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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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Dose–response curve of rat SCG nAChR currents.(A), representative nAChR current traces evoked by 10, 20, 50, 100, 200 and 400 μM ACh. (B), dose–response curve of nAChR currents fitted by nonlinear regression with logistic equation using Origin 8.0 software. Each data point represents mean ± SEMs (n = 9).
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f1: Dose–response curve of rat SCG nAChR currents.(A), representative nAChR current traces evoked by 10, 20, 50, 100, 200 and 400 μM ACh. (B), dose–response curve of nAChR currents fitted by nonlinear regression with logistic equation using Origin 8.0 software. Each data point represents mean ± SEMs (n = 9).

Mentions: According to our previous study, ACh with 1.0 μM atropine puffed onto rat SCG neurons could elicit a transient peak inward current followed by a gradual decrease at a holding potential of -60 mV (as shown in Fig. 1). The peak amplitudes and desensitization rates of nAChRs currents both increased in a concentration-dependent manner. The peak amplitude induced by 100 μM ACh was close to the maximum value, and the desensitization rate at 5 s remained relatively slow. Therefore, 100 μM ACh was chosen as the standard concentration to study the effect of bilirubin on nAChRs currents. In addition, the result of the nAChRs antagonist experiment showed that 100 µM hexamethonium bromide, a nAChRs antagonist, completely blocked the currents induced by 200 µM acetylcholine, which supports the nAChRs-mediated current specificity in our study (as shown in Fig. 2).


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)

Dose–response curve of rat SCG nAChR currents.(A), representative nAChR current traces evoked by 10, 20, 50, 100, 200 and 400 μM ACh. (B), dose–response curve of nAChR currents fitted by nonlinear regression with logistic equation using Origin 8.0 software. Each data point represents mean ± SEMs (n = 9).
© Copyright Policy - open-access
Related In: Results  -  Collection

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

f1: Dose–response curve of rat SCG nAChR currents.(A), representative nAChR current traces evoked by 10, 20, 50, 100, 200 and 400 μM ACh. (B), dose–response curve of nAChR currents fitted by nonlinear regression with logistic equation using Origin 8.0 software. Each data point represents mean ± SEMs (n = 9).
Mentions: According to our previous study, ACh with 1.0 μM atropine puffed onto rat SCG neurons could elicit a transient peak inward current followed by a gradual decrease at a holding potential of -60 mV (as shown in Fig. 1). The peak amplitudes and desensitization rates of nAChRs currents both increased in a concentration-dependent manner. The peak amplitude induced by 100 μM ACh was close to the maximum value, and the desensitization rate at 5 s remained relatively slow. Therefore, 100 μM ACh was chosen as the standard concentration to study the effect of bilirubin on nAChRs currents. In addition, the result of the nAChRs antagonist experiment showed that 100 µM hexamethonium bromide, a nAChRs antagonist, completely blocked the currents induced by 200 µM acetylcholine, which supports the nAChRs-mediated current specificity in our study (as shown in Fig. 2).

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