Medetomidine can selectively activate cardiac vagal nerve without vagal activation in gastrointestinal tract

Abstract

Purpose: Vagal activation therapy has recently become a new therapeutic option for heart failure (HF). However, electrical cervical vagal nerve stimulation (VNS) may activate the whole vagal system and cause unfavorable side-effects in non-target organs, e.g. gastrointestinal tract. We have recently reported that an α2-adrenergic agonist, medetomidine, can activate cardiac vagal nerve. Using microdialysis technique, we investigated whether medetomidine were able to selectively activate cardiac vagal nerve. Methods: In anesthetized rabbits, microdialysis probes were implanted into the right atrial wall and the anterior wall of the stomach, and were perfused by Ringer's solution containing eserine. Acetylcholine (ACh) concentrations in dialysate samples were measured by high-performance liquid chromatography. (1) Under maintenance of mean arterial pressure (MAP) using intravenous infusion of phenylephrine, we examined the effects of electrical VNS (10 Hz, 1ms, 10V) at efferent sides on both cardiac and gastric ACh releases, and investigated the effects of medetomidine on VNS-induced ACh releases. (2) We examined the effects of 100 μg/kg of intravenous medetomidine on both cardiac and gastric vagal ACh releases. Results: (1) Electrical VNS significantly decreased heart rate from 265±10 bpm at baseline to 138±12 bpm (P<0.01), and increased ACh releases to both the heart (6.7±1.2 to 14.8±1.8 nM, P<0.01) and stomach (3.8±0.8 to 181.3±65.6 nM, P<0.01). 100 μg/kg of intravenous medetomidine did not alter these increases in VNS-induced ACh releases. (2) 100 μg/kg of intravenous medetomidine significantly decreased heart rate from 273±5 bpm at baseline to 185±6 bpm (P<0.01), and MAP from 87±3 mmHg to 52±2 mmHg (P<0.01). Then, medetomidine significantly increased cardiac vagal ACh release (4.7±1.1 to 7.8±0.9 nM, P<0.05), but suppressed gastric vagal ACh release (8.0±2.6 to 3.5±1.5 nM, P<0.01). The maintenance of MAP using phenylephrine brought a further decrease in heart rate (132±7 bpm, P<0.01) and a further increase in cardiac vagal ACh release (22.3±3.6 nM, P<0.01), but suppressed gastric vagal ACh release (3.5±1.1 nM) as well as medetomidine alone. Conclusions: Electrical VNS increased vagal ACh releases to both the heart and stomach. This may cause unfavorable side-effects in non-target organs. On the other hand, medetomidine activates cardiac vagal nerve without gastric vagal activation. Selective vagal activation of medetomidine may be beneficial for vagal activation therapy in the HF patients.