Desipramine increases cardiac parasympathetic activity via α₂-adrenergic mechanism in rats

Desipramine (DMI) is a blocker of neuronal norepinephrine (NE) uptake transporter. Although intravenous DMI has been shown to cause centrally-mediated sympathoinhibition and peripheral NE accumulation, its parasympathetic effect remains to be elucidated. We hypothesized that intravenous DMI activates the cardiac vagal nerve via an α₂-adrenergic mechanism. Using a cardiac microdialysis technique, changes in myocardial interstitial acetylcholine (ACh) levels in the left ventricular free wall in response to intravenous DMI (1 mg·kg^− 1) were examined in anesthetized rats. In rats with intact vagi (n = 7), intravenous DMI increased ACh from 1.67 ± 0.43 to 2.48 ± 0.66 nM (P < 0.01). In rats with vagotomy (n = 5), DMI did not significantly change ACh (from 0.92 ± 0.16 to 0.85 ± 0.23 nM). In rats with intact vagi pretreated with intravenous yohimbine (2 mg·kg^− 1), DMI did not significantly change ACh (from 1.25 ± 0.23 to 1.13 ± 0.15 nM). In conclusion, while DMI is generally considered to be an agent that predominantly affects sympathetic neurotransmission, it can activate the cardiac vagal nerve via α₂-adrenergic stimulation in experimental settings in vivo.