Lowering of the pH of the superfusion solution (physiological phosphate buffers derived from normal Krebs solution) of mucosa-free muscle strips of the guinea-pig urinary bladder from 7.4 to 6 or 5, produced a marked increase of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI) outflow (total evoked release being 1677 +/- 287 fmol/g/35 min and 5283 +/- 484 fmol/g/35 min, respectively). The increase in CGRP-LI outflow evoked by exposure to pH 5 was abolished in strips pre-exposed to capsaicin (10 microM for 20 min), and was reduced by approximately 80% when superfusion was performed with Ca2(+)-free media. After application of pH 5 solution, capsaicin (10 microM) evoked a CGRP-LI release that amounted to 21% of controls. It is concluded that lowering of the pH induces a Ca2(+)-dependent release of CGRP-LI from capsaicin-sensitive nerves in the guinea-pig urinary bladder.