Modulation of the respiratory rhythm by gap-junction blockers 18-α-glycyrrhetinic acid and 18-β-glycyrrhetinic acid.

Gap junction proteins are expressed in the pre-Bötzinger complex of the respiratory network but it remains under discussion how they modulate the respiratory rhythm generation. In the present study we tested whether the gap junction blockers 18-β-glycyrrhetinic acid (18-β- GA) and 18-α-glycyrrhetinic acid (18-α-GA) change either the phrenic nerve (PN) discharge frequency or amplitude. The PN discharge was recorded using the working heart-brainstem preparation of adult wistar rats (P22- P28) exposed to increasing concentrations of the gap junction blockers (0.1; 1; 10; 20 μM). With the two lower concentrations (0.1; 1 μM) of 18-β-GA, PN discharge frequency decreased to 46±15% (p=0.007) of the control value while it increased to 173±57% (p=0.16) with the two higher concentrations (10; 20 μM). Surprisingly, with 18-α-GA the PN discharge frequency was not significantly changed with any of the concentrations used. Enhancing the respiratory drive with 12% CO2, the PN discharge frequency increased tendencially with rising concentrations of 18-β-GA, but again no significant change was observed with 18-α-GA. PN-amplitudes were slightly reduced over the course of the experiments, while the frequency of the heartbeat was not significantly changed at any time with any concentration.

Control of respiration in fish, amphibians and reptiles

Fish and amphibians utilise a suction/force pump to ventilate gills or lungs, with the respiratory muscles innervated by cranial nerves, while reptiles have a thoracic, aspiratory pump innervated by spinal nerves. However, fish can recruit a hypobranchial pump for active jaw occlusion during hypoxia, using feeding muscles innervated by anterior spinal nerves. This same pump is used to ventilate the air-breathing organ in air-breathing fishes. Some reptiles retain a buccal force pump for use during hypoxia or exercise. All vertebrates have respiratory rhythm generators (RRG) located in the brainstem. In cyclostomes and possibly jawed fishes, this may comprise elements of the trigeminal nucleus, though in the latter group RRG neurons have been located in the reticular formation. In air-breathing fishes and amphibians, there may be separate RRG for gill and lung ventilation. There is some evidence for multiple RRG in reptiles. Both amphibians and reptiles show episodic breathing patterns that may be centrally generated, though they do respond to changes in oxygen supply. Fish and larval amphibians have chemoreceptors sensitive to oxygen partial pressure located on the gills. Hypoxia induces increased ventilation and a reflex bradycardia and may trigger aquatic surface respiration or air-breathing, though these latter activities also respond to behavioural cues. Adult amphibians and reptiles have peripheral chemoreceptors located on the carotid arteries and central chemoreceptors sensitive to blood carbon dioxide levels. Lung perfusion may be regulated by cardiac shunting and lung ventilation stimulates lung stretch receptors.