Effects of vatinoxan on cardiorespiratory function and gastrointestinal motility during constant‐rate medetomidine infusion in standing horses

Abstract

Summary Background Medetomidine suppresses cardiovascular function and reduces gastrointestinal motility in horses mainly through peripheral α2‐adrenoceptors. Vatinoxan, a peripheral α2‐antagonist, has been shown experimentally to alleviate the adverse effects of some α2‐agonists in horses. However, vatinoxan has not been investigated during constant‐rate infusion (CRI) of medetomidine in standing horses. Objectives To evaluate effects of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine. Study design Experimental, randomised, blinded, cross‐over study. Methods Six healthy horses were given medetomidine hydrochloride, 7 μg/kg i.v., without (MED) and with (MED+V) vatinoxan hydrochloride, 140 μg/kg i.v., followed by CRI of medetomidine at 3.5 μg/kg/h for 60 min. Cardiorespiratory variables were recorded and borborygmi and sedation levels were scored for 120 min. Plasma drug concentrations were measured. The data were analysed using repeated measures ANCOVA and paired t‐tests as appropriate. Results Initially heart rate (HR) was significantly lower and mean arterial blood pressure (MAP) significantly higher with MED compared with MED+V. For example at 10 min HR (mean ± s.d.) was 26 ± 2 and 31 ± 5 beats/minute (P = 0.04) and MAP 129 ± 15 and 103 ± 13 mmHg (P<0.001) respectively. At 10 min, cardiac index was lower (P = 0.02) and systemic vascular resistance higher (P = 0.001) with MED than with MED+V. Borborygmi were reduced after MED; this effect was attenuated by vatinoxan (P<0.001). All horses were sedated with medetomidine, but the mean sedation scores were reduced with MED+V until 20 min (6.8 ± 0.8 and 4.5 ± 1.5 with MED and MED+V, respectively, at 10 min, P = 0.001). Plasma concentration of dexmedetomidine was significantly lower in the presence of vatinoxan (P = 0.01). Main limitations Experimental study with healthy, unstimulated animals. Conclusions Vatinoxan administered i.v. with a loading dose of medetomidine improved cardiovascular function and gastrointestinal motility during medetomidine CRI in healthy horses. Sedation was slightly yet significantly reduced during the first 20 min.. The Summary is available in Portuguese – see Supporting Information

Cardiorespiratory, Sedative and Antinociceptive Effects of a Medetomidine Constant Rate Infusion with Morphine, Ketamine or Both

“…Administration of medetomidine triggered sinoatrial and second-degree atrioventricular blocks. The administration of α-2 adrenergic receptor agonists cause an initial increase in systemic vascular resistance, producing hypertension and a baroreceptor-mediated reflex bradycardia, followed by a centrally mediated hypotension [34][35][36]. In our study, no difference in MAP and CI was observed in any of the procedures.…”

Pharmacodynamics and plasma concentrations of dexmedetomidine with or without vatinoxan as a constant‐rate infusion in horses anaesthetized with isoflurane—A pilot study

“…As dobutamine CRI was not discontinued before measurements of CI, it is nearly impossible to distinguish between the effects of vatinoxan and dobutamine, respectively (Pakkanen et al, 2015; Tapio, Raekallio, Mykkänen, Al‐Ramahi, et al, 2019). Nevertheless, in sedated horses co‐administration of vatinoxan to medetomidine significantly increased CI and decreased SVR ten minutes after application (Tapio, Raekallio, Mykkänen, Männikkö, et al, 2019). The MAP in our study was similarly sustained in both groups due to the fact that MAP in group VAT was maintained in physiological limits by starting a dobutamine CRI.…”

“…Tapio, Raekallio, Mykkänen, Al‐Ramahi, et al, (2019) used vatinoxan (140 µg kg −1 IV) as a bolus and a similar alpha‐2 adrenoceptor agonist drug dose compared to our study, assuming that 7 µg kg −1 IV medetomidine equals 3.5 µg kg −1 IV dexmedetomidine, observing a marked hypotension after anaesthesia induction in vatinoxan treated horses. The same dose combination was investigated in standing horses, where medetomidine induced cardiovascular changes (bradycardia, increased systemic vascular resistance) could be alleviated by vatinoxan, indicating that inhalational anaesthetics will exacerbate vasodilation leading to hypotension (Tapio, Raekallio, Mykkänen, Männikkö, et al, 2019). However, the comparability to this study is limited as vatinoxan was not given as CRI.…”

“…Besides the desirable central sedative and analgesic effects, there are characteristic peripheral cardiovascular effects including reflex bradycardia, reduced cardiac output, increased vascular resistance as well as cardiac conduction disturbances in this drug class (Yamashita et al, 2000). In addition, gastrointestinal motility is negatively affected by alpha‐2 adrenoceptor agonistic action (Tapio, Raekallio, Mykkänen, Männikkö, et al, 2019; Vainionpää et al, 2013; Vries et al, 2016).…”

Various Systemic Effects of MK-467, A Peripherally Acting α2-adrenoceptor Antagonist in Different Animal Species: An Overview

“…Likewise in horses, MK-467 averts the cardiovascular alterations commonly observed with romifidine and detomidine, when administered in combination, without affecting the sedation quality (de Vries et al, 2016;Vainionpaa et al, 2013;Tapio et al, 2018;Pakkanen et al, 2015). A study conducted by Tapio et al (2019) evaluated the effect of vatinoxan on cardiovascular function, gastrointestinal motility and on sedation level during CRI of medetomidine in standing horses. During this study, six healthy horses were given medetomidine hydrochloride, at the rate of 7 µg/kg IV without vatinoxan hydrochloride and at the rate of 140 µg/kg IV with vatinoxan hydrochloride, followed by CRI of medetomidine at 3.5 µg/kg/h for 60 min and they recorded the cardiorespiratory variables and borborygmi and sedation levels were also scored for 120 min.…”