Multiple mechanisms in the smooth muscle relaxant action of calcitonin gene-related peptide (CGRP) in the guinea-pig ureter.
We have investigated the ability of human alpha CGRP (CGRP) to inhibit the electrically-evoked myogenic contractions of the guinea-pig ureter, in comparison with the K channel opener, cromakalim, and the adenylate cyclase activator, forskolin. CGRP (0.1 nM-0.1 microM) produced a concentration-dependent inhibition of the evoked contractions; its action was prevented by the CGRP receptor antagonist, CGRP(8-37) (1 microM), while it was unaffected by the nitric oxide (NO) synthase inhibitor, L-nitroarginine (30 microM). The effect of CGRP was antagonized in a noncompetitive manner (depression of Emax, no change in EC50) by glibenclamide (1-10 microM), a blocker of ATP-sensitive potassium channels (KATP). A substantial fraction of the inhibitory effect of CGRP was glibenclamide-resistant, however. Glibenclamide also blocked the inhibitory action of cromakalim (0.1-10 microM) without affecting the inhibition produced by forskolin (0.1-30 microM). When tested in a low-K medium (extracellular K reduced from 5.9 to 1.2 mM), the inhibitory effects of CGRP, cromakalim and forskolin were enhanced. The inhibitory effect of forskolin was partly antagonized by glibenclamide when tested in a low-K medium. CGRP (0.1 microM), cromakalim (3 microM) and forskolin (10 microM) inhibited the contractile response to KCl (80 mM), which is characterized by a distinct phasic and tonic component: cromakalim selectively inhibited the phasic response to KCl with CGRP and forskolin inhibited both components. The inhibitory effect of CGRP on the phasic contraction to KCl was partly glibenclamide-(1 microM) sensitive, while that on the tonic contraction was glibenclamide-resistant. The inhibitory action of forskolin on both components of the response to KCl was unchanged by glibenclamide.(ABSTRACT TRUNCATED AT 250 WORDS)
Maggi
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Pharmacology Department, A. Menarini Pharmaceuticals, Florence, Italy.
Giuliani
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Santicioli
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D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D001120:Arginine / Q000031:analogs & derivatives / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D005576:Colforsin / Q000494:pharmacology; D019806:Cromakalim; D004305:Dose-Response Relationship, Drug; D004558:Electric Stimulation; D005905:Glyburide / Q000494:pharmacology; D006168:Guinea Pigs; D066298:In Vitro Techniques; D007545:Isoproterenol / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects*; D009130:Muscle, Smooth / Q000187:drug effects*; D019335:Nitroarginine; D010276:Parasympatholytics; D011758:Pyrroles / Q000494:pharmacology; D014513:Ureter / Q000187:drug effects*
D001578:Benzopyrans; D010276:Parasympatholytics; D011758:Pyrroles; D019806:Cromakalim; D005576:Colforsin; D019335:Nitroarginine; D001120:Arginine; D015740:Calcitonin Gene-Related Peptide; D007545:Isoproterenol; D005905:Glyburide