Though the mechanics of breathing differ fundamentally between amniotes and "lower" vertebrates, homologous rhythm generators may drive air breathing in all lunged vertebrates. In both frogs and rats, two coupled oscillators, one active during the inspiratory (I) phase and the other active during the preinspiratory (PreI) phase, have been hypothesized to generate the respiratory rhythm. We used opioids to uncouple these oscillators. In the intact rat, complete arrest of the external rhythm by opioid-induced suppression of the putative I oscillator, that is, pre-Bötz-inger complex (PBC) oscillator, did not arrest the putative PreI oscillator. In the unanesthetized frog, the comparable PreI oscillator, that is, the putative buccal/ gill oscillator, was refractory to opioids even though the comparable I oscillator, the putative lung oscillator, was arrested. Studies in en bloc brainstem preparations derived from both juvenile frogs and metamorphic tadpoles confirmed these results and suggested that opioids may play a role in the clustering of lung bursts into episodes. As the frog and rat respiratory circuitry produce functionally equivalent motor outputs during lung inflation, these data argue for a close homology between the frog and rat oscillators. We suggest that the respiratory rhythm of all lunged vertebrates is generated by paired coupled oscillators. These may have originated from the gill and lung oscillators of the earliest air breathers.

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The frog, with two distinct ventilatory acts, provides a useful model to investigate the prospective interaction of two oscillators in generating the respiratory rhythm. Building on evidence supporting the existence of separate oscillators generating buccal and lung ventilation, we have attempted to uncouple the two rhythms in the isolated brain stem preparation. Opioid preferentially inhibits the lung rhythm, suggesting an uncoupling of the lung from the buccal oscillator. Reduction of the superfusate chloride concentration alters both the buccal and the lung rhythms. Joint application of opioid and reduced-chloride superfusate leads to an increase in the variability of the buccal burst-to-lung burst intervals. This increase in variability suggests that chloride-mediated mechanisms are involved in coupling the buccal oscillator to the lung oscillator. Given the results from these interventions, we propose a simple schematic model of the frog respiratory rhythm generator, outlining the coupling of the lung and buccal oscillators.

An extracorporeal bioartificial liver (BAL) that could prevent death from hepatic encephalopathy in acute hepatic insufficiency was aimed to develop. A functional human hepatocellular carcinoma cell line (FLC-4) was cultured in a radial-flow bioreactor. The function of the BAL was tested in mini-pigs with acute hepatic failure induced by alpha-amanitin and lipopolysaccharide. When the BAL system was connected with cultured FLC-4 to three pigs with hepatic dysfunction, all demonstrated electroencephalographic improvement and survived. Relatively low plasma concentrations of S-100 beta protein, as a marker of astrocytic damage, from pigs with hepatic failure during BAL therapy were noted. BAL therapy can prevent irreversible brain damage from hepatic encephalopathy in experimental acute hepatic failure.

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