Calcitonin gene-related peptide (CGRP)-enhanced non-adrenergic non-cholinergic contraction of guinea-pig proximal colon.
1. We have investigated the effect of calcitonin gene-related peptide (CGRP) on non-adrenergic, non-cholinergic (NANC) excitatory transmission to the longitudinal muscle of the guinea-pig proximal colon. 2. In the presence of atropine (0.3 microM), guanethidine (5 microM), hexamethonium (100 microM) and indomethacin (3 microM), electrical field stimulation (EFS, 1 Hz, 0.3 ms for 10 s) produced tetrodotoxin-(300 nM)-sensitive contractions which were reduced by the combined administration of FK 888 (10 microM) and MEN 10,376 (0.3 microM), to block tachykinin NK1 and NK2 receptors, respectively. Thus, the EFS-induced NANC contractions are a tachykinin-mediated response. 3. CGRP, at concentrations higher than 0.1 nM, caused an increase in the electrically-evoked, NANC contractions in a concentration-dependent manner and at 10 nM produced a maximal effect (pEC50 = 9.20 +/- 0.17, n = 6). 4. 5-Hydroxytryptamine (5-HT, 1-100 nM) also caused an increase in the EFS-induced NANC contractions in a concentration-dependent manner and at 30 nM produced a maximal effect (pEC50 = 8.06 +/- 0.09, n = 4), but calcitonin (10-100 nM) failed to enhance the EFS-induced NANC responses. Moreover, a 5-HT4 receptor antagonist, DAU 6285 (3 microM) abolished the enhancing action of 5-HT (30 nM). 5. The combined administration of FK 888 (10 microM) plus MEN 10,376 (0.3 microM) abolished the enhancement of EFS-induced NANC contractions by CGRP (10 nM), but DAU 6285 (3 microM) had no effect on the enhancement. 6. Human CGRP8-37 (1 microM), a CGRP1 receptor antagonist had no effect on the submaximal enhancement of the electrically-evoked, NANC contractions by CGRP (1 nM).7. CGRP (30 nM) had no effect on contractions evoked by exogenous substance P (0.3-1 nM).8. These results indicate that in the guinea-pig proximal colon, CGRP produced an enhancement ofNANC contraction induced by EFS through prejunctional mechanisms and that the enhancement is mediated by the stimulation of non-CGRP1 receptors located on intramural tachykininergic neurones.Further, the possible contribution of 5-HT to the enhancing effect of CGRP appeared to be negligible.
Kojima
S
S
Department of Pharmacology, Dokkyo University School of Medicine, Tochigi, Japan.
Shimo
Y
Y
D000818:Animals; D001285:Atropine / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D003106:Colon / Q000187:drug effects* / Q000502:physiology; D004558:Electric Stimulation; D006145:Guanethidine / Q000494:pharmacology; D006168:Guinea Pigs; D018738:Hexamethonium / Q000494:pharmacology; D066298:In Vitro Techniques; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D011941:Receptors, Adrenergic / Q000187:drug effects / Q000502:physiology; D011950:Receptors, Cholinergic / Q000187:drug effects / Q000502:physiology; D012701:Serotonin / Q000494:pharmacology; D013373:Substance P / Q000494:pharmacology
D011941:Receptors, Adrenergic; D011950:Receptors, Cholinergic; D012701:Serotonin; D013373:Substance P; D018738:Hexamethonium; D001285:Atropine; D015740:Calcitonin Gene-Related Peptide; D007213:Indomethacin; D006145:Guanethidine