Localization and characterization of the subtype(s) of muscarinic receptor involved in prostacyclin synthesis in rabbit heart

H. Kan, Y. Ruan, Kafait Malik

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Abstract

The present study was conducted to localize and characterize the subtype(s) of muscarinic receptor involved in prostacyclin production elicited by the cholinergic transmitter acetylcholine (ACh) in various cell types in the rabbit heart. ACh increased prostacyclin synthesis, measured as 6-keto-prostaglandin (6-keto-PGF), in cultured coronary endothelial cells and freshly dissociated ventricular myocytes in a dose-dependent manner, but not in cultured coronary smooth muscle cells of rabbit heart. McN-A-343 {(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride}, a selective M1 muscarinic ACh receptor (mAChR) agonist, did not alter 6-keto-PGF synthesis in these cell types. ACh induced 6-keto-PGF synthesis in coronary endothelial cells and ventricular myocytes was not altered by a low concentration (0.01 μM) of pirenzepine, an M1 mAChR antagonist, but was reduced by a higher concentration (1 μM). In coronary endothelial cells, ACh-induced 6-keto-PGF production was reduced by hexahydrosila-difendial (HHSiD), an M3 mAChR antagonist, and in ventricular myocytes by both AF-DX 116 [11-{2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H-pyrido[2,3-b] -benzodiazepine-6 one}], an M2 receptor antagonist, and HHSiD. The decrease by ACh of isoproterenol-stimulated cAMP accumulation was minimized by AF-DX 116, but not by HHSiD or pirenzepine. Pertussis toxin treatment minimized ACh-induced decrease in isoproterenol-stimulated rise in cAMP, but not ACh-induced 6-keto-PGF synthesis. These data suggest that ACh stimulates prostacyclin production in coronary endothelial cells via M3 mAChR and in ventricular myocytes via M2 and M3 mAChR, and may contribute to its cardiprotective effects. Moreover, ACh induced decrease in cAMP, but not the increase in 6-Keto-PGF production, is mediated by pertussis toxin-sensitive Gαi proteins in these cells.

Original languageEnglish (US)
Pages (from-to)934-941
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume276
Issue number3
StatePublished - Mar 1 1996

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Muscarinic Receptors
Epoprostenol
Acetylcholine
Rabbits
Cholinergic Receptors
Muscle Cells
Endothelial Cells
Pirenzepine
Pertussis Toxin
Isoproterenol
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
Cholinergic Agonists
Benzodiazepines
Cholinergic Agents
Smooth Muscle Myocytes
prostaglandin F1
Chlorides

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Localization and characterization of the subtype(s) of muscarinic receptor involved in prostacyclin synthesis in rabbit heart",
abstract = "The present study was conducted to localize and characterize the subtype(s) of muscarinic receptor involved in prostacyclin production elicited by the cholinergic transmitter acetylcholine (ACh) in various cell types in the rabbit heart. ACh increased prostacyclin synthesis, measured as 6-keto-prostaglandin1α (6-keto-PGF1α), in cultured coronary endothelial cells and freshly dissociated ventricular myocytes in a dose-dependent manner, but not in cultured coronary smooth muscle cells of rabbit heart. McN-A-343 {(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride}, a selective M1 muscarinic ACh receptor (mAChR) agonist, did not alter 6-keto-PGF1α synthesis in these cell types. ACh induced 6-keto-PGF1α synthesis in coronary endothelial cells and ventricular myocytes was not altered by a low concentration (0.01 μM) of pirenzepine, an M1 mAChR antagonist, but was reduced by a higher concentration (1 μM). In coronary endothelial cells, ACh-induced 6-keto-PGF1α production was reduced by hexahydrosila-difendial (HHSiD), an M3 mAChR antagonist, and in ventricular myocytes by both AF-DX 116 [11-{2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H-pyrido[2,3-b] -benzodiazepine-6 one}], an M2 receptor antagonist, and HHSiD. The decrease by ACh of isoproterenol-stimulated cAMP accumulation was minimized by AF-DX 116, but not by HHSiD or pirenzepine. Pertussis toxin treatment minimized ACh-induced decrease in isoproterenol-stimulated rise in cAMP, but not ACh-induced 6-keto-PGF1α synthesis. These data suggest that ACh stimulates prostacyclin production in coronary endothelial cells via M3 mAChR and in ventricular myocytes via M2 and M3 mAChR, and may contribute to its cardiprotective effects. Moreover, ACh induced decrease in cAMP, but not the increase in 6-Keto-PGF1α production, is mediated by pertussis toxin-sensitive Gαi proteins in these cells.",
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AU - Ruan, Y.

