Mechanism of CGRP-induced relaxation in rat intramural coronary arteries.
1. This study investigates the mechanism of CGRP-induced relaxation in intramural coronary arteries by determining the effect of CGRP on cytosolic Ca(2+) concentration ([Ca(2+)](i)) using FURA-2 technique. 2. CGRP concentration-dependently (10 pM - 100 nM) decreased the [Ca(2+)](i) and tension of coronary arteries precontracted with either U46619 or BAY K 8644, and also of resting coronary arteries in PSS. In 36 mM K(+)-depolarized arteries, CGRP reduced only the tension without affecting the [Ca(2+)](i). 3. In 300 nM U46619- precontracted arteries, pretreatment with 10 microM thapsigargin significantly (P<0.05) attenuated the CGRP-induced reduction in the tension (but not [Ca(2+)](i)). 4. In 300 nM U46619-precontracted arteries, pretreatment with either 100 nM charybdotoxin or 100 nM iberiotoxin or 10 nM felodipine significantly (P<0.05) attenuated the CGRP-induced reduction in both [Ca(2+)](i) and tension. In contrast, 1 microM glibenclamide did not affect the CGRP-induced responses in these coronary arteries. 5. In resting coronary arteries, only pretreatment with the combination of 1 microM glibenclamide and 100 nM charybdotoxin attenuated the CGRP-induced decrease in the [Ca(2+)](i) and tension, suggesting a different mechanism of action for CGRP in resting coronary arteries. 6. We conclude that CGRP relaxes precontracted rat coronary arteries via three mechanisms: (1) a decrease in [Ca(2+)](i) by inhibiting the Ca(2+) influx through membrane hyperpolarization mediated partly by activation of the large conductance Ca(2+)-activated potassium channels, (2) a decrease in [Ca(2+)](i) presumably by sequestrating cytosolic Ca(2+) into thapsigargin-sensitive Ca(2+) storage sites and (3) a decrease in the Ca(2+)-sensitivity of the contractile apparatus. In resting coronary arteries, however, there seems to be an interplay between different types of K(+) channels.
Sheykhzade
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Department of Pharmacology, The Royal Danish School of Pharmacy, Universitetsparken 2, DK-2100 Copenhagen, Denmark. mash@mail.dfh.dk
Berg Nyborg
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NC
D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid / Q000494:pharmacology; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester / Q000494:pharmacology; D000704:Analysis of Variance; D000818:Animals; D015740:Calcitonin Gene-Related Peptide / Q000494:pharmacology*; D002118:Calcium / Q000378:metabolism; D002120:Calcium Channel Agonists / Q000494:pharmacology; D018999:Charybdotoxin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000502:physiology; D004347:Drug Interactions; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015736:Felodipine / Q000494:pharmacology; D005456:Fluorescent Dyes / Q000378:metabolism; D016257:Fura-2 / Q000378:metabolism; D005905:Glyburide / Q000494:pharmacology; D007004:Hypoglycemic Agents / Q000494:pharmacology; D066298:In Vitro Techniques; D008297:Male; D009994:Osmolar Concentration; D010455:Peptides / Q000494:pharmacology; D011188:Potassium / Q000494:pharmacology; D015221:Potassium Channels / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D012146:Rest / Q000502:physiology; D019284:Thapsigargin / Q000494:pharmacology; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology
D002120:Calcium Channel Agonists; D004791:Enzyme Inhibitors; D005456:Fluorescent Dyes; D007004:Hypoglycemic Agents; D010455:Peptides; D015221:Potassium Channels; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D018999:Charybdotoxin; D019284:Thapsigargin; D001498:3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; D019796:15-Hydroxy-11 alpha,9 alpha-(epoxymethano)prosta-5,13-dienoic Acid; C064719:iberiotoxin; D015740:Calcitonin Gene-Related Peptide; D015736:Felodipine; D011188:Potassium; D005905:Glyburide; D002118:Calcium; D016257:Fura-2