Cyst formation in conditions associated with increased renal ammoniagenesis (hypokalemia, distal renal tubular acidosis, renal mass reduction) and experimental links between increased ammoniagenesis and interstitial inflammation have suggested a role for ammonia in the pathogenesis of polycystic kidney disease (PKD). To explore this hypothesis, Han:SPRD rats, a PKD model that affects male more severely than female animals, have been used. Heterozygous cystic (Cy/+) and homozygous normal (+/+) male and female offspring of Cy/+ rats were divided at 3 wk of age into control groups drinking water and experimental groups drinking 300 mM NH4Cl, 300 mM KHCO3, 200 mM KHCO3, 200 mM KCl, 200 mM NaHCO3, or 200 mM NaCl. At 2 months of age, the rats were kept fasting from 8:00 p.m. to 8:00 a.m. in metabolic cages and urine samples were collected under mineral oil. The rats were then weighed and anesthetized for the collection of blood and kidneys. The administration of 300 mM NH4Cl, and to a lesser extent that of 200 mM NaCl, was accompanied by an increase in the urinary excretion of ammonia and aggravation of the renal cystic disease. On the other hand, the administration of 300 mM KHCO3, 200 mM KHCO3, or 200 mM NaHCO3 lowered the urinary excretion of ammonia and markedly reduced the severity of the cystic disease and interstitial inflammation. The administration of 300 mM KHCO3, and to a lesser extent that of 200 mM KHCO3, resulted in the precipitation of calcium phosphate in the medullary collecting ducts.(ABSTRACT TRUNCATED AT 250 WORDS)