Direct inhibitory effect of adrenomedullin, calcitonin gene-related peptide, calcitonin, and amylin on cholecystokinin-induced contraction of guinea-pig isolated caecal circular smooth muscle cells.
We recently reported the direct inhibitory effect of adrenomedullin on caecal circular smooth muscle cells via cAMP system. This study was designed to determine whether the structurally related peptides to adrenomedullin (i.e.; calcitonin gene-related peptide (CGRP), calcitonin, and amylin) can inhibit the cholecystokinin octapeptide (CCK-8)-induced contractile response by exerting a direct action on guinea-pig caecal circular smooth muscle cells, and to compare the inhibitory potency of these peptides. In addition, to elucidate each intracellular mechanisms, the effects of an inhibitor of cAMP-dependent protein kinase, inhibitors of particulate or soluble guanylate cyclase on the each peptide-induced relaxation were investigated. Adrenomedullin, CGRP, calcitonin, and amylin inhibited the contractile response produced by CCK-8 in a dose-dependent manner, with IC50 values of 0.14 nM, 0.37 nM, 5.4 nM, and 160 nM, respectively. An inhibitor of cAMP-dependent protein kinase significantly inhibited the relaxation produced by all of these peptides. On the contrary, inhibitors of particulate or soluble guanylate cyclase did not have any significant effect on the relaxation produced by these peptides. In this study, we demonstrated the direct inhibitory effects of the structurally related peptides to adrenomedullin (i.e.; CGRP, calcitonin, and amylin) on the isolated caecal circular smooth muscle cells via cAMP system. The order of potency was as follows; adrenomedullin falling dots CGRP > calcitonin > amylin.
Ochiai
T
T
Third Department of Internal Medicine, Faculty of Medicine, Kyushu University, 812-8582, Fukuoka, Japan. cet8405o@nyc.odn.ne.jp
Chijiiwa
Y
Y
Motomura
Y
Y
Yasuda
O
O
Harada
N
N
Nawata
H
H
D053607:Adrenomedullin; D000634:Aminoquinolines / Q000494:pharmacology; D000682:Amyloid / Q000494:pharmacology*; D000818:Animals; D002116:Calcitonin / Q000494:pharmacology*; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002766:Cholecystokinin / Q000378:metabolism*; D000242:Cyclic AMP / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006162:Guanylate Cyclase / Q000037:antagonists & inhibitors; D006168:Guinea Pigs; D006801:Humans; D020128:Inhibitory Concentration 50; D058228:Islet Amyloid Polypeptide; D007700:Kinetics; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000166:cytology* / Q000187:drug effects*; D010455:Peptides / Q000494:pharmacology*; D012844:Sincalide / Q000037:antagonists & inhibitors*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D013873:Thionucleotides / Q000494:pharmacology
D000634:Aminoquinolines; D000682:Amyloid; D004791:Enzyme Inhibitors; D058228:Islet Amyloid Polypeptide; D010455:Peptides; D013873:Thionucleotides; D053607:Adrenomedullin; C016957:adenosine-3',5'-cyclic phosphorothioate; D002116:Calcitonin; D002766:Cholecystokinin; C041715:6-anilino-5,8-quinolinedione; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D006162:Guanylate Cyclase; D015740:Calcitonin Gene-Related Peptide; D012844:Sincalide; D013755:Tetradecanoylphorbol Acetate