Glucagon-like peptide 1 (GLP-1) receptor agonists are proposed as a treatment option in patients with heart failure. However, the recommendation remains controversial because several clinical trials did not effectively improve cardiovascular outcomes in heart failure patients (1). One of the problems not settled is the concern about the positive chronotropic and sympathomimetic effect of GLP-1 receptor agonists (2).
We experimented to discover the potentially hazardous effects of chronic treatment with long-acting GLP-1 receptor agonist liraglutide on the hemodynamics and autonomic nervous system (ANS).
During general anesthesia (120 mg.kg-1 ketamine & 6 mg.kg-1 xylazine i.p.), we implanted 10-month-old male Sprague-Dawley rats (n = 14, randomly assigned to the control or treated groups, n = 7) with telemetric transmitters (HD-S11, Data Sciences, USA). Implants allowed simultaneous monitoring of aortic pressure, ECG, core body temperature, and locomotor activity. After baseline 24-hour (12 h light-dark cycles, dark started at 7.00 a.m.) recording of telemetric signals, we used pharmacological tests and 30-minute restraints to estimate ANS activity (3, 4). We applied (i.p.) liraglutide daily, gradually increasing the dose. We started with 0.1 mg/kg of liraglutide for 18 days, continued with 0.3 mg/kg for 55 days, and 1mg/kg for 59 days. We injected (i.p.) saline to control rats. Telemetric signals were recorded weekly for 24 hours. We performed pharmacological and restraint stress ANS tests one month after injecting liraglutide 0.3 mg.kg-1 or 1 mg.kg-1. In addition, we calculated time and frequency domain indices of cardiovascular variability (3, 4). Data were analyzed with the multivariate (Wilks) repeated measure ANOVA. The post hoc Tukey HSD test was used if the interaction between the main effects (treatment & time) was significant.
While body weight remained steady in control rats (645 (SD 80) g), liraglutide-treated rats lost 17 % (p < 0.001) of their body weight at the end of the experiment. We found no significant change in mean arterial pressure, but liraglutide accelerated the heart rate by 10% (p < 0.001) during the light period, increasing it from 278 (SD 10) bpm to 305 (SD 14) bpm. We recorded a significant (p < 0.001) reduction in the core body temperature (-0.4 (SD 0.2)°C) associated with liraglutide treatment during the dark period. No pharmacological tests or any heart rate variability or systolic pressure variability indices pointed to possible alterations in autonomic regulation of the hemodynamics. However, during the restraint stress test, liraglutide-treated rats showed a significantly (p = 0.013) lower elevation of mean arterial pressure by 30% and longer pre-ejection time by 28% (p = 0.011) than control rats.
In conclusion, chronic treatment with liraglutide did not affect the mean arterial pressure but accelerated heart rate during the light period. Surprisingly, we found signs of the sympatholytic effect of liraglutide, i.e., reducing the core body temperature during the dark period and prolonging pre-ejection time during the restraint stress.