Khamlichi Fatima-Zahra1, Schauerte Heike1, Mayer Werner1 , Hezler Leonie-Theresa2, Martel Eric1 , Rast Georg1 , Pairet Nicolas 1
1 Boehringer Ingelheim Pharma, Department of Drug Discovery Sciences-General Pharmacology, Biberach/Riss, Germany
2 Boehringer Ingelheim Pharma, Department of Global Biostatistics & Data Sciences, Biberach/Riss, Germany
Abstract
Background: The cardiovascular and respiratory system evaluatins are mandatory in safety pharmacology. The gold standard methods used to assess these systems in rats, whether telemetry implants for cardiac function or whole-body plethysmography (WBP) for respiratory function, have their shortcomings. One method is invasive and requires surgery, while the other involves the isolation of the rats from their congeners. In a 3Rs approach, new alternatives, such as the use of non-invasive telemetry jackets, allowing simultaneous assessment of cardiac and respiratory functions, without the evaluation of hemodynamic parameters have been considered. Studies have shown that jackets can detect cardiorespiratory physiological variations induced by pharmacological substances. However, to our knowledge, no peer-reviewed publication to date has investigated the concordance between cardiorespiratory parameters recorded simultaneously via the jackets and the reference methods, following the administration of a pharmacological compound.
Goal: The aim of this study, developed in accordance with the 3Rs principles, was to test and potentially validate the telemetry jackets by comparing data generated using this device with those obtained using gold standard methods at the same time, in the same animal, in an integrative interpretation approach.
Methods: We compared cardiac (heart rate) and respiratory (respiratory rate (RR), minute ventilation (MV), tidal volume (TV)) parameters recorded via the invasive (DSI implant), non-invasive (Jacket DECRO) telemetry systems, and via the WBP (Buxco + Notocord HEM), simultaneously in the same male rats (n = 8 rats/ pharmacological compound in a cross-over design). The recording lasted from 1 hour before, till 7 hours after the per os administration of vehicle or pharmacological reference compounds tested (Ivabradine or Theophylline) at doses of 3 mg/kg, 10 mg/kg, or 30 mg/kg each. A generalized linear model was used to assess the effects of the pharmacological compounds on physiological parameters. The Bland & Altman method was used to study the agreement between the physiological parameters recorded via jackets and the two reference methods.
Results: The jackets and reference methods both captured the expected pharmacological effects. For Ivabradine, a significant dose-dependent decrease in heart rate was observed, while no changes were noted in respiratory variables. Theophylline induced a dose-dependent increase in heart rate, RR and MV. No significant change on TV was noticed with the WBP, whereas a significant increase was shown with the jackets. Bland-Altman analysis revealed an increasing discrepancy in high TV, RR and MV values between the two devices under the experimental conditions of the studies.
Goal: The aim of this study, developed in accordance with the 3Rs principles, was to test and potentially validate the telemetry jackets by comparing data generated using this device with those obtained using gold standard methods at the same time, in the same animal, in an integrative interpretation approach.
Methods: We compared cardiac (heart rate) and respiratory (respiratory rate (RR), minute ventilation (MV), tidal volume (TV)) parameters recorded via the invasive (DSI implant), non-invasive (Jacket DECRO) telemetry systems, and via the WBP (Buxco + Notocord HEM), simultaneously in the same male rats (n = 8 rats/ pharmacological compound in a cross-over design). The recording lasted from 1 hour before, till 7 hours after the per os administration of vehicle or pharmacological reference compounds tested (Ivabradine or Theophylline) at doses of 3 mg/kg, 10 mg/kg, or 30 mg/kg each. A generalized linear model was used to assess the effects of the pharmacological compounds on physiological parameters. The Bland & Altman method was used to study the agreement between the physiological parameters recorded via jackets and the two reference methods.
Results: The jackets and reference methods both captured the expected pharmacological effects. For Ivabradine, a significant dose-dependent decrease in heart rate was observed, while no changes were noted in respiratory variables. Theophylline induced a dose-dependent increase in heart rate, RR and MV. No significant change on TV was noticed with the WBP, whereas a significant increase was shown with the jackets. Bland-Altman analysis revealed an increasing discrepancy in high TV, RR and MV values between the two devices under the experimental conditions of the studies.
Conclusion: Jackets can be used as an alternative to implanted telemetry for recording heart rate without hemodynamic parameters. Although the two respiratory methods detect pharmacological effects, further investigation is needed to determine what is the current state of the respiratory parameters.
