Home Carvedilol improves heart rate variability indices, biomarkers but not cardiac nerve density in streptozotocin-induced T2DM model of diabetic cardiac autonomic neuropathy
Article
Licensed
Unlicensed Requires Authentication

Carvedilol improves heart rate variability indices, biomarkers but not cardiac nerve density in streptozotocin-induced T2DM model of diabetic cardiac autonomic neuropathy

  • Olawale Mathias Akinlade ORCID logo EMAIL logo , Bamidele Owoyele ORCID logo and Olufemi Ayodele Soladoye
Published/Copyright: March 18, 2021
Journal of Basic and Clinical Physiology and Pharmacology
From the journal Journal of Basic and Clinical Physiology and Pharmacology Volume 33 Issue 2

Abstract

Objectives

There has been increasing recognition of the significant relationship between the autonomic nervous system and cardiovascular sequel in diabetes mellitus (DM) patients. Diabetic cardiac autonomic neuropathy (DCAN) still poses a treatment challenge in the clinical settings despite several research interventions. This study was designed to investigate the effect of carvedilol on experimentally induced DCAN in type 2 DM rat model.

Methods

DCAN was induced in 42 Wistar rats using high fat diet (HFD) for eight weeks, thereafter streptozotocin (STZ) at 25 mg/kg daily for five days. DCAN features were then assessed using non-invasive time and frequency varying holter electrocardiogram (ECG), invasive biomarkers, cardiac histology and cardiac nerve density.

Results

Carvedilol significantly ameliorated the effects of DCAN on noradrenaline (p=0.010) and advanced glycated end products (AGEs) (p<0.0001). Similarly, carvedilol reversed the reduction in levels of antioxidants, sorbitol dehydrogenase (SD) activity (p=0.009) nerve growth factors (p<0.0001) and choline acetyl-transferase (p=0.031) following DCAN induction. Furthermore, heart rate variability (HRV) indices which were also reduced with DCAN induction were also ameliorated by carvedilol. However, carvedilol had no significant effect on cardiac neuronal dystrophy and reduced cardiac nerve densities.

Conclusions

Carvedilol improves physiological HRV indices and biomarkers but not structural lesions. Early detection of DCAN and intervention with carvedilol may prevent progression of autonomic neurologic sequel.

Keywords: cardiac nerve density; Carvedilol; diabetic cardiac autonomic neuropathy; heart rate variability
Corresponding author: Dr. Olawale Mathias Akinlade, MBBS, MSc, FWACP, Neuroscience and Inflammation Unit, Department of Physiology, College of Health Sciences, University of Ilorin, Ilorin, Kwara State, Nigeria; and Internal Medicine Department, Cardiology Unit, LAUTECH Teaching Hospital, Ogbomoso, Oyo State, Nigeria, E-mail:

Acknowledgements

We acknowledge Dr Ajao FO for her technical assistance during the execution phase of the project.

  1. Research funding: None declared.

  2. Author contributions: AOM designed, performed the project work, analysed and interpreted the data. He was the main contributor in writing the manuscript. BVO designed, analysed and interpreted the data, also a major contributor in writing the manuscript. SAO designed, analysed and interpreted the data, also contributor in writing the manuscript. All authors read and approved the final manuscript.

  3. Competing interests: Authors state no conflict of interest.

  4. Informed consent: Not applicable.

  5. Ethical approval: The experimental protocol was approved and the research was conducted in accordance with the guiding principles of the University of Ilorin Ethical Review Committee (UERC) with approval number: UERC/ASN/2019/1912.

  6. Data availability statement: The datasets during and/or analysed during the current study are available from the corresponding author on reasonable request.

