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

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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 μm) or in vitro capsaicin desensitization (3 μm for 15 min). Capsaicin itself produced a transient hyperpolarization of the membrane on its first application. 2 Superfusion with human α calcitonin gene-related peptide (CGRP, 30–300 μm) 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 μm) which did not affect the hyperpolarization produced by the KATP channel opener, cromakalim (0.3 μm). 4 The KATP channel blocker, glibenclamide (1 μm) blocked both the EFS-evoked i.j.p. and the CGRP-induced hyperpolarization. 5 When evoked in a low K medium (1.2 mm, KC1 being replaced by an equimolar amount of NaC1), 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.