Summary
Effects of verapamil on the acetylcholine (ACh)-induced K+ current were examined in single atrial cells, using the tight-seal whole-cell clamp technique. The pipette solution contained guanosine-5′-triphosphate (GTP) or guanosine-5′-O-(3-thiotriphosphate) (GTP-γS, a non-hydrolysable GTP analogue). In GTP-loaded cells, ACh induced a specific K+ current, which is known to be mediated by pertussis toxin-sensitive GTP-binding (G) proteins. Verapamil (0.1–100 μM) depressed the ACh-induced K+ current in a concentration-dependent fashion. In GTP-γS-loaded cells, the K+ current remained persistently after wash-out of ACh, probably due to irreversible activation of G proteins by GTP-γS. Verapamil (0.1–100 μM) also depressed the intracellular GTP-γS-induced K+ current. However, the magnitude of verapamil-depression of the K+ current in GTP-γS-loaded cells was significantly smaller than that in GTP-loaded cells at concentrations between 1 and 10 μM of the drug. From these results, it is suggested that verapamil may block not only the function of muscarinic ACh receptors but also of G proteins and/or the K+ channel itself and thereby depress the ACh-induced K+ current in isolated atrial myocytes.
References
Breitwieser GE, Szabo G (1985) Uncoupling of cardiac muscarinic and β-adrenergic receptors from ion channels by a guanine nucleotide analogue. Nature 317:536–538
Carmeliet, E, Mubagwa K (1986) Desensitization of the acetylcholine-induced increase of potassium conductance in rabbit cardiac Purkinje fibres. J Physiol (Lond) 371:239–255
Cavey D, Vincent JP, Lazdunski M (1977) The muscarinic receptor of heart cell membranes. FEBS Lett 84:110–114
Fleckenstein A (1977) Specific pharmacology of calcium in myocardium, cardiac pacemakers, and vascular smooth muscle. Ann Rev Pharmacol Toxicol 17:149–166
Garvey HL (1969) The mechanism of action of verapamil on the sinus and AV nodes. Eur J Pharmacol 8:159–166
Hamill OP, Marty A, Neher E, Sakmann B, Sigworth FJ (1981) Improved patch-clamp techniques for high-resolution current recordings from cells and cell-free membrane patches. Pflügers Arch 391:85–100
Isenberg G, Klöckner U (1981) Calcium tolerant ventricular myocytes prepared by preincubation in a “KB medium”. Pflügers Arch 395:6–18
Kurachi Y, Nakajima T, Sugimoto T (1986) On the mechanisms of activation of muscarinic K+ channels by adenosine in isolated atrial cells: involvement of GTP-binding proteins. Pflügers Arch 407:264–274
Karachi Y, Nakajima T, Sugimoto T (1987a) Quinidine inhibition of the muscarine receptor-activated K+ channel current in atrial cells of guinea pig. Naunyn-Schmiedeberg's Arch Pharmacol 335:316–318
Kurachi Y, Nakajima T, Sugimoto T (1987b) Short-term desensitization of muscarinic K+ channel current in isolated atrial myocytes and possible role of GTP-binding proteins. Pflügers Arch 410:227–233
Melville KI, Garvey HL, Shister HE (1968) On the cardiac adrenergic blocking action of iproveratil in normal and coronary-ligated dogs. Revue Can Biol27:225
Nakajima T, Kurachi Y, Ito H, Takikawa R, Sugimoto T (1989) Anti-cholinergic effects of quinidine, disopyramide and procainamide in isolated atrial myocytes: Mediation by different molecular mechanisms. Circ Res (in press)
Pfaffinger PJ, Martin JM, Hunter DD, Nathanson NM, Hille B (1985) GTP-binding proteins couple cardiac muscarinic receptors to a K channel. Nature 317:538–540
Timour-Chah Q, Lang J, Lakhal M, Bouzouita K, Bertrix L, Faucon G (1983) Blockade by verapamil of cholinergic effects on atrial specialized tissue in the anaesthetised dog. Cardiovasc Res 17:756–761
Author information
Authors and Affiliations
Additional information
Supported by grants from the Ministry of Education, Science and Culture of Japan and the Research Program on Ca Signal Control
Send offprint requests to Y. Kurachi at the above address
Rights and permissions
About this article
Cite this article
Ito, H., Takikawa, R., Kurachi, Y. et al. Anti-cholinergic effect of verapamil on the muscarinic acetylcholine receptor-gated K+ channel in isolated guinea-pig atrial myocytes. Naunyn-Schmiedeberg's Arch Pharmacol 339, 244–246 (1989). https://doi.org/10.1007/BF00165150
Received:
Accepted:
Issue Date:
DOI: https://doi.org/10.1007/BF00165150