Molecular mechanism of cibenzoline-induced anticholinergic action in single atrial myocytes

Comparison with effect of disopyramide

Sheng-Nan Wu, T. Nakajima, T. Yamashita, E. Hamada, H. Hazama, K. Iwasawa, M. Omata, Y. Kurachi

Research output: Contribution to journalArticle

32 Citations (Scopus)

Abstract

The anticholinergic effects of cibenzoline were examined and compared with those of disopyramide in atrial myocytes isolated from guinea pig heart. The tight-seal whole-cell voltage clamp technique was performed with a patch pipette filled with guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3- thiotriphosphate) (GTPγS). In GTP-loaded cells, both acetylcholine (ACh) and adenosine (Ado) induced a specific K channel current through GTP-binding proteins by binding to the muscarinic and Ado receptors, respectively. Both cibenzoline and disopyramide suppressed the ACh-induced K current effectively in a concentration-dependent manner. The concentrations for half-maximal inhibition of the current (EC 50 ) caused by cibenzoline and disopyramide were 8 and 3 μM, respectively. In GTPγS-loaded cells, the K current was irreversibly activated because GTP binding proteins were directly elicited by GTPγS. Cibenzoline effectively caused a decrease in the GTPγS-induced K current, whereas the extent of disopyramide action on the GTPγS-induced K current was much less. Cibenzoline also caused significant inhibition of Ado- induced K current in GTP-loaded cells. However, the action of disopyramide was less effective in inhibiting Ado-induced K current. These results indicate that cibenzoline has less potent anticholinergic effects than disopyramide in atrial myocytes. In addition, cibenzoline effectively inhibits the muscarinic K channel itself and/or GTP-binding proteins coupled to the channel, whereas the effect of disopyramide is attributed mainly to blockade of muscarinic receptors. These findings provide novel understanding of the molecular mechanism of anticholinergic action of cibenzoline.

Original languageEnglish
Pages (from-to)618-623
Number of pages6
JournalJournal of Cardiovascular Pharmacology
Volume23
Issue number4
DOIs
Publication statusPublished - 1994 Jan 1

Fingerprint

Disopyramide
Cholinergic Antagonists
Guanosine Triphosphate
Muscle Cells
Guanosine 5'-O-(3-Thiotriphosphate)
Adenosine
Carrier Proteins
Muscarinic Receptors
Acetylcholine
cifenline
Purinergic P1 Receptors
Patch-Clamp Techniques
Protein Binding
Cholinergic Agents
Guinea Pigs

All Science Journal Classification (ASJC) codes

  • Pharmacology
  • Cardiology and Cardiovascular Medicine

Cite this

Wu, Sheng-Nan ; Nakajima, T. ; Yamashita, T. ; Hamada, E. ; Hazama, H. ; Iwasawa, K. ; Omata, M. ; Kurachi, Y. / Molecular mechanism of cibenzoline-induced anticholinergic action in single atrial myocytes : Comparison with effect of disopyramide. In: Journal of Cardiovascular Pharmacology. 1994 ; Vol. 23, No. 4. pp. 618-623.
@article{410efaa5b2a243d98bf6404e153714c1,
title = "Molecular mechanism of cibenzoline-induced anticholinergic action in single atrial myocytes: Comparison with effect of disopyramide",
abstract = "The anticholinergic effects of cibenzoline were examined and compared with those of disopyramide in atrial myocytes isolated from guinea pig heart. The tight-seal whole-cell voltage clamp technique was performed with a patch pipette filled with guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3- thiotriphosphate) (GTPγS). In GTP-loaded cells, both acetylcholine (ACh) and adenosine (Ado) induced a specific K channel current through GTP-binding proteins by binding to the muscarinic and Ado receptors, respectively. Both cibenzoline and disopyramide suppressed the ACh-induced K current effectively in a concentration-dependent manner. The concentrations for half-maximal inhibition of the current (EC 50 ) caused by cibenzoline and disopyramide were 8 and 3 μM, respectively. In GTPγS-loaded cells, the K current was irreversibly activated because GTP binding proteins were directly elicited by GTPγS. Cibenzoline effectively caused a decrease in the GTPγS-induced K current, whereas the extent of disopyramide action on the GTPγS-induced K current was much less. Cibenzoline also caused significant inhibition of Ado- induced K current in GTP-loaded cells. However, the action of disopyramide was less effective in inhibiting Ado-induced K current. These results indicate that cibenzoline has less potent anticholinergic effects than disopyramide in atrial myocytes. In addition, cibenzoline effectively inhibits the muscarinic K channel itself and/or GTP-binding proteins coupled to the channel, whereas the effect of disopyramide is attributed mainly to blockade of muscarinic receptors. These findings provide novel understanding of the molecular mechanism of anticholinergic action of cibenzoline.",
author = "Sheng-Nan Wu and T. Nakajima and T. Yamashita and E. Hamada and H. Hazama and K. Iwasawa and M. Omata and Y. Kurachi",
year = "1994",
month = "1",
day = "1",
doi = "10.1097/00005344-199404000-00014",
language = "English",
volume = "23",
pages = "618--623",
journal = "Journal of Cardiovascular Pharmacology",
issn = "0160-2446",
publisher = "Lippincott Williams and Wilkins",
number = "4",

}

Molecular mechanism of cibenzoline-induced anticholinergic action in single atrial myocytes : Comparison with effect of disopyramide. / Wu, Sheng-Nan; Nakajima, T.; Yamashita, T.; Hamada, E.; Hazama, H.; Iwasawa, K.; Omata, M.; Kurachi, Y.

