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The Effects of Verapamil Hydrochloride on Electrocardiographic (ECG) Parameters of Domestic Donkey (Equus asinus)
REFEREED
ORIGINAL RESEARCH
The Effects of Verapamil Hydrochloride on Electrocardiographic (ECG) Parameters of Domestic Donkey (Equus asinus) Gholam Ali Kojouri, DVM, PhD,a Ali Rezakhani, DVM, PhD,b and Ehsan Torki, DVMc ABSTRACT Verapamil hydrochloride, a calcium channel blocker, has been used in domestic animals. Its effects on electrical activities of the heart of donkeys were studied in this preliminary research work. This experiment was carried out on 10 healthy donkeys ranging in age from 4 to 7 years and mean body weight of 155 18.6 kg. The electrocardiogram (ECG) was recorded on a base apex lead before (for 3 days), during, and after verapamil injection (10, 20, 30, 40, 50, and 60 minutes). Verapamil hydrochloride (0.3 mg/kg body weight) was given via catheterizaion as an intravenous bolus over 2 minutes. Heart rate, rhythm, ECG morphology, amplitude, durations, and intervals were measured and taken into consideration and values were compared. Results showed that heart rate was significantly increased at the time of injection from 55 10.7 before injection to 77.61 12.6 beats per minute after injection (P < .05). Duration of P and T waves; P-R interval, and also P-R segment were increased (P < .05). However, duration of QRS complex, P-P and R-R intervals, and S-T segment were significantly decreased after verapamil injection (P < .05). Sinus arrest (2 cases), bradycardia (1 case), and wandering pacemaker (1 case) were recorded before treatment and verapamil injection did not affect these arrhythmias, except in one case in which sinus arrest disappeared. However, after injection of verapamil, four types of arrhythmias (wandering pacemaker [WPM], sinus tachycardia, 1st degree AVB, and 2nd degree AVB) were recognized. These arrhythmias (with the exception of tachycardia) can be related to the increase of vagal tone activity that might be attributed to the negative effect of verapamil on SA and atrioventricular block [AV] nodes.
INTRODUCTION Verapamil is a calcium channel blocker (CCB) that blocks long-lasting calcium channels, resulting in depression of cardiac and vascular functions that depend on cardiac influx.1 The antidysrhythmic effect of verapamil appears to block the slow calcium channels in the cell membrane of the cardiac conductive system. Verapamil inhibits calcium influx across the cell membranes of the SA and AV nodes. Decrement of the rate of depolarization and automaticity occurs in the SA node and heart rate decreases (negative chronotropic effect). Conversely, conductive velocity is slowed in the AV node and prolongs the refractory period. This reduces the high ventricular rate in supraventricular tachycardia caused by atrial flutter and fibrillation. In addition, normal sinus rhythm is restored by interrupting reentry at the AV node in patients with paroxysmal supraventricular tachycardia,2 including Wolff-ParkinsonWhite syndrome. Verapamil has the potential to induce sinus arrest in sick sinus syndrome and also AV block.1,3-5 Although verapamil and other CCBs have been used in some domestic animals,2,6,7 limited data are available regarding CCBs in equine species8; accordingly, we studied the acute effects of verapamil on electrocardiographic variables in healthy domestic donkeys.
MATERIALS AND METHODS Animals This study was conducted on 10 healthy nonpregnant domestic female donkeys (Equus asinus). Blood and fecal samples were taken, then animals were weighed (155 18.6 kg) and the jugular vein catheterized with a 16-gauge needle.
