Differential Rate Responses to Nicotine in Rat Heart: Evidence for Two Classes of Nicotinic Receptors

Abstract

Nicotinic acetylcholine receptors are pentameric, typically being composed of two or more different subunits. To investigate which receptor subtypes are active in the heart, we initiated a series of experiments using an isolated perfused rat heart (Langendorff) preparation. Nicotine administration (100 M) caused a brief decrease (Ϫ7 Ϯ 2%) followed by a much larger increase (17 Ϯ 5%) in heart rate that slowly returned to baseline within 10 to 15 min. The nicotine-induced decrease in heart rate could be abolished by an ␣7-specific antagonist, ␣-bungarotoxin (100 nM). In contrast, the nicotine-induced increase in heart rate persisted in the presence of ␣-bungarotoxin. These results suggest that the nicotinic acetylcholine receptors (nAChRs) that mediate the initial decrease in heart rate probably contain ␣7 subunits, whereas those that mediate the increase in heart rate probably do not contain ␣7 subunits. To investigate which subunits may contribute to the nicotine-induced increase in heart rate, we repeated our experiments with cytisine, an agonist at nAChRs that contain ␤4 subunits. The cytisine results were similar to those obtained with nicotine, thereby suggesting that the nAChRs on sympathetic nerve terminals in the heart probably contain ␤4 subunits. Thus, the results of this study show that pharmacologically distinct nAChRs are responsible for the differential effects of nicotine on heart rate. More specifically, our results suggest that ␣7 subunits participate in the initial nicotine-induced heart rate decrease, whereas ␤4 subunits help to mediate the subsequent nicotine-induced rise in heart rate.

The α7 Nicotinic Acetylcholine Receptor Subunit Exists in Two Isoforms that Contribute to Functional Ligand-Gated Ion Channels

“…Thus, this dysfunction may be in part caused by the loss of the ␣7-2-nAChR subtype in the neurons. Consistent with an important role for ␣7-AChRs in regulation of the cardiovascular system is the observation that the effects of nicotine on the heart are in part caused by activation of ␣7 receptors in autonomic neurons (Ji et al, 2002).…”

Nicotinic mechanisms in the autonomic control of organ systems

“…In addition to the putative homomeric ␣7-mediated currents that rapidly desensitize and are blocked almost irreversibly by ␣-BGT, SCG neurons express ␣7 nAChR currents that desensitize slowly and are blocked by ␣-BGT in a rapidly reversible manner . Both ␣7-mediated nAChR currents were also recorded from intracardiac ganglia (Cuevas and Berg, 1998), and data obtained in the Langendorff preparation of the heart showed that ␣7* nAChRs contribute to the negative chronotropic effects (i.e., producing slower heart rates) of nicotine (Ji et al, 2002). In the dog, ␣7* nAChRs also have a small contribution to ganglionic transmission in intracardiac ganglia (Bibevski et al, 2000).…”

“…In the rat, nAChRs containing ␤4, most likely combined with ␣3, seem to specifically contribute to the positive chronotropic effects (i.e., producing faster heart rates) of nicotine (Ji et al, 2002). In the SCG of the mouse, ␤4* nAChRs underlie a significant portion of the wildtype nAChR currents (Xu et al, 1999b), suggesting that the majority of SCG neurons express ␣3␤4* nAChRs.…”

Nicotine Induces a Long QT Phenotype in Kcnq1-Deficient Mouse Hearts

“…Nicotine is a classical autonomic neuroeffector (De Biasi, 2002). In isolated perfused heart preparations, administration of nicotine produces a brief modest slowing of heart rate that is immediately followed by a much larger transient increase in heart rate (Kottegoda, 1953;Ji et al, 2002). We and others have shown that the nicotine-induced decrease in heart rate is likely a parasympathetic response because it could be selectively blocked by the muscarinic antagonist atropine (Kottegoda, 1953;Ji et al, 2002).…”