Prostaglandin synthesis elicited by cholinergic stimuli is mediated by activation of M2 muscarinic receptors in rabbit heart

N. Jaiswal, Kafait Malik

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Abstract

This study was performed to determine the subtype of muscarinic receptors involved in the action of cholinergic stimuli on prostaglandin (PG) synthesis in the isolated rabbit heart perfused at a constant flow rate with Krebs Hanseleit buffer. Acetylcholine (ACh, 1.0-10.0 nmol), and M1 and M2 receptor agonist, and arecaidine propargyl ester (APE, 1.0-5.0 nmol), a selective M2 agonist, produced a dose-related increase in the output of 6-keto-PGF(1α) and a decrease in heart rate, whereas 4-[m-chlorophenyl carbamoyl]-2-butynyl-trimethylammonium chloride (McN-A-343, 10 nmol-1.0 μmol), a selective M1 receptor agonist, did not alter PG output. The increase in PG output or the decrease in heart rate elicited by ACh or APE was abolished by atropine (0.1 μM), and M1 and M2 receptor antagonist, and by 11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6-H-pyrido-[2,3-b] [1,4]-benzodiazepine-6-one (AF-DX-116, 1.0 μM), a selective M2 antagonist, but not by pirenzepine (1.0 μM), a selective M1 antagonist. The developed tension, which was also reduced by ACh and APE, but not by McN-A-343, was minimized by AF-DX-116 and not by lower concentrations of pirenzepine that attenuated the coronary vasodilator effect of McN-A-343. Lower doses of ACh (1.0-5.0 nmol) caused coronary vasodilation, whereas higher doses of ACh (10.0 nmol) and lower as well as higher doses of APE produced a biphasic effect - an initial vasodilation followed by vasoconstriction. The vasodilatory effect of these cholinergic agents was inhibited by atropine, AF-DX-116, and pirenzepine, whereas the vasoconstrictor component of the response was blocked by atropine and AF-DX-116 but not by pirenzepine. PG output or the changes in the mechanical parameters produced by cholinergic agonists were not altered by adrenergic receptor antagonists, phentolamine and propranolol, or by the nicotinic receptor antagonist, hexamethonium. The effect of isoproterenol or exogenous arachidonic acid to enhance PG output was not altered by pirenzepine or AF-DX-116; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by muscarinic receptor agonists. These data indicate that cardiac PG synthesis, decrease in heart rate and developed tension, and the coronary vasoconstrictor component of the response elicited by cholinergic stimuli are linked to M2 muscarinic receptors, whereas the cholinergically induced vasodilator component of the coronary response is mediated through activation of a distinct subtype of M1 or M2 muscarinic receptors.

Original languageEnglish (US)
Pages (from-to)59-66
Number of pages8
JournalJournal of Pharmacology and Experimental Therapeutics
Volume245
Issue number1
StatePublished - 1988

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Muscarinic M2 Receptors
Pirenzepine
Cholinergic Agents
Prostaglandins
Rabbits
(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride
Atropine
Heart Rate
Vasoconstrictor Agents
Muscarinic Receptors
Vasodilator Agents
Vasodilation
Muscarinic M1 Receptors
Nicotinic Antagonists
Cholinergic Agonists
Muscarinic Agonists
Hexamethonium
Adrenergic Antagonists
Cyclooxygenase Inhibitors
Phentolamine

