CALCITONIN-GENE-RELATED PEPTIDE AS INHIBITORY NEUROTRANSMITTER IN THEURETER

A dense plexus of calcitonin gene related peptide (CGRP) containing ne rve fibres is present in the mammalian ureter, from which CGRP is rele ased by depolarizing stimuli, including chemicals normally present in the urine. CGRP exerts a profound, receptor-mediated, inhibitory effec t on the evoked motility of the ureter by suppressing latent pacemaker s in the smooth muscle. This effect is largely glibenclamide sensitive , indicating the activation of potassium (K) channels in its genesis. Electrical stimulation of intramural nerves in the guinea-pig ureter p roduces a transient membrane hyperpolarization, which is blocked by gl ibenclamide or by capsaicin pretreatment, enhanced in a low-K medium, and inhibited by a CGRP receptor antagonist. Thus endogenous CGRP acts as a neurotransmitter K channel opener in the ureter. The refractory period of the guinea-pig ureter is markedly and similarly reduced by c apsaicin pretreatment or administration of a CGRP receptor antagonist, indicating that endogenous CGRP can modulate the maximal frequency of ureteral peristalsis. Using a three-chamber organ bath that enabled t he separate perfusion of the renal, middle, and bladder regions of the organ, evidence was obtained that CGRP blocks propagation of impulses along the ureter through a glibenclamide-sensitive mechanism. These f indings indicate a role of CGRP in the local regulation of ureteral mo tility and peristalsis.