Prevention of Acetylcholine-Induced Atrial Fibrillation. Shigetoshi CHIBA, M.D. and Koroku HASHIMOTO, M.D.

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1 Prevention of Acetylcholine-Induced Atrial Fibrillation by Electric Pacing Shigetoshi CHIBA, M.D. and Koroku HASHIMOTO, M.D. SUMMARY The sinus node artery of 10 dog hearts was auto-perfused with blood led from the femoral artery under constant pressure at 100mmHg by the aid of a perfusion pump. Acetylcholine and carbachol given into the sinus node artery induced atrial fibrillation following sinus arrest. Electric pacing with a frequency from 1 to 5Hz was applied to the middle part of the free wall of the right atrium. Electric pacing at a rate below the sinus rate caused some extrasystoles, but pacing at a rate above the sinus rate did not cause any extrasystoles; by pacing at a higher rate than 4.5Hz, AV block was induced. The induction of atrial fibrillation by acetylcholine or carbachol was prevented by various frequencies of electric pacing at a rate either below or above the control sinus rate. But higher frequencies of pacing, 4 to 4.5Hz, occasionally could not prevent atrial fibrillation induced by acetylcholine or carbachol. The sustained atrial fibrillation induced by carbachol was not blocked by artificial pacing of the free wall of the right atrium at any rate of electric pacing. Additional Indexing Words: Electric pacing Acetylcholine Carbachol Atrial fibrillation SA node IN 1968, Hashimoto et al7) demonstrated that atrial fibrillation was regularly induced by the administration of acetylcholine into the sinus node artery of the dog heart under constant pressure perfusion. Furthermore, Chiba and Hashimoto6) showed that carbachol administered into the sinus node artery produced sustained atrial fibrillation. In a previous paper,5) the present authors reported that acetylcholine-induced fibrillation was blocked when the pacemaker was shifted to the AV node or when electric pacing at a rate above the sinus rate was applied to the free wall of the right atrium. However, it is not clear whether electric pacing even at a rate below the sinus rate can block the induction of atrial fibrillation or whether sustained atrial fibrillation is inhibited by electric pacing applied to the right atrium. Thus, we made an attempt to investigate the blocking effects of various degrees of electric pacing From the Department of Pharmacology, Tohoku University School of Medicine, Sendai, Japan 980. Received for publication October 9,

2 146 CHIBA AND HASHIMOTO Jap. Heart J. March, 1974 applied to the free wall of the right atrium on the onset and also on the maintenance of atrial fibrillation induced by acetylcholine or carbachol. METHODS Ten mongrel dogs of both sexes weighing from 10 to 14Kg were anesthetized with sodium pentobarbital, 30mg per Kg intravenously. Direct perfusion of the sinus node artery was performed under constant perfusion pressure at 100mmHg as described in previous paper.7),8) The flow rate in the sinus node artery determined by a magnetic flow-meter (Nihon Kohden MF-2), was 2.4 }0.3ml/min (mean } S.E.) in 10 dogs. Two electric manometers (Nihon Kohden RP-2) were used to measure perfusion pressure and systemic blood pressure at the femoral artery. The heart rate was recorded with a cardiotachograph (Nihon Kohden RT-2) triggered by the R wave of lead II of the ECG. The drug solution was injected in the sinus node artery in a volume of 0.01ml over a period of 4sec by use of microinjectors (Jintan Terumo Co). In all experiments, both vagi were cut at the midcervical level. Drugs used were acetylcholine chloride (Daiichi) and carbachol chloride (Chemwey). Electric pacing was performed by stimulating the middle part of the free wall of the right atrium with square wave pulses, 5 to 10V for 1 msec (Stimulator: Nihon Kohden MES-3), via the implanted bipolar electrodes as shown in Fig.1. Fig.1. Schematic representation of the system used to perfuse the sinus node artery of the dog heart. ES: bipolar stimulating electrodes; SVC: superior vana cava; IVC: inferior vana cava; RA: right atrium; SNA: sinus node artery; P: polyethylene tubing; RT: rubber tubing.

