PROPAGATION OF IMPULSES IN THE GUINEA-PIG URETER AND ITS BLOCKADE BY CALCITONIN-GENE-RELATED PEPTIDE (CGRP)

The guinea-pig ureter was placed in a three-compartment organ bath to enable the application of electrical stimuli or drugs to its renal end (R-site), the middle region (M-site) or the bladder end (B-site) whil e recording mechanical activity at the R- and B-sites. All experiments were performed in ureters pre-exposed to capsaicin (10 mu M for 15 mi n) to prevent the release of sensory neuropeptides from afferent nerve s. Electrical field stimulation (EFS, 5-25 ms pulse width, 20 V) produ ced a phasic contraction at the site of stimulation ('direct' response to EFS) which propagated to the other end of the ureter. Section of t he ureter at the M-site abolished the propagated response to EFS; afte r section, EFS applied at the M-site induced a phasic contraction at b oth the Rand B-sites. Likewise, the application of KCI at the M-site p roduced phasic contractions at both the R- and B-sites. Tetrodotoxin ( 1 mu M), nifedipine (1 mu M) or Bay K 8644 (1 mu M) applied at the M-s ite had no influence on the direct or propagated responses to EFS; nif edipine (10 mu M) applied at the M-site abolished the propagated respo nses without affecting the direct responses to EFS. Bay K 8644 (1 mu M ) applied at the R-site produced a marked enhancement of the direct re sponse (EFS applied at R-site) while having no effect on the amplitude of the propagated response to EFS. Nifedipine (4 mu M), applied at th e R-site, produced a graded, time-dependent, inhibition of the direct response (EFS applied at R-site) and eventually suppressed it; the pro pagated response was unaffected until suppression of the direct respon se, when an all-or-none blockade of the propagated response was observ ed. When applied at the B-site (EFS at R-site), 1 mu M nifedipine prod uced a graded, time-dependent, inhibition of the propagated response a nd eventually suppressed it, without affecting the direct response to EFS. For further pharmacological analysis of drug action on the propag ated activity, EFS was applied at the R-site and drugs were applied at the M-site. Human alpha CGRP (CGRP, 0.1 mu M) or cromakalim (1-3 mu M ) were applied in superfusion at the M-site in the absence or presence of glibenclamide (1 mu M). Neither drug affected the direct response to EFS; both CGRP and cromakalim produced a reversible suppression of the propagated response. Glibenclamide suppressed the inhibitory activ ity of 1 mu M cromakalim and partly antagonized the effect of CGRP; th e blockade by glibenclamide was partly overcome by 3 mu M cromakalim. The present findings are consistent with the idea that propagation of excitation occurs because of the spread of electrical activity between smooth muscle cells of the ureter and that conduction of impulses is independent of local changes in contractility. The present results als o demonstrate that CGRP induced a conduction block along the ureter an d that this effect involves activation of glibenclamide-sensitive K ch annels. Therefore, a local release of CGRP in response to pathophysiol ogical stimuli is, in principle, capable of suppressing ureteral peris talsis and antiperistalsis.