Inhibition of M-current in cultured rat superior cervical ganglia by linopirdine: mechanism of action studies.
The mechanism involved in the blockade of M-current by linopirdine was studied in cultured rat superior cervical sympathetic ganglia using whole-cell patch clamp recording. The effects of modulators of intracellular signal transduction pathways on muscarine- or linopirdine-induced inhibition of M-current were compared. Intracellular addition of GDP-beta-S (500 microM) attenuated M-current block by muscarine (1 microM) but not that of linopirdine (10 microM). Intracellular dialysis of GTP-gamma)-S (100 microM) enhanced and prolonged muscarine-induced inhibition of M-current but had no effect on the activity of linopirdine. Intracellular BAPTA (20 mM) also inhibited the effects of muscarine without affecting those of linopirdine. Intracellular application of linopirdine had no effect on either basal M-current amplitude or the ability of linopirdine to block M-current when administered extracellularly. These results indicate that M-current inhibition by linopirdine is unlikely to be either G-protein-mediated or calcium-mediated or to involve an intracellular site of action and are, therefore, consistent with a direct block of the M-channel from its extracellular side.
Costa
A M
AM
CNS Diseases Research, DuPont Merck Research Laboratories, Wilmington, DE 19880-0400, USA.
Brown
B S
BS
D000818:Animals; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D002614:Chelating Agents / Q000494:pharmacology; D004533:Egtazic Acid / Q000031:analogs & derivatives / Q000494:pharmacology; D004558:Electric Stimulation; D004594:Electrophysiology; D019204:GTP-Binding Proteins / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D018727:Muscarinic Antagonists / Q000494:pharmacology*; D018408:Patch-Clamp Techniques; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011976:Receptors, Muscarinic / Q000187:drug effects*; D017783:Superior Cervical Ganglion / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*
D002614:Chelating Agents; D007211:Indoles; D018727:Muscarinic Antagonists; D011725:Pyridines; D011976:Receptors, Muscarinic; D004533:Egtazic Acid; D019204:GTP-Binding Proteins; C061017:linopirdine; C025603:1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid; D002118:Calcium