References

1. Saeedi, P, Petersohn, I, Salpea, P, Malanda, B, Karuranga, S, Unwin, N, et al.. Global and regional diabetes prevalence estimates for 2019 and projections for 2030 and 2045: results from the international diabetes federation diabetes atlas, 9th edition. Diabetes Res Clin Pract 2019;157:107843. https://doi.org/10.1016/j.diabres.2019.107843.Search in Google Scholar PubMed

2. Schmidt, AM. Diabetes mellitus and cardiovascular disease. Arterioscler Thromb Vasc Biol 2019;39:558–68. https://doi.org/10.1161/ATVBAHA.119.310961.Search in Google Scholar PubMed PubMed Central

3. Refaie, W. Assessment of cardiac autonomic neuropathy in long standing type 2 diabetic women. Egypt Heart J 2014;66:63–9. https://doi.org/10.1016/j.ehj.2013.06.002.Search in Google Scholar

4. Verrotti, A, Prezioso, G, Scattoni, R, Chiarelli, F. Autonomic neuropathy in diabetes mellitus. Front Endocrinol 2014;5:205. https://doi.org/10.3389/fendo.2014.00205.Search in Google Scholar PubMed PubMed Central

5. Lin, Y-D, Hsu, K-L, Wu, E-T, Tsai, M-S, Wang, C-H, Chang, C-Y, et al.. Autonomic neuropathy precedes cardiovascular dysfunction in rats with diabetes. Eur J Clin Invest 2008;38:607–14. https://doi.org/10.1111/j.1365-2362.2008.01992.x.Search in Google Scholar PubMed

6. Vinik, AI, Erbas, T, Casellini, CM. Diabetic cardiac autonomic neuropathy, inflammation and cardiovascular disease. J Diabetes Invest 2013;4:4–18. https://doi.org/10.1111/jdi.12042.Search in Google Scholar PubMed PubMed Central

7. Chan, M. Global report on diabetes. Geneva, Switzerland: WHO Press; 2016.Search in Google Scholar

8. Nam Han, C, Suvi, K, editors. International diabetes federation atlas, 8th ed. Brussels, Belgium: IDF Press; 2017.Search in Google Scholar

9. Serhiyenko, VA, Serhiyenko, AA. Cardiac autonomic neuropathy: risk factors, diagnosis and treatment. World J Diabetes 2018;9:1–24. https://doi.org/10.4239/wjd.v9.i1.1.Search in Google Scholar PubMed PubMed Central

10. Fisher, VL, Tahrani, AA. Cardiac autonomic neuropathy in patients with diabetes mellitus: current perspectives. Diabetes, Metab Syndrome Obes Targets Ther 2017;10:419–34. https://doi.org/10.2147/DMSO.S129797.Search in Google Scholar PubMed PubMed Central

11. Agashe, S, Petak, S. Cardiac autonomic neuropathy in diabetes mellitus. Methodist DeBakey Cardiovasc J 2018:14:251–6. https://doi.org/10.14797/mdcj-14-4-251.Search in Google Scholar PubMed PubMed Central

12. Depace, N, Bateman, J, Yayac, M, Siddique, M, Pinales, J, Acosta, C, et al.. Improved patient outcomes by normalizing sympathovagal balance as measured by parasympathetic and sympathetic monitoring: the benefits of carvedilol. Cardiovasc Disord Med 2018;3:1–5. https://doi.org/10.15761/cdm.1000181.Search in Google Scholar

13. Singh, VP, Bali, A, Singh, N, Jaggi, AS. Advanced glycation end products and diabetic complications. Korean J Physiol Pharmacol 2014;18:1–14.10.4196/kjpp.2014.18.1.1Search in Google Scholar

14. Packer, M, Coats, AJS, Fowler, MB, Katus, HA, Krum, H, Mohacsi, P, et al.. Effect of carvedilol on survival in severe chronic heart failure. N Engl J Med 2001;344:1651–8. https://doi.org/10.1056/NEJM200105313442201.Search in Google Scholar

15. Packer, M, Fowler, MB, Roecker, EB, Coats, AJS, Katus, HA, Krum, H, et al.. Effect of carvedilol on the morbidity of patients with severe chronic heart failure: results of the carvedilol prospective randomized cumulative survival (COPERNICUS) study. Circulation 2002;106:2194–9. https://doi.org/10.1161/01.CIR.0000035653.72855.BF.Search in Google Scholar