From the Department of Clinical Sciences, School of Veterinary Medicine, Shahrekord University, Shahrekord, Irana; Department of Clinical Studies, School of Veterinary Medicine, Shiraz University, Shiraz, Iranb; Post-graduate Student of Large Animal Internal Medicine, School of Veterinary Medicine, Tehran University, Tehran, Iran.c Reprint requests: Gholam Ali Kojouri, DVM, PhD, Department of Clinical Sciences, School of Veterinary Medicine, Shahrekord University, P.O. Box 115, Shahrekord, Iran. 0737-0806/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jevs.2007.10.007
Electrocardiogram Recording A base apex lead was used for recording electrocardiograms (ECG). The baseapex lead was attached by placing the positive electrode on the left thorax in the fifth intercostal space at the level of the point of the elbow or at the location where the apex beat was most readily palpated. The negative electrode was attached to the skin on the right jugular furrow two thirds of the way from the ramus of the mandible to the thoracic inlet. The ground electrode was attached to a location remote from the heart.9 A baseapex lead ECG was recorded from each donkey for
Journal of Equine Veterinary Science Vol 27, No 11 (2007)
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Keywords: Verapamil; ECG; Calcium blocker; Donkey; Arrhythmia
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Table 1. Changes of Heart Rate and Some ECG Parameters (BaseApex Lead) in Domestic Donkeys Treated with Verapamil Hydrochloride (0.3 mg/kg B.W. IV) Parameters Heart Time Rate/min
a
T (seconds)
PP Interval (seconds)
RR Interval (seconds)
PR Interval (seconds)
QT Interval (seconds)
PR Segment (seconds)
ST Segment (seconds)
QRS Complex (seconds)
55.1 10.68 0.113 0.01 0.14 0.05 1.10 0.27 1.10 0.21 0.21 0.03 0.47 0.09 0.10 0.03 0.35 0.08 0.10 0.01 77.60 12.59a 0.119 0.02 0.18 0.06c 0.77 0.17a 0.78 0.17a 0.22 0.05 0.39 0.06 0.10 0.05 0.28 0.06a 0.12 0.04 60.70 12.64 0.108 0.01 0.13 0.04 1.10 0.36 1.06 0.32 0.25 0.04c 0.44 0.07 0.14 0.04c 0.34 0.06 0.14 0.02 58.90 11.53 0.109 0.02 0.14 0.03 1.00 0.17 1.00 0.16 0.24 0.03c 0.46 0.06 0.15 0.05c 0.36 0.05 0.10 0.02 57.60 10.35 0.109 0.01 0.15 0.04 1.00 0.19 1.10 0.20 0.24 0.03c 0.47 0.08 0.13 0.04 0.36 0.06 0.12 0.01
56.40 9.41
0.108 0.02 0.14 0.03 1.10 0.27 1.10 0.27 0.22 0.03 0.43 0.11 0.11 0.04 0.36 0.07 0.09 0.008d
56.60 10.38 0.111 0.02 0.16 0.03 1.10 0.26 1.10 0.27 0.23 0.04 0.46 0.11 0.11 0.03 0.35 0.06 0.12 0.01 56.60 11.23 0.124 0.02b 0.16 0.03 1.10 0.26 1.10 0.27 0.24 0.03c 0.49 0.06 0.11 0.04 0.36 0.05 0.12 0.01
%.001
%.044
%.047
%.006
Significant to other times (P < .01). b Significant to 10 minutes after injection time (P < .05). c Significant to before injection (P < .05). d Significant to 10, 30, 50, and 60 minutes after injection time (P < .05).
