Superfusion of slices of the rat urinary bladder with hypertonic NaCl produced a remarkable and concentration-dependent (150-280 mM) increase in the outflow of calcitonin gene-related peptide-like immunoreactivity (CGRP-LI). This effect was completely abolished by pre-exposure of the tissue to capsaicin (10 microM for 20 min) or by superfusion with a Ca(2+)-free medium. Capsaicin (10 microM) was still able to release a consistent amount of CGRP-LI from tissue pre-exposed (20 min) to 280 mM NaCl. Similarly, hypertonic sucrose (160 mM added to the physiological salt solution) induced a consistent release of CGRP-LI that was abolished by capsaicin-pretreatment or in a Ca(2+)-free medium. The experiments demonstrate that hypertonic solutions activate the efferent function of capsaicin-sensitive neurons and suggest that this event may have some relevance in pathophysiological conditions of the lower urinary tract in which hypertonic urine may diffuse to submucosal layers.