Acid-base homeostasis depends on glutamine flow from producer organs to those capable of generating bicarbonate. Glutamine oxidation, the prerequisite metabolic transformation, can be expressed by many sites; however, net base generation requires that glutamine flow be directed to a specific organ, the kidney. Normally, glutamine flows from the periphery to the splanchnic bed, providing a major fuel and supporting ureagenesis. Glutamine flow in chronic metabolic acidosis, on the other hand, is rerouted to the kidneys; asymmetrical distribution of NH+4 and HCO3- into the urine and renal vein subserves restoration of alkaline reserves. Clearly, glutamine flows in accordance with physiological demands, yet little is known of the regulatory mechanisms. As a model, chronic metabolic acidosis alters two aspects of this vital flow, its direction and magnitude. Characteristically the direction of flow is away from the splanchnic bed and into the kidneys associated with a marked fall in arterial glutamine concentration, restoring arterial level returns flow to the splanchnic bed sink. Thus glutamine homeostasis is sacrificed to impart direction to interorgan glutamine flow. Although multiple sites contribute to glutamine homeostasis, of great strategic importance is the potent hepatic glutaminase flux activated by portal venous NH+4 fed forward by gut metabolism; local hydrogen ion concentration modulates the effectiveness of this activator. Acute regulation of flow direction can be exerted by the lungs in determining the prevailing pCO2 and cellular acidity; respiratory compensation in chronic acidosis allows the expression of hepatic glutaminase, thereby suppressing arterial glutamine concentration. The enormous magnitude of glutamine flowing from muscle to the kidneys is supported by adaptive increases in glutamine synthetase and mitochondrial glutaminase, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)