%.007
%.021
%.048
%.018
%.032
%.016
GA Kojouri et al Vol 27, No 11 (2007)
Before injection During injection 10 minutes after injection 20 minutes after injection 30 minutes after injection 40 minutes after injection 50 minutes after injection 60 minutes after injection P Values
P (seconds)
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Table 2. Changes of Some ECG Amplitudes (BaseApex Lead) in Domestic Donkeys Treated With Verapamil Hydrochloride (0.3 mg/kg B.W. IV) Parameters Time
P (mV)
r (mV)
S (mV)
T (mV)
Before injection During injection 10 minutes after injection 20 minutes after injection 30 minutes after injection 40 minutes after injection 50 minutes after injection 60 minutes after injection P Values
0.27 0.03 0.23 0.06 0.24 0.04 0.27 0.07 0.22 0.03 0.28 0.05 0.24 0.03 0.21 0.04 >.05
0.10 0.04 0.13 0.21 0.11 0.05 0.11 0.05 0.12 0.07 0.15 0.14 0.12 0.24 0.13 0.10 >.05
2.48 0.79 2.47 0.41 2.50 0.51 2.48 0.60 2.50 0.41 2.50 0.42 2.50 0.50 2.50 0.40 >.05
0.67 0.53 0.94 0.35 0.66 0.45 0.59 0.44 0.67 0.49 0.65 0.38 0.64 0.45 0.63 0.44 >.05
3 consecutive days before the experiment at a paper speed of 25 mm/second and calibration of 10 mm/mV (1 cm ¼ 1 mV). The pre-experiment ECGs were used for measuring heart rate, amplitude, duration, configuration, segments (PR and ST), and intervals (PP, RR, PR, and QT). For measuring the wave’s amplitudes, segments, and intervals, the computerized AutoCAD program was used. Verapamil Hydrochloride Injection This slow calcium channel blocker was injected at the dosage of 0.3 mg/kg body weight as an intravenous bolus over 2 minutes. ECG was taken during and at 10, 20, 30, 40, 50, and 60 minutes after injection (each time ECG was recorded for at least 1 minute) and ECG parameters were evaluated as before. Analytical Procedure Data were presented as mean SD. Differences in mean values were analyzed using analysis of variance with Dunnett’s post test (SigmaStat Ver. 2). A P-value < .05 was considered statistically significant.
RESULTS Results are summarized in Tables 1 to 3. Effects on Heart Rate As shown in Table 1, the normal heart rate before injection was 55.1 10.7 beats/min and increased significantly to 77.6 12.6 (P < .001) during injection and decreased to 60.7 12.6 and 56.6 11.2 at 10 and 60 minutes after verapamil injection, respectively. Effects on P Wave The data on morphology, duration, and amplitude of the P wave are summarized in Tables 1 and 2. The P wave shape was bifid in only one case before injection, increased significantly in five cases during injection (P < .05), and returned to the normal position. The P wave duration was significantly increased from 0.113 0.01 second before injection to 0.124 0.02 second at 60 minutes after injection (P ¼ .044).
The minimum, maximum, and mean P wave voltages before injection were 0.22, 0.32, and 0.27 0.03 mV, respectively. The P wave amplitudes did not change significantly during the experiment (P > .05). Effects on QRS Complex The shapes of QRS complexes remained unchanged throughout the experiment. Duration of the QRS complex decreased significantly from 0.10 0.01 before injection to 0.09 0.008 second at 40 minutes after injection of verapamil (P ¼ .016). The amplitudes of r and S waves were not significantly different (P > .05). Effects on T Wave Before injection the T wave was biphasic (-/þ) in seven cases and negative in three. At the time of injection, the T wave was positive in eight cases and at 10 minutes after verapamil injection biphasic, positive and negative T waves were observed in 2, 6, and 2 cases, respectively. Duration of T wave was significantly increased from 0.14 0.05 second before injection to 0.18 0.06 second during injection (P < .05) and returned to 0.13 0.04 second at 10 minutes after injection (P > .05). Effects on Intervals and Segments The P-P and R-R intervals and S-T segment decreased at the time of injection as compared with other times of experiment (P < .05). The P-R interval and P-R segment increased at 10 and 20 minutes after injection of verapamil as compared with pre-injection (P < .01). Effects on Heart Rhythm As mentioned, normal heart rhythm was recorded on 3 consecutive days before the experiment. Sinus arrest (2 cases), bradycardia (1 case), and wandering pace maker (1 case) were diagnosed before the experiment (Table 3). After injection of verapamil, some arrhythmias were recognized: (1) Sinus tachycardia was observed in eight cases during drug injection and limited to one case at 20 and 30 minutes after injection. (2) Wandering pacemaker was seen in one case at 20 minutes after verapamil injection and disappeared at 50 minutes after injection. (3)
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1 1 1 1 1 1 1 1 2 1 1 1 2 2 1 1 1 2 1 1 2 1 1 1 1 2 1 -
Time Arrhythmia
Sinus bradycardia Sinus tachycardia Sinus arrest Wandering pace maker 1st degree AV block 2nd degree AV block
8 1 2 1
40 Minutes after Injection 30 Minutes after Injection 20 Minutes after Injection 10 Minutes after Injection During Injection
Bradycardia disappeared during drug injection and reappeared at 10 minutes and remained until the end of experiment. (4) First-degree AV block was observed in two cases at the time of drug injection and was observed in only one case at 10 minutes after injection. (5) Seconddegree AV block was recorded in one case at the time of verapamil injection and remained stable to the final stage.
