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African lungfish Protopterus annectens utilized both respiratory and metabolic compensation to restore arterial pH to control levels following the imposition of a metabolic acidosis or alkalosis. Acid infusion (3 mmol kg–1 NH4Cl) to lower arterial pH by 0.24 units increased both pulmonary (by 1.8-fold) and branchial (by 1.7-fold) ventilation frequencies significantly, contributing to 4.8-fold and 1.9-fold increases in, respectively, aerial and aquatic CO2 excretion. This respiratory compensation appeared to be the main mechanism behind the restoration of arterial pH, because even though net acid excretion (JnetH+) increased following acid infusion in 7 of 11 fish, the mean increase in net acid excretion, 184.5±118.5μ mol H+ kg–1 h–1 (mean± s.e.m., N=11), was not significantly different from zero. Base infusion (3 mmol kg–1 NaHCO3) to increase arterial pH by 0.29 units halved branchial ventilation frequency, although pulmonary ventilation frequency was unaffected. Correspondingly, aquatic CO2 excretion also fell significantly (by 3.7-fold) while aerial CO2 excretion was unaffected. Metabolic compensation consisting of negative net acid excretion (net base excretion) accompanied this respiratory compensation, with JnetH+ decreasing from 88.5±75.6 to –337.9±199.4 μmol H+ kg–1 h–1 (N=8). Partitioning of net acid excretion into renal and extra-renal (assumed to be branchial and/or cutaneous) components revealed that under control conditions, net acid excretion occurred primarily by extra-renal routes. Finally, several genes that are involved in the exchange of acid–base equivalents between the animal and its environment (carbonic anhydrase, V-type H+-ATPase and Na+/HCO –3 cotransporter) were cloned, and their branchial and renal mRNA expressions were examined prior to and following acid or base infusion. In no case was mRNA expression significantly altered by metabolic acid–base disturbance. These findings suggest that lungfish, like tetrapods, alter ventilation to compensate for metabolic acid–base disturbances, a mechanism that is not employed by water-breathing fish. Like fish and amphibians, however, extra-renal routes play a key role in metabolic compensation.