In: Journal of Cardiovascular Pharmacology, Vol. 23, No. 4, 01.01.1994, p. 618-623.

Research output: Contribution to journalArticle

TY - JOUR

T1 - Molecular mechanism of cibenzoline-induced anticholinergic action in single atrial myocytes

T2 - Comparison with effect of disopyramide

AU - Wu, Sheng-Nan

AU - Nakajima, T.

AU - Yamashita, T.

AU - Hamada, E.

AU - Hazama, H.

AU - Iwasawa, K.

AU - Omata, M.

AU - Kurachi, Y.

PY - 1994/1/1

Y1 - 1994/1/1

N2 - The anticholinergic effects of cibenzoline were examined and compared with those of disopyramide in atrial myocytes isolated from guinea pig heart. The tight-seal whole-cell voltage clamp technique was performed with a patch pipette filled with guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3- thiotriphosphate) (GTPγS). In GTP-loaded cells, both acetylcholine (ACh) and adenosine (Ado) induced a specific K channel current through GTP-binding proteins by binding to the muscarinic and Ado receptors, respectively. Both cibenzoline and disopyramide suppressed the ACh-induced K current effectively in a concentration-dependent manner. The concentrations for half-maximal inhibition of the current (EC 50 ) caused by cibenzoline and disopyramide were 8 and 3 μM, respectively. In GTPγS-loaded cells, the K current was irreversibly activated because GTP binding proteins were directly elicited by GTPγS. Cibenzoline effectively caused a decrease in the GTPγS-induced K current, whereas the extent of disopyramide action on the GTPγS-induced K current was much less. Cibenzoline also caused significant inhibition of Ado- induced K current in GTP-loaded cells. However, the action of disopyramide was less effective in inhibiting Ado-induced K current. These results indicate that cibenzoline has less potent anticholinergic effects than disopyramide in atrial myocytes. In addition, cibenzoline effectively inhibits the muscarinic K channel itself and/or GTP-binding proteins coupled to the channel, whereas the effect of disopyramide is attributed mainly to blockade of muscarinic receptors. These findings provide novel understanding of the molecular mechanism of anticholinergic action of cibenzoline.

AB - The anticholinergic effects of cibenzoline were examined and compared with those of disopyramide in atrial myocytes isolated from guinea pig heart. The tight-seal whole-cell voltage clamp technique was performed with a patch pipette filled with guanosine-5'-triphosphate (GTP) or guanosine-5'-O-(3- thiotriphosphate) (GTPγS). In GTP-loaded cells, both acetylcholine (ACh) and adenosine (Ado) induced a specific K channel current through GTP-binding proteins by binding to the muscarinic and Ado receptors, respectively. Both cibenzoline and disopyramide suppressed the ACh-induced K current effectively in a concentration-dependent manner. The concentrations for half-maximal inhibition of the current (EC 50 ) caused by cibenzoline and disopyramide were 8 and 3 μM, respectively. In GTPγS-loaded cells, the K current was irreversibly activated because GTP binding proteins were directly elicited by GTPγS. Cibenzoline effectively caused a decrease in the GTPγS-induced K current, whereas the extent of disopyramide action on the GTPγS-induced K current was much less. Cibenzoline also caused significant inhibition of Ado- induced K current in GTP-loaded cells. However, the action of disopyramide was less effective in inhibiting Ado-induced K current. These results indicate that cibenzoline has less potent anticholinergic effects than disopyramide in atrial myocytes. In addition, cibenzoline effectively inhibits the muscarinic K channel itself and/or GTP-binding proteins coupled to the channel, whereas the effect of disopyramide is attributed mainly to blockade of muscarinic receptors. These findings provide novel understanding of the molecular mechanism of anticholinergic action of cibenzoline.

UR - http://www.scopus.com/inward/record.url?scp=0028348651&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0028348651&partnerID=8YFLogxK

U2 - 10.1097/00005344-199404000-00014

DO - 10.1097/00005344-199404000-00014

M3 - Article

VL - 23

SP - 618

EP - 623

JO - Journal of Cardiovascular Pharmacology

JF - Journal of Cardiovascular Pharmacology

SN - 0160-2446

IS - 4

ER -