INTRODUCTION
Varenicline is a nicotinic acetylcholine receptor (nAChR) agonist
successfully used in the treatment of nicotine addiction. Its mechanism
of action as a smoking cessation aid is mediated by partial agonism of
the α4β2 subtype. Through this mechanism, varenicline stimulates α4β2
nAChR-mediated dopamine release in the ventral tegmental area
sufficiently to reduce craving when abstinent from smoking, but inhibits
the action of nicotine on α4β2 nAChRs when smoking. Furthermore, this
drug exhibits additional effects on other nicotine addiction related
nAChR subtypes including α6β2, α3β4, and α7 (Mihalak, Carroll et
al. , 2006; Capelli, Castelletti et al. , 2011; Tammimäki, Herderet al. , 2012). However, although varenicline is a very
efficacious drug for smoking cessation, some adverse cardiovascular
side-effects have been reported in humans (Chelladurai & Sing, 2014;
Gershon, Campitelli et al. , 2018; Munarini, Marabelli et
al. , 2015; Rigotti, Pipe et al ., 2010; Singh, Loke et al., 2011)
and rats (Selçuk, Sungu et al. , 2015). Also, a case report of
varenicline-triggered pheochromocytoma crisis in a smoker has been
reported (Hukkanen, Hukkola et al. , 2010). The US Food and Drug
Administration reviewed a randomized clinical trial of 700 smokers with
cardiovascular disease who were treated with varenicline or placebo. In
this trial, adverse cardiovascular events were infrequent overall, but
certain serious events, including heart attacks, were reported more
frequently in patients treated with varenicline than in patients treated
with placebo (FDA, 2011).
Because the action of varenicline on the peripheral α3-containing
subtypes expressed in human chromaffin cells (Hone, McIntosh et
al. , 2015; Hone, McIntosh et al. , 2017) might contribute to the
cardiovascular side effects of this drug by triggering the release of
catecholamines, we previously investigated whether varenicline might
increase the firing of actions potentials in these cells. We reported
that varenicline in the presence of nicotine alters the cell’s ability
to fire action potentials in response to acetylcholine (ACh) at
therapeutically relevant concentrations and, in addition, is capable of
evoking actions potentials in the absence of ACh stimulation (Hone,
McIntosh et al. , 2017). These results prompted us to investigate
whether varenicline together with nicotine could enhance exocytosis of
secretory vesicles and catecholamine release in human chromaffin cells
of the adrenal gland. The situation in which both drugs are administered
together occurs during therapeutic treatment with varenicline in smokers
who are in the process of quitting smoking or during the use of
varenicline in conjunction with a nicotine replacement therapy (Chang,
Chiang et al. , 2015). This study was also conducted using rat
chromaffin cells due to the limitations of obtaining and working with
human cells. The main nAChR subtypes expressed in rat chromaffin cells
are, as in humans, α3β4* (Di Angelantonio, Matteoni et al. , 2003;
Hone, Rueda-Ruzafa et al. , 2020) and α7 (Hone, Rueda-Ruzafaet al. , 2020) but an α3β2β4* subtype (not investigated in human
chromaffin cells) has also been reported (Hone, Rueda-Ruzafa et
al. , 2020).