Cholinergic inhibition of slow delayed-rectifier K+ current in guinea pig sino-atrial node is not mediated by muscarinic receptors.
We studied the effects of cholinergic agonists on slow delayed-rectifier K+ current (IKs) in isolated cells from the sino-atrial node (SAN) region of guinea pig heart, using patch-clamp procedures. Carbachol (5 nM to 10 microM) inhibited IKs in guinea pig SAN cells in the absence of previous beta-adrenergic stimulation and in cells pretreated with 8-(4-chlorophenylthio)-cAMP. Neither the muscarinic antagonist atropine nor the nicotinic antagonist hexamethonium antagonized carbachol inhibition of the current. Similar results were obtained with other cholinergic agonists. Cholinergic stimulation of the muscarinic K+ current was successfully antagonized by atropine in SAN cells where inhibition of IKs persisted. Therefore, the lack of antagonist effects on inhibition of IKs cannot be attributed to either an absence of muscarinic cholinoceptors on SAN cells or a loss of antagonist activity under our experimental conditions. These data demonstrate that cholinergic agonists, including the endogenous neurotransmitter acetylcholine, decrease the amplitude of IKs in guinea pig SAN cells via a non-muscarinic, non-nicotinic, cAMP-independent mechanism. Although the precise nature of this signal transduction pathway has not been elucidated, it is clearly different from those described for regulation of other nodal currents. Differential regulation of IKs in guinea pig SAN and ventricle cannot be attributed to higher basal adenylate cyclase activity in SAN cells. The inhibitory effect of carbachol on IKs was not additive with that of verapamil, a drug that is both an allosteric muscarinic antagonist and a potassium channel-blocking agent. Cholinergic agonists may inhibit IKs in SAN cells via a direct interaction with the SAN IKs channel.
Freeman
L C
LC
Department of Physiology, University of Rochester School of Medicine and Dentistry, New York 14642-8642, USA.
Kass
R S
RS
D000494:Allosteric Regulation; D000818:Animals; D018679:Cholinergic Agonists / Q000494:pharmacology*; D051668:Delayed Rectifier Potassium Channels; D006168:Guinea Pigs; D066298:In Vitro Techniques; D008564:Membrane Potentials / Q000187:drug effects; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011976:Receptors, Muscarinic / Q000502:physiology*; D012849:Sinoatrial Node / Q000187:drug effects* / Q000502:physiology
D018679:Cholinergic Agonists; D051668:Delayed Rectifier Potassium Channels; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D024642:Potassium Channels, Voltage-Gated; D011976:Receptors, Muscarinic