All Science Journal Classification (ASJC) codes

  • Pharmacology

Cite this

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title = "Prostaglandin synthesis elicited by cholinergic stimuli is mediated by activation of M2 muscarinic receptors in rabbit heart",
abstract = "This study was performed to determine the subtype of muscarinic receptors involved in the action of cholinergic stimuli on prostaglandin (PG) synthesis in the isolated rabbit heart perfused at a constant flow rate with Krebs Hanseleit buffer. Acetylcholine (ACh, 1.0-10.0 nmol), and M1 and M2 receptor agonist, and arecaidine propargyl ester (APE, 1.0-5.0 nmol), a selective M2 agonist, produced a dose-related increase in the output of 6-keto-PGF(1α) and a decrease in heart rate, whereas 4-[m-chlorophenyl carbamoyl]-2-butynyl-trimethylammonium chloride (McN-A-343, 10 nmol-1.0 μmol), a selective M1 receptor agonist, did not alter PG output. The increase in PG output or the decrease in heart rate elicited by ACh or APE was abolished by atropine (0.1 μM), and M1 and M2 receptor antagonist, and by 11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6-H-pyrido-[2,3-b] [1,4]-benzodiazepine-6-one (AF-DX-116, 1.0 μM), a selective M2 antagonist, but not by pirenzepine (1.0 μM), a selective M1 antagonist. The developed tension, which was also reduced by ACh and APE, but not by McN-A-343, was minimized by AF-DX-116 and not by lower concentrations of pirenzepine that attenuated the coronary vasodilator effect of McN-A-343. Lower doses of ACh (1.0-5.0 nmol) caused coronary vasodilation, whereas higher doses of ACh (10.0 nmol) and lower as well as higher doses of APE produced a biphasic effect - an initial vasodilation followed by vasoconstriction. The vasodilatory effect of these cholinergic agents was inhibited by atropine, AF-DX-116, and pirenzepine, whereas the vasoconstrictor component of the response was blocked by atropine and AF-DX-116 but not by pirenzepine. PG output or the changes in the mechanical parameters produced by cholinergic agonists were not altered by adrenergic receptor antagonists, phentolamine and propranolol, or by the nicotinic receptor antagonist, hexamethonium. The effect of isoproterenol or exogenous arachidonic acid to enhance PG output was not altered by pirenzepine or AF-DX-116; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by muscarinic receptor agonists. These data indicate that cardiac PG synthesis, decrease in heart rate and developed tension, and the coronary vasoconstrictor component of the response elicited by cholinergic stimuli are linked to M2 muscarinic receptors, whereas the cholinergically induced vasodilator component of the coronary response is mediated through activation of a distinct subtype of M1 or M2 muscarinic receptors.",
author = "N. Jaiswal and Kafait Malik",
year = "1988",
language = "English (US)",
volume = "245",
pages = "59--66",
journal = "Journal of Pharmacology and Experimental Therapeutics",
issn = "0022-3565",
publisher = "American Society for Pharmacology and Experimental Therapeutics",
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TY - JOUR

T1 - Prostaglandin synthesis elicited by cholinergic stimuli is mediated by activation of M2 muscarinic receptors in rabbit heart

AU - Jaiswal, N.

