A thiorphan-sensitive mechanism regulates the action of both exogenous and endogenous calcitonin gene-related peptide (CGRP) in the guinea-pig ureter.
The aim of this study was to assess the existence of mechanisms regulating the intensity and duration of action of calcitonin gene-related peptide (CGRP), the main candidate inhibitory transmitter released from capsaicin-sensitive afferents in the guinea-pig ureter. In a first series of experiments, performed in capsaicin-pretreated ureters, exogenously administered human alpha CGRP (h alpha CGRP) produced inhibition of contractions of the guinea-pig isolated ureter evoked by direct electrical stimulation of smooth muscle. The intensity and duration of the inhibitory effect of h alpha CGRP were potentiated by the inhibitor of neutral endopeptidase, thiorphan, while captopril and bestatin were without effect. In a second series of experiments, background motility of the guinea-pig ureter was evoked by administration of endothelin-1 (ET-1): electrical stimulation of intramural nerves produced a transient suppression of the ET-1-evoked contractions, ascribable to release of endogenous CGRP. Thiorphan enhanced the inhibitory effect produced by endogenous CGRP, while bestatin and captopril were without effect. These findings demonstrate that a thiorphan-sensitive mechanism, presumably neutral endopeptidase, regulates the intensity and duration of the inhibitory activity of both exogenous and endogenous CGRP in the guinea-pig ureter. The existence of a mechanisms for inactivation of the released peptide is consistent with the proposed role of CGRP as inhibitory neurotransmitter in this preparation.
Maggi
C A
CA
Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Giuliani
S
S
D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000378:metabolism / Q000494:pharmacology*; D002211:Capsaicin / Q000494:pharmacology; D002216:Captopril / Q000494:pharmacology; D004558:Electric Stimulation; D016232:Endothelins / Q000494:pharmacology; D006168:Guinea Pigs; D006801:Humans; D007930:Leucine / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D009130:Muscle, Smooth / Q000187:drug effects* / Q000502:physiology; D015244:Thiorphan / Q000494:pharmacology*; D014513:Ureter / Q000187:drug effects* / Q000502:physiology
D016232:Endothelins; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D002216:Captopril; D015244:Thiorphan; D007930:Leucine; C012211:ubenimex; D015740:Calcitonin Gene-Related Peptide; D002211:Capsaicin