Contribution of M(2α) and M(2β) muscarinic receptors to the action of cholinergic stimuli on prostaglandin synthesis and mechanical function in the isolated rabbit heart

N. Jaiswal, G. Lambrecht, E. Mutschler, Kafait Malik

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Abstract

This study was performed to determine the subtype of M2 muscarinic receptor that is involved in the action of cholinergic agents on prostaglandin (PG) synthesis as well as on the mechanical function of the isolated rabbit heart perfused at a constant flow rate with Krebs-Henseleit buffer. The increase in PG output elicited by acetylcholine (ACh) or arecaidine propargyl ester (APE), a selective M2 agonist was attenuated by both piperidinyl]acetyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one (AF-DX 116), an M(2α) antagonist, and hexahydro-sila-difendiol (HHSiD), an M(2β) antagonist. The coronary vasodilating effect of ACh and APE was inhibited by HHSiD, but not by AF-DX 116, whereas the vasoconstrictor effect was blocked by AF-DX 116, but not by HHSiD. The decrease in heart rate produced by ACh or APE was blocked by AF-DX 116, but not by HHSiD; however, the decrease in developed tension produced by the cholinergic stimuli was abolished by all these muscarinic receptor antagonists. The increase in PG output or changes in the mechanical parameters of the heart produced by ACh or APE 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 these M2 receptor antagonists; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by ACh or APE. These data indicate that the effect of cholinergic stimuli to promote cardiac PG synthesis and decrease developed tension is mediated through the activation of both M(2α) and M(2β) subtypes of muscarinic receptors. The cholinergically induced vasodilating component of the coronary response is mediated through the activation of M(2β), whereas the coronary vasoconstriction and the decrease in heart rate is mediated through the activation of M(2α) muscarinic receptors.

Original languageEnglish (US)
Pages (from-to)104-113
Number of pages10
JournalJournal of Pharmacology and Experimental Therapeutics
Volume247
Issue number1
StatePublished - Jan 1 1988

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Muscarinic Receptors
Cholinergic Agents
Prostaglandins
Rabbits
Acetylcholine
Heart Rate
Muscarinic M2 Receptors
Nicotinic Antagonists
Hexamethonium
Muscarinic Antagonists
Adrenergic Antagonists
Cyclooxygenase Inhibitors
Phentolamine
Nicotinic Receptors
Vasoconstrictor Agents
Vasoconstriction
Isoproterenol
Arachidonic Acid
Propranolol
Indomethacin

All Science Journal Classification (ASJC) codes

  • Molecular Medicine
  • Pharmacology

Cite this

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title = "Contribution of M(2α) and M(2β) muscarinic receptors to the action of cholinergic stimuli on prostaglandin synthesis and mechanical function in the isolated rabbit heart",
abstract = "This study was performed to determine the subtype of M2 muscarinic receptor that is involved in the action of cholinergic agents on prostaglandin (PG) synthesis as well as on the mechanical function of the isolated rabbit heart perfused at a constant flow rate with Krebs-Henseleit buffer. The increase in PG output elicited by acetylcholine (ACh) or arecaidine propargyl ester (APE), a selective M2 agonist was attenuated by both piperidinyl]acetyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one (AF-DX 116), an M(2α) antagonist, and hexahydro-sila-difendiol (HHSiD), an M(2β) antagonist. The coronary vasodilating effect of ACh and APE was inhibited by HHSiD, but not by AF-DX 116, whereas the vasoconstrictor effect was blocked by AF-DX 116, but not by HHSiD. The decrease in heart rate produced by ACh or APE was blocked by AF-DX 116, but not by HHSiD; however, the decrease in developed tension produced by the cholinergic stimuli was abolished by all these muscarinic receptor antagonists. The increase in PG output or changes in the mechanical parameters of the heart produced by ACh or APE 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 these M2 receptor antagonists; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by ACh or APE. These data indicate that the effect of cholinergic stimuli to promote cardiac PG synthesis and decrease developed tension is mediated through the activation of both M(2α) and M(2β) subtypes of muscarinic receptors. The cholinergically induced vasodilating component of the coronary response is mediated through the activation of M(2β), whereas the coronary vasoconstriction and the decrease in heart rate is mediated through the activation of M(2α) muscarinic receptors.",
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T1 - Contribution of M(2α) and M(2β) muscarinic receptors to the action of cholinergic stimuli on prostaglandin synthesis and mechanical function in the isolated rabbit heart

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AU - Lambrecht, G.

AU - Mutschler, E.

AU - Malik, Kafait

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N2 - This study was performed to determine the subtype of M2 muscarinic receptor that is involved in the action of cholinergic agents on prostaglandin (PG) synthesis as well as on the mechanical function of the isolated rabbit heart perfused at a constant flow rate with Krebs-Henseleit buffer. The increase in PG output elicited by acetylcholine (ACh) or arecaidine propargyl ester (APE), a selective M2 agonist was attenuated by both piperidinyl]acetyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one (AF-DX 116), an M(2α) antagonist, and hexahydro-sila-difendiol (HHSiD), an M(2β) antagonist. The coronary vasodilating effect of ACh and APE was inhibited by HHSiD, but not by AF-DX 116, whereas the vasoconstrictor effect was blocked by AF-DX 116, but not by HHSiD. The decrease in heart rate produced by ACh or APE was blocked by AF-DX 116, but not by HHSiD; however, the decrease in developed tension produced by the cholinergic stimuli was abolished by all these muscarinic receptor antagonists. The increase in PG output or changes in the mechanical parameters of the heart produced by ACh or APE 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 these M2 receptor antagonists; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by ACh or APE. These data indicate that the effect of cholinergic stimuli to promote cardiac PG synthesis and decrease developed tension is mediated through the activation of both M(2α) and M(2β) subtypes of muscarinic receptors. The cholinergically induced vasodilating component of the coronary response is mediated through the activation of M(2β), whereas the coronary vasoconstriction and the decrease in heart rate is mediated through the activation of M(2α) muscarinic receptors.

AB - This study was performed to determine the subtype of M2 muscarinic receptor that is involved in the action of cholinergic agents on prostaglandin (PG) synthesis as well as on the mechanical function of the isolated rabbit heart perfused at a constant flow rate with Krebs-Henseleit buffer. The increase in PG output elicited by acetylcholine (ACh) or arecaidine propargyl ester (APE), a selective M2 agonist was attenuated by both piperidinyl]acetyl-5,11-dihydro-6H-pyrido-[2,3-b][1,4]-benzodiazepine-6-one (AF-DX 116), an M(2α) antagonist, and hexahydro-sila-difendiol (HHSiD), an M(2β) antagonist. The coronary vasodilating effect of ACh and APE was inhibited by HHSiD, but not by AF-DX 116, whereas the vasoconstrictor effect was blocked by AF-DX 116, but not by HHSiD. The decrease in heart rate produced by ACh or APE was blocked by AF-DX 116, but not by HHSiD; however, the decrease in developed tension produced by the cholinergic stimuli was abolished by all these muscarinic receptor antagonists. The increase in PG output or changes in the mechanical parameters of the heart produced by ACh or APE 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 these M2 receptor antagonists; however, the cyclooxygenase inhibitor indomethacin abolished the output of PG elicited by these agents or by ACh or APE. These data indicate that the effect of cholinergic stimuli to promote cardiac PG synthesis and decrease developed tension is mediated through the activation of both M(2α) and M(2β) subtypes of muscarinic receptors. The cholinergically induced vasodilating component of the coronary response is mediated through the activation of M(2β), whereas the coronary vasoconstriction and the decrease in heart rate is mediated through the activation of M(2α) muscarinic receptors.

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