The subunit composition of nicotinic acetylcholine receptors (nAChR) that mediate synaptic transmission in autonomic pathways remain incompletely elucidated. Conotoxin (ctx) MII blocks the majority (~70%) of cholinergic ganglionic transmission in vivo but acts on both α3/β2 and α6/β2 nAChR (only 5.6-fold higher affinity for α3/β2 vs. α6/β2). We used a more specific nAChR blocker to investigate the hypothesis that α6/β2 nAChR play a functional role in ganglionic transmission. Methods 4 dogs were anesthetized and underwent cervical vagal nerve stimulations (VSTIM). The artery supplying the sinus node was perfused with Tyrodes solution in vivo. Sinus cycle length (SCL) was measured after 3, 5, and 10 Hz VSTIM before and after perfusion with ctx MII-H9A;L15A (2020-fold higher affinity for α6/β2 vs. α3/β2). Results At baseline VSTIM prolonged SCL by 345±38, 476±43, 901±125 msec. Perfusion with ctx MII-H9A;L15A resulted in similar responses to VSTIM (300±29, 449±37, 866±125 msec, p>0.05, ANOVA) suggesting that blockade of α6/β2 did not alter responsiveness. Hexamethonium abolished responses to VSTIM confirming that the ganglion was perfused entirely by the cannulated sinus node artery. Conclusion The previously reported blockade in this ganglion by ctx MII is attributable specifically to α3/β2 nAChR and not α6 containing receptors.

We have shown previously that exposure to intermittent nicotinic acetylcholine receptor (nAChR) agonist (DMPP) in dogs during pacing induced heart failure (HF) development results in prevention of parasympathetic down-regulation. We hypothesized that treatment with DMPP during development of HF can result in improved physiologic parameters. Methods Dogs underwent rapid pacing at 250 bpm and were treated with 300mcg of DMPP IV weekly for 6 weeks. During HF development, we recorded RR responses to DMPP injection, LV volumes (echo), and standard deviation (SD) of RR interval in conscious dogs (n=4 treated and 4 untreated). Results Results shown are at 42 days of pacing. Maximal RR following DMPP was 2133 msec±155 vs. 626 msec±15 with vehicle. EDV was less dilated in the treated group vs. untreated (71±3.5 ml vs. 81±1.9 ml). SD of RR was higher in the treated group at 42 days (131±2.5 vs. 51±12 msec) reflecting preserved parasympathetic tone. Conclusions Treatment with a nicotinic receptor agonist during HF development preserved ganglionic sensitivity to agonist, increased resting parasympathetic tone and attenuated adverse cardiac remodeling. These data suggest that repeated exposure to a nicotinic agonist during the development of HF can prevent the loss of parasympathetic control in HF and helps to preserve myocardial function, possibly mediated by preventing loss of nAChR ganglionic function.