CHOLINERGIC INHIBITION OF SLOW DELAYED-RECTIFIER K-PIG SINOATRIAL NODE IS NOT MEDIATED BY MUSCARINIC RECEPTORS( CURRENT IN GUINEA)

We studied the effects of cholinergic agonists on slow delayed-rectifi er K+ current (I-Ks) in isolated cells from the sino-atrial node (SAN) region of guinea pig heart, using patch-clamp procedures. Carbachol ( 5 nM to 10 mu M) inhibited I-Ks 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 atropin e nor the nicotinic antagonist hexamethonium antagonized carbachol inh ibition of the current. Similar results were obtained with other choli nergic agonists. Cholinergic stimulation of the muscarinic K+ current was successfully antagonized by atropine in SAN cells where inhibition of I-Ks persisted. Therefore, the lack of antagonist effects on inhib ition of I-Ks 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 agon ists, including the endogenous neurotransmitter acetylcholine, decreas e the amplitude of I-Ks in guinea pig SAN cells via a non-muscarinic, nonnicotinic, cAMP-independent mechanism. Although the precise nature of this signal transduction pathway has not been elucidated, it is cle arly different from those described for regulation of other nodal curr ents. Differential regulation of I-Ks in guinea pig SAN and ventricle cannot be attributed to higher basal adenylate cyclase activity in SAN cells. The inhibitory effect of carbachol on I-Ks was not additive wi th that of verapamil, a drug that is both an allosteric muscarinic ant agonist and a potassium channel-blocking agent. Cholinergic agonists m ay inhibit I-Ks in SAN cells via a direct interaction with the SAN I-K s channel.