HEMODYNAMIC EFFECTS OF SOME SEDATIVE DRUGS IN TRASLATIONAL MURINE MODELS

Dexmedetomidine (DEX) and Acepromazine (ACP) are powerful sedatives with remarkable hemodynamic effects, Several phenothiazines and α2-agonist molecules have long been used in translational research separately or in combination. However, their individual or synergistic peripheral hemodynamic effects have not been fully described in different laboratory animal species in spite of their relevance in cardiovascular studies. Some authors reported an attenuation of α2-adrenergic agonist pressor response with the acepromazine-xylazine combination in dogs. Laser Doppler Imaging (LDPI) and High frequency ultrasound echocardiography (HRE) provides best noninvasive measurement of cardiovascular function in mice. The aim of the study was to investigate noninvasively the cardiovascular effects of DEX, of ACP and of their combination in isoflurane (ISO) anesthetized mice. Methods Forty five age-matched and sex-paired CD1 mice, 8 to 10 weeks old, were randomly assigned to one of three experimental groups and underwent 1.5% ISO anesthesia, followed by intraperitoneal injection of either 5 mg/kg ACP, or 1 mg/kg DEX, or by their combination. Body temperature was adjusted to 36 °C. Heart (HR) and respiratory (RR) rates were monitored. Hind paws blood flow (Perfusion Units, volt) was recorded by LDPI apparatus (Periscan®, laser beam power = 1 mV; wavelength = 670 nm; pixel size = 0.25x0.25 mm2; scanner head distance =15 cm; scanning area = 3x2 cm2; scanning time = 2 minutes). An high-resolution ultrasound imaging system (Vevo 770, VisualSonics, transducer frequency 40 MHz, focal length 6 mm, frame rate 30 Hz, spatial resolution 30 μm) synchronized to the electrocardiographic signal was used. A two-dimensional (B-mode) and motion-mode (M-mode) imaging of the left ventricular short axis was taken just at the level of the papillary muscles. Peripheral perfusion (PP), ejection fraction (EF) and fractional shortening (FS) were recorded 10’ and 20’ before and at different intervals after treatments. A further measurement was recorded after reversing dexmedetomidine by the α2-antagonist atipamezole (ATP). We compared PP, HR, RR, EF and FS values at different times by paired non parametric Wilcoxon test and inter-groups differences by One Way Friedman ANOVA. When appropriate, a post hoc analysis by Mann Whitney test was made. Significance was set at P <0.05. Results RR decreased in all groups without significant differences to baseline (P>0.05). ACP increased PP (P=0.005) and reduced FS (P<0.05) over time. DEX sharply reduced PP, HR, EF and FS (P<0.001) after 5 minutes, followed by an increase after 15 minutes (P=0.008), showing a biphasic effect. ACP+DEX decreased (P<0.001) HR, PP, EF and FS reaching steady values after 5 minutes (P>0.05); ATP brought back values such close to baseline (P>0.05). Conclusions In mice ACP+DEX produced more temperate hemodynamic values compared to those following single agents, lessening DEX biphasic hemodynamic pattern. Traslational imaging allows noninvasive and accurate measurements of hemodynamic effects of different sedatives in mice models.