AU - Malik, Kafait

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N2 - The present study was conducted to localize and characterize the subtype(s) of muscarinic receptor involved in prostacyclin production elicited by the cholinergic transmitter acetylcholine (ACh) in various cell types in the rabbit heart. ACh increased prostacyclin synthesis, measured as 6-keto-prostaglandin1α (6-keto-PGF1α), in cultured coronary endothelial cells and freshly dissociated ventricular myocytes in a dose-dependent manner, but not in cultured coronary smooth muscle cells of rabbit heart. McN-A-343 {(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride}, a selective M1 muscarinic ACh receptor (mAChR) agonist, did not alter 6-keto-PGF1α synthesis in these cell types. ACh induced 6-keto-PGF1α synthesis in coronary endothelial cells and ventricular myocytes was not altered by a low concentration (0.01 μM) of pirenzepine, an M1 mAChR antagonist, but was reduced by a higher concentration (1 μM). In coronary endothelial cells, ACh-induced 6-keto-PGF1α production was reduced by hexahydrosila-difendial (HHSiD), an M3 mAChR antagonist, and in ventricular myocytes by both AF-DX 116 [11-{2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H-pyrido[2,3-b] -benzodiazepine-6 one}], an M2 receptor antagonist, and HHSiD. The decrease by ACh of isoproterenol-stimulated cAMP accumulation was minimized by AF-DX 116, but not by HHSiD or pirenzepine. Pertussis toxin treatment minimized ACh-induced decrease in isoproterenol-stimulated rise in cAMP, but not ACh-induced 6-keto-PGF1α synthesis. These data suggest that ACh stimulates prostacyclin production in coronary endothelial cells via M3 mAChR and in ventricular myocytes via M2 and M3 mAChR, and may contribute to its cardiprotective effects. Moreover, ACh induced decrease in cAMP, but not the increase in 6-Keto-PGF1α production, is mediated by pertussis toxin-sensitive Gαi proteins in these cells.

AB - The present study was conducted to localize and characterize the subtype(s) of muscarinic receptor involved in prostacyclin production elicited by the cholinergic transmitter acetylcholine (ACh) in various cell types in the rabbit heart. ACh increased prostacyclin synthesis, measured as 6-keto-prostaglandin1α (6-keto-PGF1α), in cultured coronary endothelial cells and freshly dissociated ventricular myocytes in a dose-dependent manner, but not in cultured coronary smooth muscle cells of rabbit heart. McN-A-343 {(4-hydroxy-2-butynyl)-1-trimethylammonium-m-chlorocarbanilate chloride}, a selective M1 muscarinic ACh receptor (mAChR) agonist, did not alter 6-keto-PGF1α synthesis in these cell types. ACh induced 6-keto-PGF1α synthesis in coronary endothelial cells and ventricular myocytes was not altered by a low concentration (0.01 μM) of pirenzepine, an M1 mAChR antagonist, but was reduced by a higher concentration (1 μM). In coronary endothelial cells, ACh-induced 6-keto-PGF1α production was reduced by hexahydrosila-difendial (HHSiD), an M3 mAChR antagonist, and in ventricular myocytes by both AF-DX 116 [11-{2-[(diethylamino)methyl]-1-piperidinyl]acetyl-5,11-dihydro-6H-pyrido[2,3-b] -benzodiazepine-6 one}], an M2 receptor antagonist, and HHSiD. The decrease by ACh of isoproterenol-stimulated cAMP accumulation was minimized by AF-DX 116, but not by HHSiD or pirenzepine. Pertussis toxin treatment minimized ACh-induced decrease in isoproterenol-stimulated rise in cAMP, but not ACh-induced 6-keto-PGF1α synthesis. These data suggest that ACh stimulates prostacyclin production in coronary endothelial cells via M3 mAChR and in ventricular myocytes via M2 and M3 mAChR, and may contribute to its cardiprotective effects. Moreover, ACh induced decrease in cAMP, but not the increase in 6-Keto-PGF1α production, is mediated by pertussis toxin-sensitive Gαi proteins in these cells.

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