16. Poole-Wilson, PA, Swedberg, K, Cleland, JGF, Di Lenarda, A, Hanrath, P, Komajda, M, et al.. Comparison of carvedilol and metoprolol on clinical outcomes in patients with chronic heart failure in the Carvedilol or Metoprolol European Trial (COMET): randomised controlled trial. Lancet 2003;362:7–13. https://doi.org/10.1016/s0140-6736(03)13800-7.Search in Google Scholar

17. Potočnik, N, Perše, M, Cerar, A, Injac, R, Finderle, Ž. Cardiac autonomic modulation induced by doxorubicin in a rodent model of colorectal cancer and the influence of fullerenol pretreatment. PloS One 2017;12:e0181632. https://doi.org/10.1371/journal.pone.0181632.Search in Google Scholar PubMed PubMed Central

18. Li, X, Matta, SM, Sullivan, RD, Bahouth, SW. Carvedilol reverses cardiac insufficiency in AKAP5 knockout mice by normalizing the activities of calcineurin and CaMKII. Cardiovasc Res 2014;104:270–9. https://doi.org/10.1093/cvr/cvu209.Search in Google Scholar PubMed PubMed Central

19. Ahmad, A. Carvedilol can replace insulin in the treatment of type 2 diabetes mellitus. J Diabetes Metabol 2017;08:1–6. https://doi.org/10.4172/2155-6156.1000726.Search in Google Scholar

20. Bakris, GL, Fonseca, V, Katholi, RE, McGill, JB, Messerli, FH, Phillips, RA, et al.. Metabolic effects of carvedilol vs. metoprolol in patients with type 2 diabetes mellitus and hypertension. J Am Med Assoc 2004;292:2227. https://doi.org/10.1001/jama.292.18.2227.Search in Google Scholar PubMed

21. Huang, H, Shan, J, Pan, X-H, Wang, H-P, Qian, L-B, Xia, Q. Carvedilol improved diabetic rat cardiac function depending on antioxidant ability. Diabetes Res Clin Pract 2007;75:7–13. https://doi.org/10.1016/j.diabres.2006.04.016.Search in Google Scholar PubMed

22. Arini, PD, Liberczuk, S, Mendieta, JG, Santa María, M, Bertrán, GC. Electrocardiogram delineation in a wistar rat experimental model. Comput Math Methods Med 2018;2018:1–10. https://doi.org/10.1155/2018/2185378.Search in Google Scholar PubMed PubMed Central

23. Konopelski, P, Ufnal, M Electrocardiography in rats: a comparison to human. Physiol Res 2016;65:717–25.10.33549/physiolres.933270Search in Google Scholar PubMed

24. Metelka, R, Cibičková, L, Gajdová, J, Krystyník, O. Heart rate variability evaluation in the assessment of cardiac autonomic neuropathy in patients with type 2 diabetes. Cor Vasa 2018;60:e335–44. https://doi.org/10.1016/j.crvasa.2017.05.001.Search in Google Scholar

25. Singh, N, Moneghetti, KJ, Christle, JW, Hadley, D, Froelicher, V, Plews, D. Heart rate variability: an old metric with new meaning in the era of using mHealth technologies for health and exercise training guidance. Part Two: prognosis and training. Arrhythmia Electrophysiol Rev 2018;7:247–55. https://doi.org/10.15420/aer.2018.30.2.Search in Google Scholar PubMed PubMed Central

26. Malik, M. Heart rate variability: standards of measurement, physiological interpretation, and clinical use. Circulation 1996;93:1043–65.10.1093/oxfordjournals.eurheartj.a014868Search in Google Scholar

27. Young, HA, Benton, D. Heart-rate variability: a biomarker to study the influence of nutrition on physiological and psychological health? Behav Pharmacol 2018;29:140–51. https://doi.org/10.1097/fbp.0000000000000383.Search in Google Scholar

28. Ernst, G. Heart-rate variability—more than heart beats? Front Public Health 2017;5:240. https://doi.org/10.3389/fpubh.2017.00240.Search in Google Scholar PubMed PubMed Central

