Differential rate responses to nicotine in rat heart: evidence for two classes of nicotinic receptors.
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 microM) caused a brief decrease (-7 +/- 2%) followed by a much larger increase (17 +/- 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 alpha7-specific antagonist, alpha-bungarotoxin (100 nM). In contrast, the nicotine-induced increase in heart rate persisted in the presence of alpha-bungarotoxin. These results suggest that the nicotinic acetylcholine receptors (nAChRs) that mediate the initial decrease in heart rate probably contain alpha7 subunits, whereas those that mediate the increase in heart rate probably do not contain alpha7 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 beta4 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 beta4 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 alpha7 subunits participate in the initial nicotine-induced heart rate decrease, whereas beta4 subunits help to mediate the subsequent nicotine-induced rise in heart rate.
Ji
Susan
S
Department of Pharmacology, Georgetown University Medical Center, 3900 Reservoir Road NE, Washington, DC 20007, USA.
Tosaka
Toshimasa
T
Whitfield
Bernard H
BH
Katchman
Alexander N
AN
Kandil
Abdurrahman
A
Knollmann
Bjoern C
BC
Ebert
Steven N
SN
D000818:Animals; D005260:Female; D005731:Ganglionic Stimulants / Q000494:pharmacology*; D006339:Heart Rate / Q000187:drug effects* / Q000502:physiology*; D066298:In Vitro Techniques; D009206:Myocardium / Q000378:metabolism*; D009538:Nicotine / Q000494:pharmacology*; D010477:Perfusion; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000145:classification* / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor
C579165:Chrna7 protein, rat; D005731:Ganglionic Stimulants; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; D009538:Nicotine