AU - Malik, Kafait

PY - 1988

Y1 - 1988

N2 - This study was performed to determine the subtype of muscarinic receptors involved in the action of cholinergic stimuli on prostaglandin (PG) synthesis in the isolated rabbit heart perfused at a constant flow rate with Krebs Hanseleit buffer. Acetylcholine (ACh, 1.0-10.0 nmol), and M1 and M2 receptor agonist, and arecaidine propargyl ester (APE, 1.0-5.0 nmol), a selective M2 agonist, produced a dose-related increase in the output of 6-keto-PGF(1α) and a decrease in heart rate, whereas 4-[m-chlorophenyl carbamoyl]-2-butynyl-trimethylammonium chloride (McN-A-343, 10 nmol-1.0 μmol), a selective M1 receptor agonist, did not alter PG output. The increase in PG output or the decrease in heart rate elicited by ACh or APE was abolished by atropine (0.1 μM), and M1 and M2 receptor antagonist, and by 11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6-H-pyrido-[2,3-b] [1,4]-benzodiazepine-6-one (AF-DX-116, 1.0 μM), a selective M2 antagonist, but not by pirenzepine (1.0 μM), a selective M1 antagonist. The developed tension, which was also reduced by ACh and APE, but not by McN-A-343, was minimized by AF-DX-116 and not by lower concentrations of pirenzepine that attenuated the coronary vasodilator effect of McN-A-343. Lower doses of ACh (1.0-5.0 nmol) caused coronary vasodilation, whereas higher doses of ACh (10.0 nmol) and lower as well as higher doses of APE produced a biphasic effect - an initial vasodilation followed by vasoconstriction. The vasodilatory effect of these cholinergic agents was inhibited by atropine, AF-DX-116, and pirenzepine, whereas the vasoconstrictor component of the response was blocked by atropine and AF-DX-116 but not by pirenzepine. PG output or the changes in the mechanical parameters produced by cholinergic agonists were not altered by adrenergic receptor antagonists, phentolamine and propranolol, or by the nicotinic receptor antagonist, hexamethonium. The effect of isoproterenol or exogenous arachidonic acid to enhance PG output was not altered by pirenzepine or AF-DX-116; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by muscarinic receptor agonists. These data indicate that cardiac PG synthesis, decrease in heart rate and developed tension, and the coronary vasoconstrictor component of the response elicited by cholinergic stimuli are linked to M2 muscarinic receptors, whereas the cholinergically induced vasodilator component of the coronary response is mediated through activation of a distinct subtype of M1 or M2 muscarinic receptors.

AB - This study was performed to determine the subtype of muscarinic receptors involved in the action of cholinergic stimuli on prostaglandin (PG) synthesis in the isolated rabbit heart perfused at a constant flow rate with Krebs Hanseleit buffer. Acetylcholine (ACh, 1.0-10.0 nmol), and M1 and M2 receptor agonist, and arecaidine propargyl ester (APE, 1.0-5.0 nmol), a selective M2 agonist, produced a dose-related increase in the output of 6-keto-PGF(1α) and a decrease in heart rate, whereas 4-[m-chlorophenyl carbamoyl]-2-butynyl-trimethylammonium chloride (McN-A-343, 10 nmol-1.0 μmol), a selective M1 receptor agonist, did not alter PG output. The increase in PG output or the decrease in heart rate elicited by ACh or APE was abolished by atropine (0.1 μM), and M1 and M2 receptor antagonist, and by 11-[2-[(diethylamino)methyl]-1-piperidinyl]acetyl]-5, 11-dihydro-6-H-pyrido-[2,3-b] [1,4]-benzodiazepine-6-one (AF-DX-116, 1.0 μM), a selective M2 antagonist, but not by pirenzepine (1.0 μM), a selective M1 antagonist. The developed tension, which was also reduced by ACh and APE, but not by McN-A-343, was minimized by AF-DX-116 and not by lower concentrations of pirenzepine that attenuated the coronary vasodilator effect of McN-A-343. Lower doses of ACh (1.0-5.0 nmol) caused coronary vasodilation, whereas higher doses of ACh (10.0 nmol) and lower as well as higher doses of APE produced a biphasic effect - an initial vasodilation followed by vasoconstriction. The vasodilatory effect of these cholinergic agents was inhibited by atropine, AF-DX-116, and pirenzepine, whereas the vasoconstrictor component of the response was blocked by atropine and AF-DX-116 but not by pirenzepine. PG output or the changes in the mechanical parameters produced by cholinergic agonists were not altered by adrenergic receptor antagonists, phentolamine and propranolol, or by the nicotinic receptor antagonist, hexamethonium. The effect of isoproterenol or exogenous arachidonic acid to enhance PG output was not altered by pirenzepine or AF-DX-116; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by muscarinic receptor agonists. These data indicate that cardiac PG synthesis, decrease in heart rate and developed tension, and the coronary vasoconstrictor component of the response elicited by cholinergic stimuli are linked to M2 muscarinic receptors, whereas the cholinergically induced vasodilator component of the coronary response is mediated through activation of a distinct subtype of M1 or M2 muscarinic receptors.

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