TY - JOUR
T1 - Interaction of the antiarrhythmic drug amiodarone with the muscarinic receptor in rat heart and brain
AU - Cohen-Armon, Malca
AU - Schreiber, Gabriel
AU - Sokolovsky, Mordechai
PY - 1984
Y1 - 1984
N2 - The possible interaction between the muscarinic receptor and the antiarrhythmic drug amiodarone was studied physiologically in the guinea pig ileum, as well as by competition binding experiments in rat brain and cardiac tissues, using the highly specific tritiated muscarinic antagonist N-methyl-4-piperidyl benzilate. In these studies, amiodarone was found to affect both antagonist and agonist binding to the muscarinic receptor. The drug’s inhibitory effect on the binding of antagonist to cerebral cortex muscarinic receptors was consistent with mutually exclusive binding of the compounds [K1 = (1.0 ± 0.2)10-5 M]. On the other hand, in the brain stem and in cardiac tissues (atrium and ventricle) the inhibitory effect on the binding of muscarinic antagonist could not be fitted to a simple model of competitive inhibition. The possible mode of interaction is discussed. Compared with its activity in the cerebral cortex, amiodarone was a more potent inhibitor of muscarinic antagonist binding in the brain stem and in the atrium and ventricle of the heart [apparent K1 values were (6.5 ± 0.1)10-6, (4.0 ± 0.1)10-6, and (4.0 ± 0.1)10-6 M, respectively]. In view of the K1 values and the serum concentration of amiodarone observed therapeutically (10-6 M), the effect of amiodarone on the muscarinic system may have clinical relevance. In both the brain stem and the cardiac preparations, amiodarone converted sites that bind agonist with high affinity into low-affinity sites. Agonist binding in the cerebral cortex was not affected.
AB - The possible interaction between the muscarinic receptor and the antiarrhythmic drug amiodarone was studied physiologically in the guinea pig ileum, as well as by competition binding experiments in rat brain and cardiac tissues, using the highly specific tritiated muscarinic antagonist N-methyl-4-piperidyl benzilate. In these studies, amiodarone was found to affect both antagonist and agonist binding to the muscarinic receptor. The drug’s inhibitory effect on the binding of antagonist to cerebral cortex muscarinic receptors was consistent with mutually exclusive binding of the compounds [K1 = (1.0 ± 0.2)10-5 M]. On the other hand, in the brain stem and in cardiac tissues (atrium and ventricle) the inhibitory effect on the binding of muscarinic antagonist could not be fitted to a simple model of competitive inhibition. The possible mode of interaction is discussed. Compared with its activity in the cerebral cortex, amiodarone was a more potent inhibitor of muscarinic antagonist binding in the brain stem and in the atrium and ventricle of the heart [apparent K1 values were (6.5 ± 0.1)10-6, (4.0 ± 0.1)10-6, and (4.0 ± 0.1)10-6 M, respectively]. In view of the K1 values and the serum concentration of amiodarone observed therapeutically (10-6 M), the effect of amiodarone on the muscarinic system may have clinical relevance. In both the brain stem and the cardiac preparations, amiodarone converted sites that bind agonist with high affinity into low-affinity sites. Agonist binding in the cerebral cortex was not affected.
KW - Amiodarone
KW - Antagonist and agonist binding
KW - Guinea pig
KW - Mode of interaction
KW - Muscarinic receptor
KW - Rat
UR - http://www.scopus.com/inward/record.url?scp=0021720487&partnerID=8YFLogxK
U2 - 10.1097/00005344-198411000-00023
DO - 10.1097/00005344-198411000-00023
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AN - SCOPUS:0021720487
SN - 0160-2446
VL - 6
SP - 1148
EP - 1155
JO - Journal of Cardiovascular Pharmacology
JF - Journal of Cardiovascular Pharmacology
IS - 6
ER -