Mechanism of the hypertensive response to central injection of nicotine in conscious rats

Abstract

The purpose of this study was to examine the effects of nicotine administered directly into the CNS on mean arterial pressure (MAP) and heart rate to avoid the direct peripheral action of the drug. Also, because nicotine has been reported to enhance the release of endogenous brain acetylcholine, we sought to determine the role of this mechanism in mediating the cardiovascular response. Normotensive Wistar rats were previously implanted with indwelling intracerebroventricular (ICV) cannula guides and an arterial line (iliac artery) for central injection of drugs and measurement of MAP and heart rate, respectively. Rats received a series of increasing doses of nicotine (or saline vehicle) from 2–100 μg (in a 10 μl volume) with each dose separated by at least 1 day. MAP increased immediately following all doses of nicotine; however, the maximal response was obtained following the 50 μg dose (higher doses actually produced lower responses). In general, the hypertensive response began immediately after injection, peaked within 2–3 min and returned to baseline within about 20 min. Heart rate changes were often not dramatic and highly variable. In order to examine the dependence of the pressor response to nicotine on brain acetylcholine, rats were pretreated with 20 μg (ICV) of hemicholinium-3 (HC-3) 1 h prior to nicotine to deplete endogenous acetylcholine. HC-3 pretreatment resulted in a significant reduction in the magnitude and duration of the pressor response to nicotine. Likewise, pretreatment with atropine inhibited the pressor response to subsequent injection of nicotine. Nicotine enhanced the release of [ 3H]acetylcholine from brain slices in vitro at concentrations likely achieved in the in vivo studies. These data support the concept that ICV injection of nicotine induces a pressor response through the release of endogenous acetylcholine possibly acting on central muscarinic receptors.