29. DeBeck, LD, Petersen, SR, Jones, KE, Stickland, MK. Heart rate variability and muscle sympathetic nerve activity response to acute stress: the effect of breathing. Am J Physiol Regul Integr Comp Physiol 2010;299:R80–91. https://doi.org/10.1152/ajpregu.00246.2009.Search in Google Scholar PubMed PubMed Central

30. Shah, AS, El Ghormli, L, Vajravelu, ME, Bacha, F, Farrell, RM, Gidding, SS, et al.. Heart rate variability and cardiac autonomic dysfunction: prevalence, risk factors, and relationship to arterial stiffness in the treatment options for type 2 diabetes in adolescents and youth (TODAY) study. Diabetes Care 2019;42:2143–50. https://doi.org/10.2337/dc19-0993.Search in Google Scholar PubMed PubMed Central

31. Bernardi, L, Spallone, V, Stevens, M, Hilsted, J, Frontoni, S, Pop-Busui, R, et al.. Methods of investigation for cardiac autonomic dysfunction in human research studies. Diabetes Metabol Res Rev 2011;27:654–64. https://doi.org/10.1002/dmrr.1224.Search in Google Scholar PubMed

32. Aslam, N, Kedar, A, Nagarajarao, HS, Reddy, K, Rashed, H, Cutts, T, et al.. Serum catecholamines and dysautonomia in diabetic gastroparesis and liver cirrhosis. Am J Med Sci 2015;350:81–6. https://doi.org/10.1097/maj.0000000000000523.Search in Google Scholar

33. Dimitropoulos, G, Tahrani, AA, Stevens, MJ. Cardiac autonomic neuropathy in patients with diabetes mellitus. World J Diabetes 2014;5:17–39. https://doi.org/10.4239/wjd.v5.i1.17.Search in Google Scholar PubMed PubMed Central

34. Porojan, M, Costin, S, Laura, P, Anca, C, Pop, D, Dumitraşcu, DL. Autonomic neuropathy and plasma catecholamine in patients with diabetes mellitus | request PDF. Rom J Intern Med 2010;48:341–5.Search in Google Scholar

35. Rolim, LC, de Souza, JST, Dib, SA. Tests for early diagnosis of cardiovascular autonomic neuropathy: critical analysis and relevance. Front Endocrinol 2013;4:173. https://doi.org/10.3389/fendo.2013.00173.Search in Google Scholar PubMed PubMed Central

36. Grosset, AA, Loayza-Vega, K, Adam-Granger, É, Birlea, M, Gilks, B, Nguyen, B, et al.. Hematoxylin and eosin counterstaining protocol for immunohistochemistry interpretation and diagnosis. Appl Immunohistochem Mol Morphol 2019;27:558–63. https://doi.org/10.1097/pai.0000000000000626.Search in Google Scholar PubMed

37. Vlassara, H, Uribarri, J. Advanced glycation end products (AGE) and diabetes: cause, effect, or both? Curr Diabetes Rep 2014;14:453. https://doi.org/10.1007/s11892-013-0453-1.Search in Google Scholar PubMed PubMed Central

38. Rhee, SY, Kim, YS. The role of advanced glycation end products in diabetic vascular complications. Diabetes Metab J 2018;42:188–95. https://doi.org/10.4093/dmj.2017.0105.Search in Google Scholar PubMed PubMed Central

39. Wallin, BG. Muscle sympathetic activity and plasma concentrations of noradrenaline. Acta Physiol Scand Suppl 1984;527:21–4.Search in Google Scholar

40. Zygmunt, A, Stanczyk, J. Methods of evaluation of autonomic nervous system function. Arch Med Sci 2010;6:11–8. https://doi.org/10.5114/aoms.2010.13500.Search in Google Scholar PubMed PubMed Central

41. Thorp, AA, Schlaich, MP. Relevance of sympathetic nervous system activation in obesity and metabolic syndrome. J Diabetes Res 2015;2015:341583. https://doi.org/10.1155/2015/341583.Search in Google Scholar PubMed PubMed Central