3 Vol.15 ELECTRIC PACING AND ATRIAL FIBRILLATION 147 No.2 RESULTS Electric pacing of the right atrium: Fig.2 shows the effects of various frequencies of electric pacing on the middle part of the free wall of the right atrium. Electric pacing at a rate below the sinus rate did not influence the initial sinus rate but some extrasystoles were induced as shown in Fig.2 (1 and 1.5Hz). The maximum rate of electric pacing to which the right atrium could respond was approximately 4.5Hz. Above a rate of 4.5Hz, second degree AV block occurred. In part H of Fig.2, 2:1 block is shown at a frequency of 5Hz. Effect of electric pacing on onset of acetylcholine-induced atrial fibrillation: In 1968, the present authors7) reported that increasing doses of acetylcholine injected into the sinus node artery induced prominent depression of the sinus rhythm with the sudden appearance of atrial fibrillation; 10ƒÊg of acetylcholine induced atrial fibrillation in nearly all animals. When electric pacing above the sinus rate was applied to the right atrium, the onset of atrial fibrillation induced by 10ƒÊg of acetylcholine was usually blocked. Fig.3 shows that various frequencies of electric pacing prevents the induction of atrial fibrillation by 10ƒÊg of acetylcholine injected into the sinus node artery. A larger amount of acetylcholine was necessary to induce atrial fibrillation when electric pacing was applied as shown in Fig.4, showing that electric pacing prevents the onset of fibrillation even with 30ƒÊg of acetylcholine but not when atrial Fig.2. Effects of various frequencies of electric pacing (1 to 5Hz) on the free wall of the right atrium. SBP: systemic blood pressure; HR: heart rate; ECG, RAL: right auricular lead.

4 148 CHIBA AND HASHIMOTO Jap. Heart J. M arch, 1974 Fig.3. Prevention of acetylcholine (ACh)-induced atrial fibrillation by various frequencies of electric pacing of the free wall of the right atrium. SBP: systemic blood pressure; HR: heart rate; EP: electric pacing; ECG, RAL: right auricular lead. Fig.4. Effects of 3Hz of electric pacing on increasing doses of actylcholine (ACh) injected into the sinus node artery. SBP: systemic blood pressure; HR: heart rate. fi brillation was induced by 50ƒÊg of acetylcholine. Further observation elucidated the mode of preventive action of electric pacing as follows: higher frequencies of electric pacing occasionally failed to prevent the atrial fibrillation induced by a large amount of acetylcholine as shown in Fig.5. This experiment shows that 4Hz of electric pacing could not prevent atrial fibrillation which was completely prevented by either 2 or 3Hz of electric pacing. Summarized data are shown in Table I. When electric pacing at a rate below the sinus rate was applied, sinus rate was not changed although extrasystoles were frequently induced. Even under these conditions, acetylcholine-induced atrial fibrillation was frequently but not always prevented as shown in Table I.

5 Vol.15 ELECTRIC PACING AND ATRIAL FIBRILLATION 149 No.2 Fig.5. Prevention of atrial fibrillation induced by a large amount of acetylcholine (ACh), 50ƒÊg, by 2 and 3Hz of electric pacing and no prevention by a higher frequency of electric pacing (4Hz). SBP: systemic blood pressure; HR: heart rate. Table I. Effect of Electric Pacing of the Free Wall of the Right Atrium on the Onset of Atrial Fibrillation Induced by Acetylcholine (ACh) into the Sinus Node Artery No blocking effect of electric pacing on sustained atrial fibrillation: Sustained atrial fibrillation was induced by the injection of carbachol into the sinus node artery as reported previously.6) When 0.1ƒÊg of carbachol was injected into the sinus node artery, atrial fibrillation occurred just after a brief period of sinus arrest and continued for more than 2min. The onset of atrial fibrillation induced by carbachol also was prevented by electric pacing of the atrium, but sustained atrial fibrillation was not blocked in any experiment by any frequency of electric pacing. Fig.6 shows that 3Hz of electric pacing prevented the induction of atrial fibrillation with 0.1ƒÊg of carbachol, but electric pacing failed to block the sustained atrial fibrillation which occurred immediately after interruption of pacing. Fig.7 shows that electric pacing at a rate a little below or a little above the sinus rate (2 or 3Hz) prevents the induction of

