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) 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.
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Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
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D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D005905:Glyburide / Q000494:pharmacology*; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000294:innervation / Q000378:metabolism; D009469:Neuromuscular Junction / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D010446:Peptide Fragments / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects*; D013395:Sucrose; D013779:Tetrodotoxin / Q000494:pharmacology; D014513:Ureter / Q000187:drug effects / Q000294:innervation / Q000378:metabolism
D018377:Neurotransmitter Agents; D010446:Peptide Fragments; D015221:Potassium Channels; C058636:calcitonin gene-related peptide (8-37); D013779:Tetrodotoxin; D013395:Sucrose; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin; D005905:Glyburide