Microcirculatory impact of vatinoxan and fentanyl in male Wistar rats sedated with medetomidine and midazolam

Alpha2-adrenoceptor agonists, such as medetomidine, are pivotal drugs in laboratory rodent sedation and anesthesia. However, they induce marked systemic cardiovascular adverse effects, which can be mitigated with vatinoxan, a peripherally acting alpha2-adrenoceptor antagonist. We investigated the impact of vatinoxan (5 mg/kg) and fentanyl (0.010 mg/kg), an opioid-receptor agonist, on cutaneous microcirculation in male Wistar rats sedated with medetomidine (0.25 mg/kg) and midazolam (2.0 mg/kg). Mean arterial blood pressure (MAP) and pulse rate (PR) were measured. Cutaneous microcirculation was assessed with simultaneous quantification of laser-Doppler flow (LDF) and tissue hemoglobin saturation (T-HbO2). Data were analyzed with Dunn’s tests, Student’s t-tests and Spearman’s correlation tests with Bonferroni-adjusted alpha-levels when appropriate. Overall median [range] LDF (139 [95–561] vs. 120 [72–201] perfusion units) and T-HbO2 (57 [39–75] vs. 41 [18–75] %) from pooled data including all time points were significantly higher (p < 0.001) for the treatments with vatinoxan. Similarily, pooled MAP was lower with vatinoxan (92 ± 14 mmHg [mean ± SD]) than without it (139 ± 18 mmHg) (p < 0.001). Furthermore, MAP was moderately negatively correlated with LDF (Spearman’s rho = − 0.439, p < 0.001). Pooled pulse rates were also significantly higher with the addition of vatinoxan (323 ± 33 bpm) compared with treatments without it (281 ± 29 bpm) (p < 0.001). Fentanyl did not significantly alter any of the outcomes. The addition of vatinoxan alleviated the hypertension and improved pulse rate, cutaneous microcirculation and tissue oxygenation in male Wistar rats sedated with these medetomidine-based protocols. By reducing the peripheral adverse effects attributed to medetomidine, vatinoxan may contribute to refinement of laboratory rodent sedation.