INHIBITORY TRANSMITTER ACTION OF CALCITONIN-GENE-RELATED PEPTIDE IN GUINEA-PIG URETER VIA ACTIVATION OF GLIBENCLAMIDE-SENSITIVE K-CHANNELS

1 In single sucrose gap, electrical field stimulation (EFS, 1-5 Hz) pr oduced graded hyperpolarization of the membrane of the guinea-pig uret er smooth muscle, which was blocked by tetrodotoxin (0.3 mu M) or in v itro capsaicin desensitization (3 mu M for 15 min). Capsaicin itself p roduced a transient hyperpolarization of the membrane on its first app lication. 2 Superfusion with human alpha calcitonin gene-related pepti de (CGRP, 30-300 mM) likewise produced a transient hyperpolarization o f the membrane, mimicking the neurogenic inhibitory junction potential (i.j.p.). The hyperpolarization by CGRP was unaffected by tetrodotoxi n, indicating a postjunctional site of action. 3 Both the EFS-evoked i .j.p. and the CGRP-induced hyperpolarization were inhibited by the CGR P receptor antagonist, CGRP(8-37) (0.3-3 mu M) which did not affect th e hyperpolarization produced by the K-ATP channel opener, cromakalim ( 0.3 mu M). 4 The K-ATP channel blocker, glibenclamide (1 mu M) blocked both the EFS-evoked i.j.p. and the CGRP-induced hyperpolarization. 5 When evoked in a low K medium (1.2 mM, KCl being replaced by an equimo lar amount of NaCl), the EFS-evoked i.j.p. and the CGRP-induced hyperp olarization were both markedly enhanced, consistent with the idea that opening of K channels underlies both responses. 6 The present finding s provide direct electrophysiological evidence for a neurotransmitter role of CGRP, released from the peripheral endings of capsaicin-sensit ive primary afferent neurones, in the guinea-pig ureter. The action of both exogenous and endogenous CGRP involves the activation of glibenc lamide-sensitive (K-ATP) potassium channels.