Rollema_2014_Nicotine.Tob.Res_16_733

INTRODUCTION: It has been suggested that varenicline-induced activation of nicotinic acetylcholine receptors (nAChRs) could play a role in the cardiovascular (CV) safety of varenicline. However, since preclinical studies showed that therapeutic varenicline concentrations have no effect in models of CV function, this study examined in vitro profiles of varenicline and nicotine at nAChR subtypes possibly involved in CV control.
METHODS: Concentration-dependent functional effects of varenicline and nicotine at human alpha3beta4, alpha3alpha5beta4, alpha7, and alpha4beta2 nAChRs expressed in oocytes were determined by electrophysiology. The proportion of nAChRs predicted to be activated and inhibited by concentrations of varenicline (1mg b.i.d.) and of nicotine in smokers was derived from activation-inhibition curves for each nAChR subtype.
RESULTS: Human varenicline and nicotine concentrations can desensitize and inhibit nAChRs but cause only low-level activation of alpha3beta4, alpha4beta2 (<2%), alpha7 (<0.05%), and alpha3alpha5beta4 (<0.01%) nAChRs, which is consistent with literature data. Nicotine concentrations in smokers are predicted to inhibit larger fractions of alpha3beta4 (48%) and alpha3alpha5beta4 (10%) nAChRs than therapeutic varenicline concentrations (11% and 0.6%, respectively) and to inhibit comparable fractions of alpha4beta2 nAChRs (42%-56%) and alpha7 nAChRs (16%) as varenicline.
CONCLUSIONS: Nicotine and varenicline concentrations in patients and smokers are predicted to cause minimal activation of ganglionic alpha3beta4* nAChRs, while their functional profiles at alpha3beta4, alpha3alpha5beta4, alpha7, and alpha4beta2 nAChRs cannot explain that substituting nicotine from tobacco with varenicline would cause CV adverse events in smokers who try to quit. Other pharmacological properties that could mediate varenicline-induced CV effects have not been identified.