ABSTRACT
Background and Purpose : Cardiovascular side effects from
varenicline, and a case report of a hypertensive crisis event in a
patient with pheochromocytoma being treated with varenicline, have been
reported. The goal of the present study was to determine if such side
effects might derive, in part, from increased exocytosis of secretory
vesicles and subsequent catecholamine release triggered by varenicline
in chromaffin cells of the adrenal gland.
Experimental Approach : We performed electrophysiological plasma
membrane capacitance (Cm) and carbon fiber amperometry
experiments to evaluate the effect of varenicline on exocytosis and
catecholamine release, respectively, at concentrations reached during
varenicline therapy (100 nM). Experiments were conducted in the absence
or presence of nicotine, at plasma concentrations achieved right after
smoking (250 nM) or steady-state concentrations (110 nM), in chromaffin
cells of the adrenal gland obtained from human organ donors or rats.
Key Results : Varenicline increased the exocytosis of secretory
vesicles and the release of catecholamines from human chromaffin cells
in the presence of nicotine. Comparable results were found using rat
chromaffin cells; varenicline alone or in the presence of acute or
steady-state concentrations of nicotine found in human plasma increased
exocytosis. These effects were not due to an increase of
Cm or currents triggered by the nicotinic agonists
alone.
Conclusion and Implications : Therapeutic concentrations of
varenicline in the presence of nicotine increased exocytosis and
catecholamine release from human chromaffin cells. These results should
be taken into account in nicotine addiction therapies when varenicline
is used.