The effects of tertiapin-Q on responses of the sinoatrial pacemaker of the guinea-pig heart to vagal nerve stimulation and muscarinic agonists.
Using Langendorff preparations of the guinea-pig heart, we have examined the participation of the acetylcholine (ACh)-activated potassium channel, IK,ACh, in the bradycardia produced by electrical stimulation of the vagus (parasympathetic) nerve and muscarinic agonists (ACh and bethanecol, bolus i.a.). Hearts from young animals (160-250 g) were perfused with Krebs-Henseleit solution, and pacemaker frequency was determined from the P wave of an ECG. Tertiapin-Q was used to block IK,ACh. Vagal stimulation (10 s trains at 2, 5 and 10 Hz) produced graded reductions in atrial rate that were substantially attenuated, and to a similar extent, by 300 nm and 1 microm tertiapin-Q (to 0.42 +/- 0.12, mean +/- s.d., of the control values; P < 0.001). Acetylcholine (3 nmol) produced brief graded bradycardias that were also attenuated by tertiapin-Q (0.24 +/- 0.24; P = 0.006). Similar results were obtained when experiments were repeated in 2 mm Cs+ (to block the hyperpolarization-activated pacemaker current). Bethanecol (30, 50 and 70 nmol), a muscarinic agonist with no appreciable nicotinic activity, produced sustained bradycardias that were attenuated by 300 nm tertiapin-Q (0.36 +/- 0.21; P < 0.0001). The responses to vagal stimulation and ACh developed more slowly in tertiapin-Q, indicating that a rapidly acting mechanism had been blocked. Responses to vagal stimulation were faster in 2 mm Cs+. Together, these observations show that ACh released from parasympathetic nerve varicosities exerts a considerable part of its effect on the pacemaker by activating IK,ACh and acts in a manner not readily distinguishable from that of directly applied muscarinic agonists.
Bolter
Chris P
CP
Department of Physiology, School of Medical Sciences, University of Otago, PO Box 913, Dunedin 9054, New Zealand. chris.bolter@stonebow.otago.ac.nz
English
Duane J
DJ
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001158:Arteries / Q000187:drug effects / Q000502:physiology; D001514:Bee Venoms / Q000494:pharmacology*; D018723:Bethanechol / Q000494:pharmacology; D001683:Biological Clocks / Q000187:drug effects* / Q000502:physiology*; D002586:Cesium / Q000494:pharmacology; D003326:Coronary Circulation / Q000187:drug effects; D003627:Data Interpretation, Statistical; D004558:Electric Stimulation; D004562:Electrocardiography / Q000187:drug effects; D005260:Female; D006168:Guinea Pigs; D008297:Male; D018721:Muscarinic Agonists / Q000494:pharmacology*; D026902:Potassium Channel Blockers / Q000494:pharmacology*; D012849:Sinoatrial Node / Q000187:drug effects* / Q000502:physiology*; D014630:Vagus Nerve / Q000502:physiology*; D014665:Vasodilator Agents / Q000494:pharmacology
D001514:Bee Venoms; D018721:Muscarinic Agonists; D026902:Potassium Channel Blockers; D014665:Vasodilator Agents; D018723:Bethanechol; D002586:Cesium; C029738:tertiapin; D000109:Acetylcholine