6 150 CHIBA AND HASHIMOTO Jap. Heart J. March, 1974 Fig.6. Sustained artrial fibrillation induced by 0.1ƒÊg of carbachol. Prevention of induction of atrial fibrillation by 3Hz of electric pacing and no effect of electric pacing on the maintenance of atrial fibrillation, when pacing was interrupted. SBP: systemic blood pressure; HR: heart rate. Fig.7. Effect of various frequencies of electric pacing on the effects of carbachol injected into the sinus node artery. SBP: systemic blood pressure; HR: heart rate. atrial fibrillation induced by carbachol although a high frequency of electric pacing (4Hz) fails to prevent the onset of atrial fibrillation, which is similar to the mode of response to acetylcholine. DISCUSSION In 1910, Rothberger and Winterberg10) produced atrial fibrillation by rapid stimulation of the auricle of the heart usually treated with nicotine but sometimes without any prior treatment. Burn et al in 19553) showed that,

7 Vol.15 ELECTRIC PACING AND ATRIAI FIBRILLATION 151 No.2 during the infusion of acetylcholine, stimulation of the right auricle caused the onset of atrial fibrillation which continued even when the stimulation was interrupted. They reported that the rates of stimulation per min necessary to cause fibrillation ranged from 85 to 570 per min. They considered that the factors concerned in the production of fibrillation might be a shortening of the refractory period by acetylcholine with appearance of a supernormal phase of excitability, first demonstrated in cardiac tissue by Adrian in ) In 1968, Hashimoto et al7) reported that atrial fibrillation was induced in almost all cases without any electric stimulation just by injecting 10ƒÊg of acetylcholine alone into the sinus node artery of the dog heart. They also demonstrated in these cases that induction of atrial fibrillation was blocked not only by treatment with atropine but also by anti-adrenergic drugs, i.e. dichlorisoproterenol, propranolol, guanethidine, brethylium and pretreatment with reserpine. Thus, they suggested that the participation of an adrenergic mechanism may play an important role for the induction of atrial fibrillation by acetylcholine. In 1962, Amory and West2) reported that direct electric stimulation of the SA node simulates stimulation of the adrenergic and cholinergic nerves to the heart in the isolated rabbit heart preparation. Recently, Kubota and Hashimoto (unpublished) showed that different effects were induced by various intensities of electric stimulation from the subthreshold for myocardial stimulation up to the driving stimulation frequency applied to different parts of atrium. Threshold stimulation of the SA node region induced atrial fibrillation during stimulation and a poststimulatory acceleration of sinus rate which was blocked by propranolol, using the isolated blood-perfused SA node preparation of the dog. These results indicate that electric stimulation readily causes catecholamine release in the part, especially in the SA node region. In the experiments of Burn et al,3) it is considered that stimulation of the right auricle caused catecholamine release and then readily induced atrial fibrillation during infusion of acetylcholine. In this study, application of acetylcholine was limited to the SA node region and electric pacing was performed on the free wall of the right atrium where stimulation of cardiac nerves was scarcely involved. Furthermore acetylcholine given into the sinus node artery acts selectively on the SA node region and it does not reach the area of the pacing electrodes. Thus, electric pacing was not influenced directly by injected acetylcholine. As shown in the previous paper,5) we demonstrated that atrial fibrillation resulting from the administration of acetylcholine into the sinus node artery did not occur when the pacemaker activity had been shifted to the AV node. In those experiments, the pacemaker shift from the SA node to the AV node was obtained by selective injection of norepinephrine into the posterior septal artery (=AV node artery).4),9) Furthermore, the induction of atrial fibrillation produced

