Inhibitory transmitter action of calcitonin gene-related peptide in guinea-pig ureter via activation of glibenclamide-sensitive K channels

Abstract

1. In single sucrose gap, electrical field stimulation (EFS, 1-5 Hz) produced graded hyperpolarization of the membrane of the guinea-pig ureter smooth muscle, which was blocked by tetrodotoxin (0.3 microM) or in vitro capsaicin desensitization (3 microM for 15 min). Capsaicin itself produced a transient hyperpolarization of the membrane on its first application. 2. Superfusion with human alpha calcitonin gene-related peptide (CGRP, 30-300 mM) likewise produced a transient hyperpolarization of the membrane, mimicking the neurogenic inhibitory junction potential (i.j.p.). The hyperpolarization by CGRP was unaffected by tetrodotoxin, indicating a postjunctional site of action. 3. Both the EFS-evoked i.j.p. and the CGRP-induced hyperpolarization were inhibited by the CGRP receptor antagonist, CGRP(8-37) (0.3-3 microM) which did not affect the hyperpolarization produced by the KATP channel opener, cromakalim (0.3 microM). 4. The KATP channel blocker, glibenclamide (1 microM) 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 equimolar amount of NaCl), the EFS-evoked i.j.p. and the CGRP-induced hyperpolarization were both markedly enhanced, consistent with the idea that opening of K channels underlies both responses. 6. The present findings provide direct electrophysiological evidence for a neurotransmitter role of CGRP, released from the peripheral endings of capsaicin-sensitive primary afferent neurones, in the guinea-pig ureter. The action of both exogenous and endogenous CGRP involves the activation of glibenclamide-sensitive (KATP) potassium channels.