Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats

Jutkiewicz, E. M., Rice, K. C., Carroll, F., & Woods, J. H. (2013). Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats. Drug and Alcohol Dependence, 131(3), 284-297. DOI: 10.1016/j.drugalcdep.2012.12.021

Background
Tobacco cessation pharmacotherapies currently are limited to nicotine itself, the partial nicotine agonists varenicline and cytisine, and the antidepressant bupropion. Compared with agonists, nicotinic antagonists such as the noncompetitive, nonselective compound mecamylamine, and the competitive, ?4?2-preferring antagonist dihydro-?-erythroidine (DH?E) may be a novel approach to the treatment of tobacco smoking as both are effective antagonists of nicotine's central effects. Considering nicotinic acetylcholine receptors mediate critical peripheral effects of acetylcholine, such as cardiovascular effects, it is important to study how nicotinic antagonists would alter the cardiovascular system and the cardiovascular changes induced by nicotine.

Methods
The effects of several nicotinic agonists and antagonists on blood pressure and heart rate were measured in conscious, unrestrained rats following parenteral administration using a telemetry system.

Results
Nicotine and other nicotinic receptor agonists (epibatidine, varenicline, and cytisine) produced similar increases in blood pressure, whereas their effects on heart rate were biphasic. The cardiovascular changes were attenuated by the nonselective nicotine antagonist, mecamylamine, but the peripherally restricted antagonist hexamethonium blocked only the agonist-induced changes in blood pressure. The ?7-preferring antagonist, MLA, and the ?4?2-preferring antagonist, DH?E, were much less effective in blocking the agonist-induced cardiovascular changes, indicating that nicotine's cardiovascular effects, are due to activation at autonomic ganglia involving nicotinic receptor subtypes other than ?4, ?7, or ?2.

Conclusions
The data indicate that the cardiovascular effects of nicotine and nicotine-like agents are mediated through receptor mechanisms that are distinct from those that mediate the central effects of nicotine.