Patterns of nicotinic receptor antagonism II: Cardiovascular effects in rats

Abstract

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, α4β2-preferring antagonist dihydro-β-erythroidine (DHβE) 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 α7-preferring antagonist, MLA, and the α4β2-preferring antagonist, DHβE, 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 α4, α7, or β2. 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.

Varenicline and Adverse Cardiovascular Events: A Systematic Review and Meta‐Analysis of Randomized Controlled Trials

“…Varenicline is a partial agonist of the α4‐β2 nicotinic acetylcholine receptor (nAchR) and a full agonist of the α3‐β4 and α7 nAchRs. These receptors have been shown to potentially modulate cardiovascular function 11, 54, 55, 56. Varenicline activates α4‐β2 and α7 nAchRs at rates similar to those of nicotine and is a greater agonist than nicotine at the α3‐β4 nAchR 57.…”

“…These receptors have been shown to potentially modulate cardiovascular function. 11,[54][55][56] Varenicline activates a4-b2 and a7 nAchRs at rates similar to those of nicotine and is a greater agonist than nicotine at the a3-b4 nAchR. 57 However, it is unknown whether partial activation of these receptors can lead to major changes in cardiovascular health, as the role of these receptors in modulating the cardiovascular system is not well studied.…”

Nicotine plus a high-fat diet triggers cardiomyocyte apoptosis

“…Furthermore, our data suggest a direct role of nicotine on cardiac SIRT1-FGF21-AMPK signaling in mice fed HFD. Indeed, nicotinic receptors are present in the heart (Ni et al 2010; Jutkiewicz et al 2013). The clinical implication of this study is that smoking plus HFD lead to heart failure and other forms of cardiomyopathy and that anti-apoptotic agents might help to prevent this.…”

Evaluation of the cardiovascular effects of varenicline in rats

“…Studies have reported that varenicline has high efficacy in its agonist activity at α7 receptor subtypes, and may mediate nicotinic agonist-induced increases in sympathetic activity. 22 , 40 Jutkiewicz et al reported that although varenicline significantly decreased HR, it could engender all cardiovascular responses. 40 Our results showed no significant change in HR for both the acute and chronic groups, whereas there was a significant decrease in MBP values in the V2 treatment group compared with the C2 group.…”

“… 22 , 40 Jutkiewicz et al reported that although varenicline significantly decreased HR, it could engender all cardiovascular responses. 40 Our results showed no significant change in HR for both the acute and chronic groups, whereas there was a significant decrease in MBP values in the V2 treatment group compared with the C2 group. Although the change in BP was statistically significant, we believe that this result should be disregarded because of the relatively high measurements in the C2 group.…”