DISCUSSION
Before Injection
Table 3. Frequency of Arrhythmias and the Effect of Verapamil (0.3 mg/kg B.W. IV) on Cardiac Rhythm in Donkeys
50 Minutes after Injection
60 Minutes after Injection
502
The current study was conducted to determine the effects of verapamil injection on ECG parameters in healthy donkeys. Calcium channel blockers are a major class of drugs that are used in treatment of cardiac arrhythmias. Calcium channel blockers are broadly divided into dihydropyridines (eg, nifedipine) and non-dihydropyridines (eg, verapamil). Verapamil suppresses conduction through the atrioventricular node; it is effective on both AV reciprocating tachycardia and AV nodal reentrant tachycardia. It is also useful to reduce ventricular response during atrial fibrillation/flutter.1,4 This agent inhibits the voltage-dependent calcium channel in vascular smooth muscle and also myocardial slow calcium channels.5 As previously reported, verapamil significantly suppressed AV node conduction and slightly decreased mean blood pressure. Although no significant changes occurred in the filling pressure and contractility of the left ventricle, sinus automaticity, cardiac output, intraventricular conduction, ventricular repolarization phase, and refractoriness,10 these findings showed the benefit of verapamil for treatment of supraventricular arrhythmias such as atrial fibrillation/flutter.2 Verapamil’s antiarrhythmic effects are believed to be brought about largely by its action on the sinoatrial (SA) and atrioventricular (AV) nodes. This was confirmed in this study based on recording AV block and longer P-R interval after injection. Verapamil is also a potent smooth muscle relaxant with vasodilatory properties, as well as a depressant of myocardial contractility, and these effects are largely independent of autonomic influences. Tachycardia that was observed after verapamil injection in our cases could be attributable to hypotension induced by the drug rather than excitement. Using calcium channel blocker in normal horses produced arterial vasodilation and depressing effects on the myocardium and nodal tissues.8 In the current study, some arrhythmias such as sinus arrest stabilized after verapamil injection. In addition, a new case of wandering pacemaker at 20 minutes after treatment was observed. These may be related to decreasing effect of verapamil on the rate of depolarization and automaticity in the SA node. The occurrence of sinus tachycardia may be a reflex attributable to hypotension caused by verapamil injection, which disappeared at 10 minutes after injection. First-degree AV block was recognized during and at 10 minutes after verapamil injection. The second-degree AV block was recorded at the time of injection and stabilized in all times after injection (except at 20 minutes). These two arrhythmias are considered normal variations.11 These
GA Kojouri et al Vol 27, No 11 (2007)
conduction disorders often are associated with high vagal tone and may occur with sinus bradycardia or sinus arrhythmia.12,13 At the time of verapamil injection, hypotension and sympathetic activity led to tachycardia. Because of the physiologic response, and intervention of parasympathetic activity, heart rate was decreased by sluggish depolarization of the SA node and an increase of refractory period in the AV node cells. It is known that vagal activity is generally a depressant to heart rate, atrioventricular conduction, excitability, and myocardial inotropic (contractile) state. However, because vagotonia shortens the action potential and refractory period of atrial myocytes, high vagal activity may be predisposing factors in the development of atrial fibrillation.13 Conversely, calcium channel blockers such as verapamil bind to slow Ca2þ channels and prevent them from opening, which decreases the entry of calcium into cardiac muscle cells during an action potential. Because Ca2þ entry is the primary depolarizing event during the plateau (phase 2) of the cardiac action potential, one major effect of a Ca2þ channel blocker is to lower the plateau. A secondary consequence is to lengthen the action potential. The action potential is longer because of a complicated effect of the height of the plateau on Kþ channels that close at the beginning of a cardiac action potential and then, after a period, reopen. Kþ channel reopening helps repolarization of the cell to a resting state at the end of the action potential. The length of period before Kþ channels reopen depends on the membrane voltage during the action potential. Specifically, when the plateau is lower than normal, the Kþ channels stay closed for a longer time. This prolongs the action potential and postpones repolarization. Drugs that lengthen the cardiac action potential also lengthen the refractory period. Therefore, it is less likely that those early extra action potentials form in ectopic pacemakers or that they do not propagate even if they are formed. The SA and AV nodes do not have fast Naþ channels; instead, Ca2þ entry through slow Ca2þ channels is the main event in the slow action potentials of these cells. These action potentials are also lengthened. Low-amplitude, long action potentials propagate very slowly from cell to cell, which decreases the likelihood that early extra action potentials form or propagate in SA or AV node cells. By increasing the refractoriness and decreasing the conductive velocity of AV node cells, Ca2þ channel blockers induce most of the atrial action potentials that are dissipated in the AV node and not to be conducted to the ventricular bundle branches.12
503
Calcium channel blockers can affect blood pressure and influence the cardiac rhythm. Therefore, cases with sinus tachycardia in this study could be attributable to low blood pressure as a result of verapamil. Blood pressure was not recorded in this study because of technical limitations, so it would be difficult to disregard the effect of blood pressure on the cardiac rhythm and consequently on the ECG intervals.
REFERENCES 1. Cheung BMY, Kumana CR. Calcium channel blockers revisited. Hong Kong Med J 2002;8:300–301. 2. Kittleson M, Keene B, Pion P, Woodfield J. Verapamil administration for acute termination of supraventricular tachycardia in dogs. J Am Vet Med Assoc 1996;1931:525–1529. 3. Hahn AB, Oestreich SJK, Barkin RL. Mosby’s pharmacology in nursing, 6th ed. St Louis: The Mosby Company; 1986:464–468. 4. Takahashi N, Saikawa T. Calcium channel antagonists and arrhythmias. Clin Calcium 2005;15:1651–1655. 5. Opie LH. Calcium channel antagonist, part 1: fundamental properties: mechanisms, classification, sites of action. Cardiovasc Drugs Ther 1987;1:411–430. 6. Bright JM, Golden AL, Gompf RE, Walker MA, Toal RL. Evaluation of the calcium channel-blocking agents diltiazem and Verapamil for treatment of feline hypertrophic cardiomyopathy. J Vet Int Med 1991;5:272–282. 7. Young L, Gunther VL. Atrial fibrillation in horses: new treatment choice for the new millennium. J Vet Int Med 2005;19:631–632. 8. Schwarzwald CC, Bonagura JD, Luis-Fuetes V. Effects of diltiazem on hemodynamic variables and ventricular function in healthy horses. J Vet Int Med 2005;19:703–711. 9. Reef VB, McGuirk SM. Diseases of the cardiovascular system In: Smith BP (ed). Large animal internal medicine, 3rd ed. St Louis: Mosby; 2002:443–445. 10. Shiina H, Sugiyama A, Takahara A, Satoh Y, Hashimoto K. Comparison of the electropharmacological effects of Verapamil and propranolol in the halothane anesthetized in vivo canine model under monophasic action potential monitoring. Jpn Circ J 2000;64: 777–782. 11. Gabriel F, Lekeux P. Cardiac arrhythmias encountered in 159 Belgian riding horses. Ann Med Vet 1986;130:205–214. 12. Cunningham JG. Textbook of veterinary physiology, 3rd ed. Philadelphia: WB Saunders; 2002:135–137. 13. Reed SM, Bayly WM, Sellon DC. Equine internal medicine, 2nd ed. St. Louis, MO: WB Saunders; 2004:360, 443.
