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Bilirubin modulates acetylcholine receptors in rat superior cervical ganglionic neurons in a bidirectional manner.

Zhang C, Wang Z, Dong J, Pan R, Qiu H, Zhang J, Zhang P, Zheng J, Yu W - Sci Rep (2014)

Bottom Line: Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89.These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade.Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China [2] Department of Anesthesiology, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China.

ABSTRACT
Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 μM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 µM) of bilirubin suppressed the currents with an IC50 of 4 ± 0.5 μM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.

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Enhanced inhibition of nAChRs by bilirubin pre-application.(A), representative nAChR current traces evoked by ACh alone (control), coapplied with bilirubin, bilirubin pre-application, and ACh alone (recovery), respectively. (B), graph showing the percentage of current inhibition when 100 μM ACh was coapplied with 4.5 μM bilirubin with or without 4.5 μM bilirubin preapplication. All data points are expressed as mean ± SEMs (n = 6).
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f7: Enhanced inhibition of nAChRs by bilirubin pre-application.(A), representative nAChR current traces evoked by ACh alone (control), coapplied with bilirubin, bilirubin pre-application, and ACh alone (recovery), respectively. (B), graph showing the percentage of current inhibition when 100 μM ACh was coapplied with 4.5 μM bilirubin with or without 4.5 μM bilirubin preapplication. All data points are expressed as mean ± SEMs (n = 6).

Mentions: To further clarify whether direct blockade of nAChR channels by bilirubin depended on different states of nAChRs, we first pre-applied 4.5 μM bilirubin and then co-applied 4.5 μM bilirubin with ACh, finding that pre-application of high concentrations of bilirubin further increased the inhibition of the peak nAChRs currents induced by co-application of bilirubin with ACh (53 ± 5% vs 66 ± 4%, n = 6; P < 0.05), indicating that bilirubin preferred to bind to the closed stated nAChRs (Fig. 7).


Bilirubin modulates acetylcholine receptors in rat superior cervical ganglionic neurons in a bidirectional manner.

Zhang C, Wang Z, Dong J, Pan R, Qiu H, Zhang J, Zhang P, Zheng J, Yu W - Sci Rep (2014)

Enhanced inhibition of nAChRs by bilirubin pre-application.(A), representative nAChR current traces evoked by ACh alone (control), coapplied with bilirubin, bilirubin pre-application, and ACh alone (recovery), respectively. (B), graph showing the percentage of current inhibition when 100 μM ACh was coapplied with 4.5 μM bilirubin with or without 4.5 μM bilirubin preapplication. All data points are expressed as mean ± SEMs (n = 6).
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4265787&req=5

f7: Enhanced inhibition of nAChRs by bilirubin pre-application.(A), representative nAChR current traces evoked by ACh alone (control), coapplied with bilirubin, bilirubin pre-application, and ACh alone (recovery), respectively. (B), graph showing the percentage of current inhibition when 100 μM ACh was coapplied with 4.5 μM bilirubin with or without 4.5 μM bilirubin preapplication. All data points are expressed as mean ± SEMs (n = 6).
Mentions: To further clarify whether direct blockade of nAChR channels by bilirubin depended on different states of nAChRs, we first pre-applied 4.5 μM bilirubin and then co-applied 4.5 μM bilirubin with ACh, finding that pre-application of high concentrations of bilirubin further increased the inhibition of the peak nAChRs currents induced by co-application of bilirubin with ACh (53 ± 5% vs 66 ± 4%, n = 6; P < 0.05), indicating that bilirubin preferred to bind to the closed stated nAChRs (Fig. 7).

Bottom Line: Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89.These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade.Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.

View Article: PubMed Central - PubMed

Affiliation: 1] Department of Anesthesiology, Eastern Hepatobiliary Surgery Hospital, the Second Military Medical University, Shanghai, China [2] Department of Anesthesiology, Xinhua Hospital, Shanghai Jiaotong University, Shanghai, China.

ABSTRACT
Autonomic dysfunction as a partial contributing factor to cardiovascular instability in jaundiced patients is often associated with increased serum bilirubin levels. Whether increased serum bilirubin levels could directly inhibit sympathetic ganglion transmission by blocking neuronal nicotinic acetylcholine receptors (nAChRs) remains to be elucidated. Conventional patch-clamp recordings were used to study the effect of bilirubin on nAChRs currents from enzymatically dissociated rat superior cervical ganglia (SCG) neurons. The results showed that low concnetrations (0.5 and 2 μM) of bilirubin enhanced the peak ACh-evoked currents, while high concentrations (3 to 5.5 µM) of bilirubin suppressed the currents with an IC50 of 4 ± 0.5 μM. In addition, bilirubin decreased the extent of desensitization of nAChRs in a concentration-dependent manner. This inhibitory effect of bilirubin on nAChRs channel currents was non-competitive and voltage independent. Bilirubin partly improved the inhibitory effect of forskolin on ACh-induced currents without affecting the action of H-89. These data suggest that the dual effects of enhancement and suppression of bilirubin on nAChR function may be ascribed to the action mechanism of positive allosteric modulation and direct blockade. Thus, suppression of sympathetic ganglionic transmission through postganglionic nAChRs inhibition may partially contribute to the adverse cardiovascular effects in jaundiced patients.

Show MeSH
Related in: MedlinePlus