adults aged ≥18 years—United States, 2005–2010. Accessed 12/10/2012. www.cdc.gov/tobacco/data_statistics/fact_sheets/cessation/quitting/index.htm.

  2. Krupski, W. C., Olive, G. C., Weber, C. A., & Rapp, J. H. (1987). Comparative effects of hypertension and nicotine on injury induced myointimal thickening. Surgery, 102, 409–415.

    PubMed  CAS  Google Scholar 

  3. Benowitz, N. L., Hansson, A., & Jacob, P., I. I. I. (2002). Cardiovascular effects of nasal and transdermal nicotine and cigarette smoking. Hypertension, 39, 1107–1112.

    Article  PubMed  CAS  Google Scholar 

  4. Fishebein, L., O’Brien, P., Hutson, A., Theriaque, D., Stacpoole, P. W., & Flotte, T. (2000). Pharmacokinetics and pharmacodynamic effects of nicotine nasal spray devices on cardiovascular and pulmonary function. Journal of Investigative Medicine, 48, 435–440.

    Google Scholar 

  5. Martins, L. C., Ferreira-Melo, S. E., Sabha, M., Coelho, O. R., Yugar-Toledo, J. C., Quinaglia, T., et al. (2009). Acute effects of pharmacotherapies in blood pressure in normotensive moderate smokers. Blood Pressure, 18(4), 255–260.

    PubMed  CAS  Google Scholar 

  6. Mundal, H. H., Hjemdahl, P., & Ghesdal, K. (1995). Acute effects of low dose nicotine gum on platelet function in non-smoking hypertensive and normotensive men. European Journal of Clinical Pharmacology, 41, 411–416.

    Google Scholar 

  7. Yugar-Toledo, J. C., Ferreira-Melo, E., Sabha, M., Nogueira, E. A., Coelho, O., Colombo, F. M. C., et al. (2005). Blood pressure circadian rhythm and endothelial function in heavy smokers: Acute effects of transdermal nicotine. Journal of Clinical Hypertension, 7, 721–729.

    Article  PubMed  CAS  Google Scholar 

  8. Khoury, Z., Comans, P., Lerer, K., Gavish, A., & Tzivoni, D. (1996). Effects of transdermal nicotine patches on ambulatory ecg monitoring findings: A double-blind study in healthy smokers. Cardiovascular Drugs and Therapy, 10, 179–184.

    Article  PubMed  CAS  Google Scholar 

  9. Mahmarian, J. J., Moye, L. A., Nasser, G. A., Nagueh, S. F., Bloom, M. F., Benowitz, N. L., et al. (1997). Nicotine patch therapy in smoking cessation reduces the extent of exercise-induced myocardial ischemia. Journal of the American College of Cardiology, 30, 125–130.

    Article  PubMed  CAS  Google Scholar 

  10. Tanus-Santos, J. E., Toledo, J. C., Cittadiono, M., Sabha, M., Rocha, J. C., & Moreno, H., Jr. (2001). Cardiovascular effects of transdermal nicotine in mildly hypertensive smokers. American Journal of Hypertension, 14, 601–614.

    Article  Google Scholar 

  11. Thorup, C., Jose, C. L., Gross, S. S., Moore, L. C., & Goligorsky, M. S. (1999). Carbon monoxide induces vasodilation and nitric oxide release but suppresses endothelial NOS. American Journal of Physiology, 277, F882–F889.

    PubMed  CAS  Google Scholar 

  12. Zornoff, L. A., Matsubara, L. S., Matsubara, B. B., Okoshi, M. P., Okoshi, K., Dal Pai-Silva, M., et al. (2006). Beta-carotene supplementation attenuates cardiac remodeling induced by one-month tobacco-smoke exposure in rats. Toxicological Sciences, 90, 259–266.

    Article  PubMed  CAS  Google Scholar 

  13. Meurrens, K., Ruf, S., Ross, G., Schleef, R., von Holt, K., & Schlüter, K. D. (2007). Smoking accelerates the progression of hypertension-induced myocardial hypertrophy to heart failure in spontaneously hypertensive rats. Cardiovascular Research, 76, 311–322.

    Article  PubMed  CAS  Google Scholar 

  14. Danser, J., van Kesteren, C., Bax, W., Tavenier, M., Derkx, F., Saxena, P., et al. (1997). Prorenin, renin, angiotensinogen, and angiotensin-converting enzyme in normal and failing human hearts: Evidence for renin binding. Circulation, 96, 220–226.

    Article  PubMed  CAS  Google Scholar 

  15. Iwata, M., Cowling, R., Yeo, S., & Greenberg, B. (2011). Targeting the ACE2-Ang-(1–7) pathway in cardiac fibroblasts to treat cardiac remodeling and heart failure. Journal of Molecular and Cellular Cardiology, 51, 542–547.