ORIGINAL RESEARCH
The Effects of Verapamil Hydrochloride on Electrocardiographic (ECG) Parameters of Domestic Donkey (Equus asinus) Gholam Ali Kojouri, DVM, PhD,a Ali Rezakhani, DVM, PhD,b and Ehsan Torki, DVMc ABSTRACT Verapamil hydrochloride, a calcium channel blocker, has been used in domestic animals. Its effects on electrical activities of the heart of donkeys were studied in this preliminary research work. This experiment was carried out on 10 healthy donkeys ranging in age from 4 to 7 years and mean body weight of 155 18.6 kg. The electrocardiogram (ECG) was recorded on a base apex lead before (for 3 days), during, and after verapamil injection (10, 20, 30, 40, 50, and 60 minutes). Verapamil hydrochloride (0.3 mg/kg body weight) was given via catheterizaion as an intravenous bolus over 2 minutes. Heart rate, rhythm, ECG morphology, amplitude, durations, and intervals were measured and taken into consideration and values were compared. Results showed that heart rate was significantly increased at the time of injection from 55 10.7 before injection to 77.61 12.6 beats per minute after injection (P < .05). Duration of P and T waves; P-R interval, and also P-R segment were increased (P < .05). However, duration of QRS complex, P-P and R-R intervals, and S-T segment were significantly decreased after verapamil injection (P < .05). Sinus arrest (2 cases), bradycardia (1 case), and wandering pacemaker (1 case) were recorded before treatment and verapamil injection did not affect these arrhythmias, except in one case in which sinus arrest disappeared. However, after injection of verapamil, four types of arrhythmias (wandering pacemaker [WPM], sinus tachycardia, 1st degree AVB, and 2nd degree AVB) were recognized. These arrhythmias (with the exception of tachycardia) can be related to the increase of vagal tone activity that might be attributed to the negative effect of verapamil on SA and atrioventricular block [AV] nodes.
INTRODUCTION Verapamil is a calcium channel blocker (CCB) that blocks long-lasting calcium channels, resulting in depression of cardiac and vascular functions that depend on cardiac influx.1 The antidysrhythmic effect of verapamil appears to block the slow calcium channels in the cell membrane of the cardiac conductive system. Verapamil inhibits calcium influx across the cell membranes of the SA and AV nodes. Decrement of the rate of depolarization and automaticity occurs in the SA node and heart rate decreases (negative chronotropic effect). Conversely, conductive velocity is slowed in the AV node and prolongs the refractory period. This reduces the high ventricular rate in supraventricular tachycardia caused by atrial flutter and fibrillation. In addition, normal sinus rhythm is restored by interrupting reentry at the AV node in patients with paroxysmal supraventricular tachycardia,2 including Wolff-ParkinsonWhite syndrome. Verapamil has the potential to induce sinus arrest in sick sinus syndrome and also AV block.1,3-5 Although verapamil and other CCBs have been used in some domestic animals,2,6,7 limited data are available regarding CCBs in equine species8; accordingly, we studied the acute effects of verapamil on electrocardiographic variables in healthy domestic donkeys.
MATERIALS AND METHODS Animals This study was conducted on 10 healthy nonpregnant domestic female donkeys (Equus asinus). Blood and fecal samples were taken, then animals were weighed (155 18.6 kg) and the jugular vein catheterized with a 16-gauge needle.
