Bilirubin Modulates Acetylcholine Receptors In Rat Superior Cervical Ganglionic Neurons In a Bidirectional Manner

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.

Bilirubin acts as a multipotent guardian of cardiovascular integrity: more than just a radical idea

“…Furthermore, bilirubin may modulate neurotransmitter release via activation of presynaptic PKA signaling (53). Finally, bilirubin modulates ganglionic transmission, enhancing acetylcholine-triggered currents at low concentrations while concentration dependently inhibiting nicotinic acetylcholine receptor desensitization at higher levels (113). These observations are consistent with the potential involvement of hyperbilirubinemia in suppression of sympathetic transmission and altered cardiovascular control in liver disease.…”

Acute bilirubin ditaurate exposure attenuates ex vivo platelet reactive oxygen species production, granule exocytosis and activation

“…Perturbation of calcium homeostasis and inhibition of nerve terminal vesicle exocytosis by BR, both through calcium dependent and independent mechanisms, has been previously reported [40]. BR modulation of nicotinic acetylcholine receptor function via the PKA pathway is one hypothesis by which bilirubin may modulate presynaptic neurotransmitter release [40,41]. Concentrations of BR above 3 μM suppressed nicotinic acetylcholine receptor (nAChRα7) channel current in a non-competitive manner [41].…”

“…BR modulation of nicotinic acetylcholine receptor function via the PKA pathway is one hypothesis by which bilirubin may modulate presynaptic neurotransmitter release [40,41]. Concentrations of BR above 3 μM suppressed nicotinic acetylcholine receptor (nAChRα7) channel current in a non-competitive manner [41]. Platelets express nAChRα7 subunits that form functional Ca 2+ channels and increase platelet aggregation in response to ADP and TXA 2 [42].…”

Influence of Nicotine from Diverse Delivery Tools on the Autonomic Nervous and Hormonal Systems

“…As follows from the data presented above ( Figure 1 ), just one smoked nicotine-free cigarette with a filter increases the level of carboxyhemoglobin in the blood 2.5 times, and repeated smoking sessions with an interval of 1.5 h increases it six times. Moderate hypoxia stimulates heme oxygenase and the production of bilirubin, which increases HRV through the mechanism of suppression of sympathetic ganglionic signaling through the inhibition of postganglionic receptors nAChRs [ 35 ]. In addition, numerous case studies have described cardiac abnormalities in the form of repolarization, arrhythmias and prolongation of the QT interval even after mild carbon monoxide poisoning [ 36 ].…”