8 152 CHIBA AND HASHIMOTO Jap. Heart J. March, 1974 by acetylcholine was prevented even when the loss of SA dominance of pacemaker activity in the right atrium was caused by electric pacing.5) Thus, it was concluded that dominance activity of the SA pacemaker is necessary for the induction of atrial fibrillation by acetylcholine. In this study, we confirmed that various frequencies of electric pacing at a rate either below or above the sinus rate usually prevented the induction of atrial fibrillation with acetylcholine when pacing was applied distant from the SA node area. It was recognized that electric pacing with no direct relation with the sinus rate increased the threshold for inducing atrial fibrillation by acetylcholine. Furthermore, the onset of atrial fibrillation induced not only by acetylcholine but also by carbachol was prevented by electric pacing. In previous papers,4),5) it was demonstrated that a pacemaker shift to the AV node occasionally inhibits even a sustained atrial fibrillation induced by carbachol or an infusion of acetylcholine. Therefore, we had considered that not only the onset but also the maintenance of atrial fibrillation would be blocked by a pacemaker shift to the free wall of the right atrium. But in this study, in all instances, electric pacing of the right atrium failed to stop the sustaining of atrial fibrillation induced by carbachol. In 1953, Scherf11) reported that atrial fibrillation was blocked by the cooling of both the SA and AV nodes simultaneously. He suggested that the AV node might probably have an important role in the maintenance of atrial fibrillation induced by acetylcholine. It is possible then that the AV node pacemaker may have a more important effect than the free wall pacemaker. From this study and a previous paper,5) it is suggested that the dominance of pacemaker activity might have an important role on the induction of atrial fi brillation and the pacemaker activity of the AV node might have some role on the maintenance of atrial fibrillation induced by acetylcholine or carbachol. ACKNOWLEDGEMENTS The study was supported in part by Pharmacological Research Foundation, the Toyo Jozo Co, Ltd and Squibb Institute for Medical Research. The authors express many thanks to Prof. Joanne I. Moore, Oklahoma University Medical College for her criticism. REFERENCES 1. Adrian ED: The recovery process of excitable tissue. J Physiol (Lond) 54: 1, Amory DW, West TC: Chronotropic response following direct electrical stimulation of the isolated sinoatrial node. A pharmacologic evaluation. J. Pharmacol Exp Ther 137: 14, Burn JH, Vaughan Williams EM, Walker JM: The effects of acetylcholine in the heart

9 Vol.15 ELECTRIC PACING AND ATRIAL FIBRILLATION 153 No.2 lung preparation including the production of auricular fibrillation. J Physiol (Lond) 128: 277, Chiba S, Hashimoto K: Interruption of atrial fibrillation by pacemaker shift induced by the selective use of noradrenaline into the AV node artery. Tohoku J Exp Med 94: 411, Chiba S, Hashimoto K: Blocking of acetylcholine-induced fibrillation by use of norepinephrine into the AV node artery. Jap J Physiol 20: 560, Chiba S, Hashimoto K: Sustained atrial fibrillation induced by carbachol, methacholine and bethanechol. Jap J Pharmacol 21: 167, Hashimoto K, Chiba S, Tanaka S, Hirata M, Suzuki Y: Adrenergic mechanism participating in induction of atrial fibrillation by ACh. Am J Physiol 215: 1183, Hashimoto K, Tanaka S, Hirata M, Chiba S: Responses of the sino-atrial node to change in pressure in the sinus node artery. Circulat Res21: 297, Nadeau RA, Amir Jahd AK: Selective perfusion of the A-V node of the dog by cannulation of the posterior septal artery. Rev Canad Biol 24: 291, Rotheberger J, Winterberg H: Uber das Elektrokardiogramm bei Flimmern der Vorhofe. Pflug Arch ges Physiol 131: 387, Scherf D: Auricular flutter and fibrillation originating in the atrioventricular node. Arch Exple Path Pharmakol 219: 30, 1953