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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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The dose-response curve for bilirubin.The inhibitory rate of nAChR currents by bilirubin in SCG neurons was normalized to the control response induced by 100 μM ACh. Each data point is expressed as means ± SEMs (n = 5).
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f4: The dose-response curve for bilirubin.The inhibitory rate of nAChR currents by bilirubin in SCG neurons was normalized to the control response induced by 100 μM ACh. Each data point is expressed as means ± SEMs (n = 5).

Mentions: Bilirubin puffed onto rat SCG neurons did not elicit any current at holding potential of −60 mV, but bilirubin modulated the nAChRs currents bidirectionally (Fig. 3) (n = 5, each). At low concentrations (0.5 and 2 μM), bilirubin increased the peak nAChRs currents induced by 100 μM acetylcholine by 113 ± 30% and 69 ± 22% respectively, and decreased the extent of desensitization 5 s after ACh puff by 37 ± 3% and 35 ± 10%, respectively. At high concentrations (3, 4 and 5 μM), bilirubin suppressed the peak current by 9 ± 5%, 36 ± 9% and 73 ± 5% respectively, and decreased the desensitization rate by 42 ± 13%, 49 ± 11% and 94 ± 4% respectively (Fig. 3) (n = 5). To calculate the IC50 value of bilirubin-induced nAChRs current inhibition, the peak nAChRs current in the presence of bilirubin was normalized to the base current induced by 100 μM ACh only. The IC50 and Hill slope for bilirubin was 4 ± 0.5 μM and 1.0 respectively (n = 5) (Fig. 4). However, our data demonstrated that both potentiation and suppression of nAChRs currents by bilirubin were accompanied with a decrease in nAChRs desensitization.


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)

The dose-response curve for bilirubin.The inhibitory rate of nAChR currents by bilirubin in SCG neurons was normalized to the control response induced by 100 μM ACh. Each data point is expressed as means ± SEMs (n = 5).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f4: The dose-response curve for bilirubin.The inhibitory rate of nAChR currents by bilirubin in SCG neurons was normalized to the control response induced by 100 μM ACh. Each data point is expressed as means ± SEMs (n = 5).
Mentions: Bilirubin puffed onto rat SCG neurons did not elicit any current at holding potential of −60 mV, but bilirubin modulated the nAChRs currents bidirectionally (Fig. 3) (n = 5, each). At low concentrations (0.5 and 2 μM), bilirubin increased the peak nAChRs currents induced by 100 μM acetylcholine by 113 ± 30% and 69 ± 22% respectively, and decreased the extent of desensitization 5 s after ACh puff by 37 ± 3% and 35 ± 10%, respectively. At high concentrations (3, 4 and 5 μM), bilirubin suppressed the peak current by 9 ± 5%, 36 ± 9% and 73 ± 5% respectively, and decreased the desensitization rate by 42 ± 13%, 49 ± 11% and 94 ± 4% respectively (Fig. 3) (n = 5). To calculate the IC50 value of bilirubin-induced nAChRs current inhibition, the peak nAChRs current in the presence of bilirubin was normalized to the base current induced by 100 μM ACh only. The IC50 and Hill slope for bilirubin was 4 ± 0.5 μM and 1.0 respectively (n = 5) (Fig. 4). However, our data demonstrated that both potentiation and suppression of nAChRs currents by bilirubin were accompanied with a decrease in nAChRs desensitization.

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