Main Indices of Laboratory Rabbit Cardiovascular System

Introduction. Rabbits, ferrets, dogs, miniature pigs and monkeys are considered to be the preferable test systems for assessing the efficacy of the developed medicinal products for the cardiovascular system. The heart rate and distribution of cardiac ion channels in the heart of these species is similar to that in the human heart. The present work focuses on rabbits as they are one of the most widely used species in preclinical research, however, the results of measurements carried out on a sufficient sample of intact animals can hardly be found in the open sources. Thus, the aim of the study is to determine the features of the electrocardiogram and to establish the reference intervals of the key cardiovascular indices as well as of the blood pressure in the sexually mature laboratory rabbits of different breeds, ages and sexes, and to compare the obtained data with that in the literature sources.

Materials and Methods. The study was conducted at JSC “Research-and-Manufacturing Company “Home of Pharmacy” (Leningrad Region) in the period from 2019 to 2024. 597 electrocardiograms and 863 values of systolic and diastolic blood pressure in rabbits of various breeds and sexes aged 4 to 8 months were analysed and reference intervals for them were calculated. To minimise possible variability of parameters caused by stress and motor activity of animals, they were anesthetized during physiological studies with a drug containing tiletamine and zolazepam (5 mg / kg) in combination with xylazine hydrochloride (1–2 mg / kg) administered intramuscularly or intravenously. The data were retrieved by recording the background values in all rabbits in the experiment (before administering the studied medicinal products), as well as in rabbits in the control and intact groups. Reference intervals were calculated using a nonparametric (number of values more than 120) or robust (number of values less than 120) methods.

Results. When studying the electrocardiograms of rabbits, the highest variability was noted in the P wave. Also, the absence of one of the Q, S, T waves in one or two leads and absence of S-T and T-P intervals were frequently observed. When comparing rabbit breeds and body weight ranges, no significant differences were found in the calculated reference intervals of the indices assessed. When comparing to the literature sources, the electrocardiogram parameters mainly matched the obtained reference intervals, except for the QRS interval. The obtained intervals of blood pressure indices in the state of anaesthesia were significantly lower than the values presented in the literature for the awaken animals.

Discussion and Conclusion. The calculated reference intervals of the most of electrocardiogram parameters in different rabbit breeds are comparable to the data available in literature and do not significantly vary in relation to age, weight and sex. The obtained reference intervals and the described features of the electrocardiogram of rabbits can be used in the analysis and interpretation of data received during preclinical research.

1. Hornyik T, Rieder M, Castiglione A, Major P, Baczko I, Brunner M et al. Transgenic Rabbit Models for Cardiac Disease Research. British Journal of Pharmacology. 2022;179(5):938–957. https://doi.org/10.1111/bph.15484

2. Kaese S, Frommeyer G, Verheule S, van Loon G, Gehrmann J, Breithardt G et al. The ECG in CardiovascularRelevant Animal Models of Electrophysiology. Herzschrittmachertherapie und Elektrophysiologie. 2013;24(2):1–8. https://doi.org/10.1007/s00399-013-0260-z

3. Joukar S. A Comparative Review on Heart Ion Channels, Action Potentials and Electrocardiogram in Rodents and Human: Extrapolation of Experimental Insights to Clinic. Laboratory Animal Research. 2021;37(1):25. https://doi.org/10.1186/s42826-021-00102-3

4. Peng X. Transgenic Rabbit Models for Studying Human Cardiovascular Diseases. Comparative Medicine. 2012;62(6):472–479.

5. Samidurai A, Ockaili R, Cain C, Roh SK, Filippone SM, Kraskauskas D et al. Preclinical Model of Type 1 Diabetes and Myocardial Ischemia/Reperfusion Injury in Conscious Rabbits–Demonstration of Cardioprotection with Rapamycin. STAR Protocols. 2021;2(3):100772. https://doi.org/10.1016/j.xpro.2021.100772

6. Odening KE, Bodi I, Franke G, Rieke R, Ryan de Medeiros A, Perez-Feliz S et al. Transgenic Short-QT Syndrome 1 Rabbits Mimic the Human Disease Phenotype with QT/Action Potential Duration Shortening in the Atria and Ventricles and Increased Ventricular Tachycardia/Ventricular Fibrillation Inducibility. European Heart Journal. 2019;40(10):842–853. https://doi.org/10.1093/eurheartj/ehy761

7. Ton AN, Liu SH, Lo LW, Khac TC, Chou YH, Cheng WH et al. Renal Artery Denervation Prevents Ventricular Arrhythmias in Long QT Rabbit Models. Scientific Reports. 2022;12(1):2904. https://doi.org/10.1038/s41598-022-06882-5

8. Logantha SJRJ, Cai XJ, Yanni J, Jones CB, Stephenson RS, Stuart L et al. Remodeling of the Purkinje Network in Congestive Heart Failure in the Rabbit. Circulation. Heart failure. 2021;14(7):e007505. http://doi.org/10.1161/CIRCHEARTFAILURE.120.007505

9. Makarova MN, Makarov VG. Rabbits in Preclinical Research. Laboratory Animals for Science. 2023;(3):18–43. (In Russ.) https://doi.org/10.57034/2618723X-2023-03-02

10. Engalycheva GN, Syubaev RD, Goryachev DV. Safety Pharmacology Studies of Medicinal Products: Evaluation of Results. Vedomosti Nauchnogo tsentra ekspertizy sredstv meditsinskogo primeneniya (Regulatory Research and Medicine Evaluation). 2017;7(2):92–97. (In Russ.)