From the Department of Clinical Sciences, School of Veterinary Medicine, Shahrekord University, Shahrekord, Irana; Department of Clinical Studies, School of Veterinary Medicine, Shiraz University, Shiraz, Iranb; Post-graduate Student of Large Animal Internal Medicine, School of Veterinary Medicine, Tehran University, Tehran, Iran.c Reprint requests: Gholam Ali Kojouri, DVM, PhD, Department of Clinical Sciences, School of Veterinary Medicine, Shahrekord University, P.O. Box 115, Shahrekord, Iran. 0737-0806/$ - see front matter Ó 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.jevs.2007.10.007
Electrocardiogram Recording A base apex lead was used for recording electrocardiograms (ECG). The baseapex lead was attached by placing the positive electrode on the left thorax in the fifth intercostal space at the level of the point of the elbow or at the location where the apex beat was most readily palpated. The negative electrode was attached to the skin on the right jugular furrow two thirds of the way from the ramus of the mandible to the thoracic inlet. The ground electrode was attached to a location remote from the heart.9 A baseapex lead ECG was recorded from each donkey for
Journal of Equine Veterinary Science Vol 27, No 11 (2007)
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Keywords: Verapamil; ECG; Calcium blocker; Donkey; Arrhythmia
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Table 1. Changes of Heart Rate and Some ECG Parameters (BaseApex Lead) in Domestic Donkeys Treated with Verapamil Hydrochloride (0.3 mg/kg B.W. IV) Parameters Heart Time Rate/min
a
T (seconds)
PP Interval (seconds)
RR Interval (seconds)
PR Interval (seconds)
QT Interval (seconds)
PR Segment (seconds)
ST Segment (seconds)
QRS Complex (seconds)
55.1 10.68 0.113 0.01 0.14 0.05 1.10 0.27 1.10 0.21 0.21 0.03 0.47 0.09 0.10 0.03 0.35 0.08 0.10 0.01 77.60 12.59a 0.119 0.02 0.18 0.06c 0.77 0.17a 0.78 0.17a 0.22 0.05 0.39 0.06 0.10 0.05 0.28 0.06a 0.12 0.04 60.70 12.64 0.108 0.01 0.13 0.04 1.10 0.36 1.06 0.32 0.25 0.04c 0.44 0.07 0.14 0.04c 0.34 0.06 0.14 0.02 58.90 11.53 0.109 0.02 0.14 0.03 1.00 0.17 1.00 0.16 0.24 0.03c 0.46 0.06 0.15 0.05c 0.36 0.05 0.10 0.02 57.60 10.35 0.109 0.01 0.15 0.04 1.00 0.19 1.10 0.20 0.24 0.03c 0.47 0.08 0.13 0.04 0.36 0.06 0.12 0.01
56.40 9.41
0.108 0.02 0.14 0.03 1.10 0.27 1.10 0.27 0.22 0.03 0.43 0.11 0.11 0.04 0.36 0.07 0.09 0.008d
56.60 10.38 0.111 0.02 0.16 0.03 1.10 0.26 1.10 0.27 0.23 0.04 0.46 0.11 0.11 0.03 0.35 0.06 0.12 0.01 56.60 11.23 0.124 0.02b 0.16 0.03 1.10 0.26 1.10 0.27 0.24 0.03c 0.49 0.06 0.11 0.04 0.36 0.05 0.12 0.01
%.001
%.044
%.047
%.006
Significant to other times (P < .01). b Significant to 10 minutes after injection time (P < .05). c Significant to before injection (P < .05). d Significant to 10, 30, 50, and 60 minutes after injection time (P < .05).
%.007
%.021
%.048
%.018
%.032
%.016
GA Kojouri et al Vol 27, No 11 (2007)
Before injection During injection 10 minutes after injection 20 minutes after injection 30 minutes after injection 40 minutes after injection 50 minutes after injection 60 minutes after injection P Values
P (seconds)
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Table 2. Changes of Some ECG Amplitudes (BaseApex Lead) in Domestic Donkeys Treated With Verapamil Hydrochloride (0.3 mg/kg B.W. IV) Parameters Time
P (mV)
r (mV)
S (mV)
T (mV)
Before injection During injection 10 minutes after injection 20 minutes after injection 30 minutes after injection 40 minutes after injection 50 minutes after injection 60 minutes after injection P Values
0.27 0.03 0.23 0.06 0.24 0.04 0.27 0.07 0.22 0.03 0.28 0.05 0.24 0.03 0.21 0.04 >.05
0.10 0.04 0.13 0.21 0.11 0.05 0.11 0.05 0.12 0.07 0.15 0.14 0.12 0.24 0.13 0.10 >.05
2.48 0.79 2.47 0.41 2.50 0.51 2.48 0.60 2.50 0.41 2.50 0.42 2.50 0.50 2.50 0.40 >.05
0.67 0.53 0.94 0.35 0.66 0.45 0.59 0.44 0.67 0.49 0.65 0.38 0.64 0.45 0.63 0.44 >.05
3 consecutive days before the experiment at a paper speed of 25 mm/second and calibration of 10 mm/mV (1 cm ¼ 1 mV). The pre-experiment ECGs were used for measuring heart rate, amplitude, duration, configuration, segments (PR and ST), and intervals (PP, RR, PR, and QT). For measuring the wave’s amplitudes, segments, and intervals, the computerized AutoCAD program was used. Verapamil Hydrochloride Injection This slow calcium channel blocker was injected at the dosage of 0.3 mg/kg body weight as an intravenous bolus over 2 minutes. ECG was taken during and at 10, 20, 30, 40, 50, and 60 minutes after injection (each time ECG was recorded for at least 1 minute) and ECG parameters were evaluated as before. Analytical Procedure Data were presented as mean SD. Differences in mean values were analyzed using analysis of variance with Dunnett’s post test (SigmaStat Ver. 2). A P-value < .05 was considered statistically significant.