42. Spallone, V. Update on the impact, diagnosis and management of cardiovascular autonomic neuropathy in diabetes: what is defined, what is new, and what is unmet. Diabetes Metab J 2019;43:3. https://doi.org/10.4093/dmj.2018.0259.Search in Google Scholar PubMed PubMed Central

43. Spallone, V, Ziegler, D, Freeman, R, Bernardi, L, Frontoni, S, Pop-Busui, R, et al.. Cardiovascular autonomic neuropathy in diabetes: clinical impact, assessment, diagnosis, and management. Diabetes Metabol Res Rev 2011;27:639–53.10.1002/dmrr.1239Search in Google Scholar PubMed

44. Yang, B. Assessment of cardiac autonomic neuropathy (CAN) in Type I diabetic mice [Dr dissertation (All Dissertation All Years)]. Worcester Polytechnic Institute; 2011.Search in Google Scholar

45. Dandona, P, Ghanim, H, Brooks, DP. Antioxidant activity of carvedilol in cardiovascular disease. J Hypertens 2007;25:731–41. https://doi.org/10.1097/hjh.0b013e3280127948.Search in Google Scholar

46. Huang, H, Shan, J, Pan, X-H, Wang, H-P, Qian, L-B. Carvedilol protected diabetic rat hearts via reducing oxidative stress. J Zhejiang Univ - Sci B 2006;7:725–31.10.1631/jzus.2006.B0725Search in Google Scholar PubMed PubMed Central

47. Diogo, CV, Deus, CM, Lebiedzinska-Arciszewska, M, Wojtala, A, Wieckowski, MR, Oliveira, PJ. Carvedilol and antioxidant proteins in a type I diabetes animal model. Eur J Clin Invest 2017;47:19–29. https://doi.org/10.1111/eci.12696.Search in Google Scholar PubMed

48. Fazan, RJ, Ballejo, G, Salgado, MCO, Moraes, MFD, Salgado, HC. Heart rate variability and baroreceptor function in chronic diabetic rats. Hypertension 1997;30:632–5. https://doi.org/10.1161/01.hyp.30.3.632.Search in Google Scholar PubMed

49. Guzzetti, S, Borroni, E, Garbelli, PE, Ceriani, E, Bella, PD, Montano, N, et al.. Symbolic dynamics of heart rate variability. Circulation 2005;112:465–70. https://doi.org/10.1161/circulationaha.104.518449.Search in Google Scholar PubMed

50. Goldberger, JJ, Challapalli, S, Tung, R, Parker, MA, Kadish, AH. Relationship of heart rate variability to parasympathetic effect. Circulation 2001;103:1977–83. https://doi.org/10.1161/01.cir.103.15.1977.Search in Google Scholar PubMed

51. Sacha, J. Interplay between heart rate and its variability: a prognostic game. Front Physiol 2014;5:347. https://doi.org/10.3389/fphys.2014.00347.Search in Google Scholar PubMed PubMed Central

52. Wang, HM, Huang, SC. SDNN/RMSSD as a surrogate for LF/HF: a revised investigation. Model Simulat Eng 2012;2012:16. https://doi.org/10.1155/2012/931943.Search in Google Scholar

53. Sammito, S, Böckelmann, I. Reference values for time- and frequency-domain heart rate variability measures. Heart Rhythm 2016;13:1309–16. https://doi.org/10.1016/j.hrthm.2016.02.006.Search in Google Scholar PubMed

54. Shaffer, F, Ginsberg, JP. An overview of heart rate variability metrics and norms. Front Public Health 2017;5:258. https://doi.org/10.3389/fpubh.2017.00258.Search in Google Scholar PubMed PubMed Central

55. Altini, M. How to make sense of your Apple watch heart rate variability (HRV) data | by Marco Altini | Medium [Internet]. Available from: https://medium.com/@altini_marco/how-to-make-sense-of-your-apple-watch-heart-rate-variability-hrv-data-89bf4a510438 [Accessed 8 Dec 2020].Search in Google Scholar

