title: Functional interactions of varenicline and nicotine with nAChR subtypes implicated in cardiovascular control.
abstract: BACKGROUND
  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 α3β4, α3α5β4, α7, and α4β2 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 α3β4, α4β2 (<2%), α7 (<0.05%), and α3α5β4 (<0.01%) nAChRs, which is consistent with literature data. Nicotine concentrations in smokers are predicted to inhibit larger fractions of α3β4 (48%) and α3α5β4 (10%) nAChRs than therapeutic varenicline concentrations (11% and 0.6%, respectively) and to inhibit comparable fractions of α4β2 nAChRs (42%-56%) and α7 nAChRs (16%) as varenicline.
  
  
  CONCLUSIONS
  Nicotine and varenicline concentrations in patients and smokers are predicted to cause minimal activation of ganglionic α3β4* nAChRs, while their functional profiles at α3β4, α3α5β4, α7, and α4β2 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.
authors.affiliation: Rollema Biomedical Consulting, Mystic, CT;
authors.forename: Hans
authors.initials: H
authors.lastname: Rollema
authors.forename: Cristina
authors.initials: C
authors.lastname: Russ
authors.forename: Theodore C
authors.initials: TC
authors.lastname: Lee
authors.forename: Raymond S
authors.initials: RS
authors.lastname: Hurst
authors.forename: Daniel
authors.initials: D
authors.lastname: Bertrand
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology*; D006801:Humans; D009538:Nicotine / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology*; D009865:Oocytes; D011485:Protein Binding; D011810:Quinoxalines / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*; D014029:Tobacco Use Disorder / Q000188:drug therapy; D000068580:Varenicline; D014982:Xenopus laevis
chemical_list: D001552:Benzazepines; D018722:Nicotinic Agonists; D011810:Quinoxalines; D011978:Receptors, Nicotinic; D009538:Nicotine; D000068580:Varenicline