    Article  PubMed  CAS  Google Scholar 

  16. Malayeri, A. A., Natori, S., Bahrami, H., Bertoni, A. G., Kronmal, R., Lima, J. A., et al. (2008). Relation of aortic wall thickness and distensibility to cardiovascular risk factors (from the multi-ethnic study of atherosclerosis (MESA)). American Journal of Cardiology, 102, 491–496.

    Article  PubMed  Google Scholar 

  17. Schluter, K. D., & Wenzel, S. (2008). Angiotensin II: A hormone involved in and contributing to pro-hypertrophic cardiac networks and target of anti-hypertrophic cross-talks. Pharmacology & Therapeutics, 119, 311–325.

    Article  Google Scholar 

  18. Wang, S., Zhang, C., Zhang, M., Liang, B., Zhu, H., Lee, J., et al. (2012). Activation of AMP-activated protein kinase α2 by Nic instigates formation of abdominal aortic aneurysms in mice in vivo. Nature Medicine, 18, 902–910.

    Article  PubMed  CAS  Google Scholar 

  19. Zhang, S., Day, I., & Ye, S. (2001). Nicotine-induced changes in gene expression by human coronary artery endothelial cells. Atherosclerosis, 154, 277–283.

    Article  PubMed  CAS  Google Scholar 

  20. Osergren, J. B. (2006). Angiotensin receptor blockade with candesartan in heart failure: Findings from the candesartan in heart failure-assessment of reduction in mortality and morbidity (CHARM) programme. Journal of Hypertension, 24(suppl), S3–S7.

    Article  Google Scholar 

  21. Fernie, J. M., Douglas, A. N., Lamb, D., & Ruckley, V. A. (1983). Right ventricular hypertrophy in a group of coal workers. Thorax, 38, 436–442.

    Article  PubMed  CAS  Google Scholar 

  22. Li, J. M., Cui, T. X., Shiuch, T., Liu, H. W., Min, L. J., Okumura, M., et al. (2004). Nicotine enhances angiotensin II-induced mitogenic response in vascular smooth muscle cells and fibroblasts. Arteriosclerosis, Thrombosis, and Vascular Biology, 24, 80–84.

    Article  PubMed  Google Scholar 

  23. Shasha, S. M., Damal, H., Kristal, B., Galetzky, G., Roguin, N., & Shkolnik, T. (1993). Red cell filterability in cigarette smokers and its relations to cardiac hypertrophy. Atherosclerosis, 98, 91–98.

    Article  PubMed  CAS  Google Scholar 

  24. Loennechen, J., Nilsen, O., Arbo, I., Aadahl, P., Nilsen, T., Waldum, H., et al. (2002). Chronic exposure to carbon monoxide and nicotine: Endothelin ETA receptor antagonism attenuates carbon monoxide-induced myocardial hypertrophy in rat. Toxicology and Applied Pharmacology, 178, 8–14.

    Article  PubMed  CAS  Google Scholar 

  25. Castardeli, E., Duarte, D., Minicucci, M., Azevedo, P., Matsubara, B., Matusbara, L., et al. (2007). Tobacco smoke-induced left ventricular remodelling is not associated with metalloproteinase-2 or -9 activation. European Journal of Heart Failure, 9, 1081–1085.

    Article  PubMed  CAS  Google Scholar 

  26. O’Callagan, C., & Williams, B. (2000). Mechanical strain-induced extracellular matrix production by human vascular smooth muscle cells. Hypertension, 36, 319–324.

    Article  Google Scholar 

  27. Matta, S. G., Balfour, D. J., Benowitz, N. L., Boyd, R. T., Buccafusco, J. J., Caggiula, A. R., et al. (2007). Guidelines on nicotine dose selection for in vivo research. Psychopharmacology (Berl), 190, 269–319.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

This project was funded by a Grant from the National Institutes of Health (ES014639).

Conflict of interest

The authors declare they have no known conflicts of interest with the present work.

Author information

Authors and Affiliations

  1. Department of Pharmaceutical Sciences, MSC09 5360, College of Pharmacy, 1 University of New Mexico, Albuquerque, NM, 87131-0001, USA

    E. Sage Colombo, Joshua Davis, Mehran Makvandi, Mario Aragon, Selita N. Lucas, Michael L. Paffett & Matthew J. Campen

Authors
  1. E. Sage Colombo
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Joshua Davis
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Mehran Makvandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Mario Aragon
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Selita N. Lucas
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Michael L. Paffett
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Matthew J. Campen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Matthew J. Campen.

Additional information

E. Sage Colombo and Joshua Davis have contributed equally to this study.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Colombo, E.S., Davis, J., Makvandi, M. et al. Effects of Nicotine on Cardiovascular Remodeling in a Mouse Model of Systemic Hypertension. Cardiovasc Toxicol 13, 364–369 (2013). https://doi.org/10.1007/s12012-013-9217-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12012-013-9217-z

Keywords

Search

Navigation