56. McCraty, R, Shaffer, F. Heart rate variability: new perspectives on physiological mechanisms, assessment of self-regulatory capacity, and health risk. Global Adv Health Med 2015;4:46–61. https://doi.org/10.7453/gahmj.2014.073.Search in Google Scholar PubMed PubMed Central

57. Lee, PG, Hohman, TC, Cai, F, Regalia, J, Helke, CJ. Streptozotocin-induced diabetes causes metabolic changes and alterations in neurotrophin content and retrograde transport in the cervical vagus nerve. Exp Neurol 2001;170:149–61. https://doi.org/10.1006/exnr.2001.7673.Search in Google Scholar PubMed

Received: 2020-09-10
Accepted: 2021-01-02
Published Online: 2021-03-18

© 2021 Walter de Gruyter GmbH, Berlin/Boston

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Use of cannabinoids for the treatment of patients with post-traumatic stress disorder
  4. Traditional knowledge to clinical trials: a review on nutritional and therapeutic potential of Pithecellobium dulce
  5. Original Articles
  6. Protective role of protocatechuic acid in carbon tetrachloride-induced oxidative stress via modulation of proinflammatory cytokines levels in brain and liver of Wistar rats
  7. Association of glycaemic status and outcomes in diabetic foot problems: a retrospective evidence from South India
  8. Piperine protects oxidative modifications in human erythrocytes
  9. Effects of Artemisia supplementation on anorexia in hemodialysis patients: a randomized, double-blind placebo-controlled trial
  10. A tablet derived from Andrographis paniculata complements dihydroartemisinin-piperaquine treatment of malaria in pregnant mice
  11. Role of interleukin-2 and interleukin-18 in newly diagnosed type 2 diabetes mellitus
  12. Levels of lead, aluminum, and zinc in occupationally exposed workers of North-Western India
  13. Gonadotropin levels reduced in seven days immobilization stress-induced depressive-like behavior in female rats
  14. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on pulmonary function in hypertensive patients
  15. Carvedilol improves heart rate variability indices, biomarkers but not cardiac nerve density in streptozotocin-induced T2DM model of diabetic cardiac autonomic neuropathy
https://doi.org/10.1515/jbcpp-2020-0282
Keywords for this article
cardiac nerve density; Carvedilol; diabetic cardiac autonomic neuropathy; heart rate variability

Articles in the same Issue

  1. Frontmatter
  2. Reviews
  3. Use of cannabinoids for the treatment of patients with post-traumatic stress disorder
  4. Traditional knowledge to clinical trials: a review on nutritional and therapeutic potential of Pithecellobium dulce
  5. Original Articles
  6. Protective role of protocatechuic acid in carbon tetrachloride-induced oxidative stress via modulation of proinflammatory cytokines levels in brain and liver of Wistar rats
  7. Association of glycaemic status and outcomes in diabetic foot problems: a retrospective evidence from South India
  8. Piperine protects oxidative modifications in human erythrocytes
  9. Effects of Artemisia supplementation on anorexia in hemodialysis patients: a randomized, double-blind placebo-controlled trial
  10. A tablet derived from Andrographis paniculata complements dihydroartemisinin-piperaquine treatment of malaria in pregnant mice
  11. Role of interleukin-2 and interleukin-18 in newly diagnosed type 2 diabetes mellitus
  12. Levels of lead, aluminum, and zinc in occupationally exposed workers of North-Western India
  13. Gonadotropin levels reduced in seven days immobilization stress-induced depressive-like behavior in female rats
  14. Comparative effects of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on pulmonary function in hypertensive patients
  15. Carvedilol improves heart rate variability indices, biomarkers but not cardiac nerve density in streptozotocin-induced T2DM model of diabetic cardiac autonomic neuropathy
Sign up now to receive a 20% welcome discount
Institutional Access
How does access work?
Have an idea on how to improve our website?
Please write us.
© 2025 De Gruyter Brill
Downloaded on 13.9.2025 from https://www.degruyterbrill.com/document/doi/10.1515/jbcpp-2020-0282/html
Scroll to top button