OBJECTIVE This study was performed to investigate the influence of calcitonin gene-related peptide (CGRP) and substance P (SP) on the intra-urethral pressure in female rats, as both these neuropeptides have been demonstrated to occur in nerve fibres throughout all layers of the intrinsic external urethral sphincter of the rat. METHODS Both CGRP and SP were administered intra-arterially relatively close to the bladder in ketamine-anaesthetized female rats. The maximum urethral pressure (MUP) was recorded continuously using a 4 F microtip single-transducer catheter. RESULTS Pronounced effects on the intra-urethral pressure were found with both CGRP and SP. CGRP at the maximum dose given (10 micrograms) induced an immediate, pronounced, long-lasting decrease in pressure from 28 +/- 4 to 10 +/- 2 cmH(2)O, amounting to 65% of the MUP. SP (10 micrograms) instead induced a forceful, phasic, peak-like contractile response with a 170% increase in urethral pressure from 33 +/- 6 to 87 +/- 6 cmH(2)O of the initial control level of MUP. Antagonists to CGRP and SP did not induce any pressure changes per se. CONCLUSIONS These results indicate that both CGRP and SP are of importance for the peripheral motor regulation of the external urethral sphincter, and hence possibly also of physiological importance for lower urinary tract function during essential parts of the micturition cycle.