11. Sarazan RD, Mittelstadt S, Guth B, Koerner J, Zhang J, Pettit S. Cardiovascular Function in Nonclinical Drug Safety Assessment: Current Issues and Opportunities. International Journal of Toxicology. 2011;30(3):272–286. https://doi.org/10.1177/1091581811398963

12. Melentiev ON. Injectable Agents and Their Combinations Used for Anesthesia of Rabbits. (In Russ.) URL: https://www.vetusklinika.ru/article/rabbit/anaesthesia/injectable-drugs/ (accessed: 28.05.2025).

13. Razina AV, Frolova AI, Sergeev MA. The Optimization of General Anesthetic Technique in Rabbits. Actual Questions of Veterinary Biology. 2010;(1(5)):32–35. (In Russ.)

14. Akimov DYu, Makarova MN, Gushchina SV, Khan SO, Shabanov PD. The Influence of a Combination of Xylazine with Tilethamine + Zolezapam on Some Parameters of Rabbits under Anesthesia of Different Depths. Tekhnologii zhivykh sistem. 2024;21(1):63–74. (In Russ.) https://doi.org/10.18127/j20700997-202401-06

15. Xinyuan Liu, Dingwu He, Liuqing Pei, Suming Zhang. Singularity Detection of the Rabbit Electrocardiogram: An Evolutionary Spectral Method. Progress in Natural Science. 2009;19(10):1317–1326. https://doi.org/10.1016/j.pnsc.2009.01.009

16. Farkas A, Batey AJ, Coker SJ. How to Measure Electrocardiographic QT Interval in the Anaesthetized Rabbit. Journal of Pharmacological and Toxicological Methods. 2004;50(3):175–185. https://doi.org/10.1016/j.vascn.2004.05.002

17. Saitanov AO. The Electrocardiogram of Healthy Rabbits in Standard and Chest Leads and Methods of Recording It. Bulletin of Experimental Biology and Medicine. 1960;49(6):620–626.

18. Lord B, Boswood A, Petrie A. Electrocardiography of the Normal Domestic Pet Rabbit. Veterinary Record. 2010;167(25):961–965. https://doi.org/10.1136/vr.c3212

19. Evgina SA, Saveliev LI. Current Theory and Practice of Reference Interval. Laboratory Service. 2019;8(2):36–44. (In Russ.) https://doi.org/10.17116/labs2019802136

20. Makhmudova ZhA. Dynamics of ECG Parameters in Rabbits with Catecholamine Myocardial Necrosis under Conditions of Different Altitudes. Problemy sovremennoy nauki i obrazovaniya. 2016;(43):59–62. (In Russ.)

21. Daly CH, Higgins V, Adeli K, Grey VL, Hamid JS. Reference Interval Estimation: Methodological Comparison Using Extensive Simulations and Empirical Data. Clinical Biochemistry. 2017;50(18):1145–1158. https://doi.org/10.1016/j.clinbiochem.2017.07.005

22. Kiyoshi Ichihara, Yesim Ozarda, JulianBarth, George Klee, Ling Qiu, Rajiv Erasmus et al. A Global Multicenter Study on Reference Values: 1. Assessment of Methods for Derivation and Comparison of Reference Intervals. Clinica Chimica Acta. 2017;467:70–82. https://doi.org/10.1016/j.cca.2016.09.016

23. Friedrichs KR, Harr KE, Freeman KP, Szladovits B, Walton RM, Barnhart KF et al. ASVCP Reference Interval Guidelines: Determination of de Novo Reference Intervals in Veterinary Species and Other Related Topics. Veterinary Clinical Pathology. 2012;41(4):441–453. https://doi.org/10.1111/vcp.12006

24. Yushkov BG, Korneva YeA, Chereshnev VA. The Concept of Norm in Physiology and Pathology. Physiological Constants in Laboratory Animals: Monograph. Ekaterinburg: Ural Branch of the Russian Academy of Sciences; 2021. 864 p. (In Russ.)

25. Dominguez R. The Systolic Blood Pressure of the Normal Rabbit Measured by a Slightly Modified van Leersum Method. The Journal of Experimental Medicine. 1927;46(3):443–461. https://doi.org/10.1084/jem.46.3.443

26. Williams LG, Wagner KT, Samaniego N, Singh V, Ryan JM, Auerbach DS. Surgical Implant Procedure and Wiring Configuration for Continuous Long-Term EEG/ECG Monitoring in Rabbits. Journal of Visualized Experiments: JoVE. 2025;(215):e67620. https://doi.org/10.3791/67620

27. Palozi RAC, Guarnier LP, Romão PVM, Nocchi SR, Dos Santos CC, Lourenço ELB et al. Pharmacological Safety of Plinia Cauliflora (Mart.) Kausel in Rabbits. Toxicology Reports. 2019;6:616–624. https://doi.org/10.1016/j.toxrep.2019.06.017

28. Semenko N, Kuchyn I, Frank M, Belka K, Milokhov D, Korshun O. Sevoflurane Reduces the Cardiac Toxicity of Bupivacaine Compared with Propofol in Rabbits: an Experimental Study Using Early Electrocardiographic Detection and Measurement of Toxic Plasma Concentration. Anaesthesiology Intensive Therapy. 2024;56(4):224–230. https://doi.org/10.5114/ait.2024.145167

29. Vertiprakhov VG, Sadykhov EF, Burova MA. Determination of Blood Pressure Indixes in Broiler Chickens and Rabbits to Assess Cardiovascular Function. Timiryazev Biological Journal. 2023;1(3):37–42. (In Russ.) https://doi.org/10.26897/2949-4710-2023-3-37-42