Atrial and ventricular adenylate cyclase activity and atrial membrane potentials were measured in hearts from hatched chicks at 2-3 days after intravenous administration of pertussis toxin (0.5-1.0 micrograms, total) or saline. Both in atrium and ventricle, treatment with pertussis toxin antagonized inhibition by carbachol of basal and isoproterenol-stimulated adenylate cyclase activity without changing either basal or isoproterenol-stimulated adenylate cyclase. In atria from pertussis toxin-treated animals (5.4 mM potassium), carbachol hyperpolarized the resting membrane by 0.3 +/- 0.3 mV (n = 9) and did not increase resting potassium conductance. In contrast, carbachol hyperpolarized the resting membrane by 4.5 +/- 0.8 mV (n = 11) and increased resting potassium conductance more than 4-fold in saline-treated animals. Carbachol did not significantly affect the atrial action potential peak or duration at 50% repolarization of pertussis toxin-treated animals. This muscarinic agonist reduced action potential peak by 7.8 +/- 1.2 mV and the duration at 50% repolarization by 22.1 +/- 3.0 msec in atria from saline-treated animals. Pertussis toxin treatment also prevented the negative inotropic effect and the inhibition of calcium-dependent action potentials caused by carbachol in atrial muscle. Neither the affinity nor the maximal specific binding of [3H]quinuclidinyl benzilate in ventricular homogenates was changed by pertussis toxin treatment. The apparent affinity of carbachol for muscarinic receptor was slightly (approximately 2-fold) diminished in pertussis toxin-treated animals. The inhibition of carbachol-induced hyperpolarization by pertussis toxin treatment implicates a guanosine 5'-triphosphate-dependent protein (Ni or a similar protein) as an essential link that permits muscarinic receptor to regulate atrial potassium channels.

Muscarinic agonists can stimulate rather than inhibit cardiac muscle in some preparations. In left atria from hatched chicks, treatment with pertussis toxin reversed the membrane action of carbachol from hyperpolarization to depolarization and reversed the inotropic effect of carbachol from negative to positive. Acetylcholine also depolarized the membrane and increased the force of contraction in atria from pertussis-toxin-treated chicks although oxotremorine did not. These cholinergic responses were blocked by atropine but not by adrenoceptor antagonists, suggesting that they are mediated via muscarinic receptors and are not due to actions of endogenously released catecholamines. Muscarinic receptor stimulation leads to two distinct biochemical responses in chick atria: inhibition of adenylate cyclase and activation of phosphoinositide (PI) hydrolysis. The former is lost in atria from pertussis-toxin-treated chicks, whereas the PI response persists. The pharmacologic characteristics of the PI response resemble those of the depolarization and positive inotropic response. Both are insensitive to blockade by pertussis toxin, require high concentrations of carbachol, and are elicited by acetylcholine but not by oxotremorine. The present study suggests that muscarinic agonist-induced PI turnover may be responsible for the membrane depolarization and positive inotropic effects of carbachol and acetylcholine; that an increase in Na + conductance underlies these responses; and that it is stimulated either by an increase of intracellular calcium mobilized by inositol triphosphate and/or by activation by protein kinase C. 2 " 4 In frog ventricular muscle, acetylcholine inhibits the opening of Ca 2+ channels by activating a cyclic guanosine monophosphate (cGMP)-dependent phosphodiesterase that diminishes cAMP content.5 Muscarinic receptors are also linked to activation of atrial K + channels through a guanine nucleotide binding protein, apparently G, and/or G O . 6~9Guanine nucleotide binding proteins obtained from human erythrocytes 10 and from bovine cerebral cortex" have been shown to activate muscarinic K + channels directly in isolated atrial cell membrane patches. Received December 12, 1986; accepted April 3, 1987. Although there is significant disagreement between these reports concerning the suitability of G o (from brain) and the role of a/3y vs. fiy subunits as components of the reaction, the results substantiate the previously advanced conclusion that no second messenger need be involved for muscarinic agonists to open K + channels. 7 " 9 Muscarinic agonists thereby increase a specific K + conductance, hyperpolarize the membrane, and decrease action potential duration , 79 Acetylcholine is proposed to act on specific K + channels that are distinct from background K channels (i KI ) in sinoatrial node, atrial muscle, and Purkinje fibers.12 " 15 The reduced influx of Ca 2+ and the increased efflux of K + both contribute to the negative inotropic action of muscarinic agonists in atrial muscle.1 Treatment of ch...

SUMMARYWe studied the electrophysiologic effects of intravenous adenosine triphosphate disodium (ATP-2Na) on 15 patients with paroxysmal supraventricular tachycardias (PSVTs). One patient had sinus node (SN) reentry and 2 patients had intraatrial (IA) reentry. Five patients had AV nodal reentry and 7 patients had atrioventricular reentrant tachycardias (AVRTs) with accessory pathways (APs). ATP-2Na was injected during ventricular pacing (VP) in patients with AVRTs with APs. A bolus injection of ATP-2Na terminated all the PSVTs within 40 sec except in one case of IA reentry. The sites of block at the termination were the atrium in SN reentry and IA reentry, between A and H (AH) block or between H and A (HA) block in AV nodal reentry and AH block in all the AVRTs with APs. ATP-2Na during VP in patients with AVRTs with APs produced the changes of atrial activation sequences in 3 patients, induction of PSVT in 2 patients and a Mobitz type II VA block in 2 patients. The former two phenomena suggested a retrograde AV nodal block and raised the possibility of a simple test for retrograde atrial fusion during VP in patients with WPW syndrome. Chest discomfort of short duration was most commonly noted after ATP-2Na. Inosine pretreatment potentiated the effects of ATP-2Na. This combination may further alleviate the side effects of ATP-2Na, while preserving the effective action of ATP-2Na for rapid termination of PSVTs. Additional Indexing Words: Electrophysiologic effectsParoxysmal supraventricular tachycardias Ventricular pacing ATP-2Na potentiation by inosine

We studied the electrophysiologic effects of intravenous adenosine triphosphate disodium (ATP-2Na) on 17 patients with paroxysmal supraventricular tachycardias (PSVTs). One patient had sinus node (SN) reentry, two had intraatrial (IA) reentry, 7 patients had AV nodal reentry and seven had atrioventricular reentrant tachycardias (AVRTs) with accessory pathways (APs). ATP-2Na was injected during ventricular pacing in patients with AV nodal reentry and AVRTs with APs. A bolus injection of ATP-2Na terminated all the PSVTs within 50 s except for one case of IA reentry (case 2). The sites of block at termination were the atrium in SN reentry and IA reentry, between A and H (AH) or between H and A (HA) in AV nodal reentry, and AH block in all the PSVTs with APs. The sites of action on the patients with AV nodal reentry were both the antegrade and retrograde pathways, while the modes of block were Mobitz type I and type II, respectively. ATP-2Na during ventricular pacing in patients with AV nodal reentry produced Mobitz type II ventriculoatrial block (VAB) in four of seven cases. ATP-2Na during ventricular pacing in patients with AVRTs with APs produced changes of atrial activation sequences in two patients, induction of PSVT in two patients, and Mobitz type II VA block in three patients. The former two phenomena suggested a retrograde AV nodal block and raised the possibility of a simple test for retrograde atrial fusion during ventricular pacing in patients with WPW syndrome. Chest discomfort of short duration was most commonly noted after ATP-2Na administration.

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