RESULTS Results are summarized in Tables 1 to 3. Effects on Heart Rate As shown in Table 1, the normal heart rate before injection was 55.1 10.7 beats/min and increased significantly to 77.6 12.6 (P < .001) during injection and decreased to 60.7 12.6 and 56.6 11.2 at 10 and 60 minutes after verapamil injection, respectively. Effects on P Wave The data on morphology, duration, and amplitude of the P wave are summarized in Tables 1 and 2. The P wave shape was bifid in only one case before injection, increased significantly in five cases during injection (P < .05), and returned to the normal position. The P wave duration was significantly increased from 0.113 0.01 second before injection to 0.124 0.02 second at 60 minutes after injection (P ¼ .044).
The minimum, maximum, and mean P wave voltages before injection were 0.22, 0.32, and 0.27 0.03 mV, respectively. The P wave amplitudes did not change significantly during the experiment (P > .05). Effects on QRS Complex The shapes of QRS complexes remained unchanged throughout the experiment. Duration of the QRS complex decreased significantly from 0.10 0.01 before injection to 0.09 0.008 second at 40 minutes after injection of verapamil (P ¼ .016). The amplitudes of r and S waves were not significantly different (P > .05). Effects on T Wave Before injection the T wave was biphasic (-/þ) in seven cases and negative in three. At the time of injection, the T wave was positive in eight cases and at 10 minutes after verapamil injection biphasic, positive and negative T waves were observed in 2, 6, and 2 cases, respectively. Duration of T wave was significantly increased from 0.14 0.05 second before injection to 0.18 0.06 second during injection (P < .05) and returned to 0.13 0.04 second at 10 minutes after injection (P > .05). Effects on Intervals and Segments The P-P and R-R intervals and S-T segment decreased at the time of injection as compared with other times of experiment (P < .05). The P-R interval and P-R segment increased at 10 and 20 minutes after injection of verapamil as compared with pre-injection (P < .01). Effects on Heart Rhythm As mentioned, normal heart rhythm was recorded on 3 consecutive days before the experiment. Sinus arrest (2 cases), bradycardia (1 case), and wandering pace maker (1 case) were diagnosed before the experiment (Table 3). After injection of verapamil, some arrhythmias were recognized: (1) Sinus tachycardia was observed in eight cases during drug injection and limited to one case at 20 and 30 minutes after injection. (2) Wandering pacemaker was seen in one case at 20 minutes after verapamil injection and disappeared at 50 minutes after injection. (3)
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1 1 1 1 1 1 1 1 2 1 1 1 2 2 1 1 1 2 1 1 2 1 1 1 1 2 1 -
Time Arrhythmia
Sinus bradycardia Sinus tachycardia Sinus arrest Wandering pace maker 1st degree AV block 2nd degree AV block
8 1 2 1
40 Minutes after Injection 30 Minutes after Injection 20 Minutes after Injection 10 Minutes after Injection During Injection
Bradycardia disappeared during drug injection and reappeared at 10 minutes and remained until the end of experiment. (4) First-degree AV block was observed in two cases at the time of drug injection and was observed in only one case at 10 minutes after injection. (5) Seconddegree AV block was recorded in one case at the time of verapamil injection and remained stable to the final stage.
DISCUSSION
Before Injection
Table 3. Frequency of Arrhythmias and the Effect of Verapamil (0.3 mg/kg B.W. IV) on Cardiac Rhythm in Donkeys
50 Minutes after Injection
60 Minutes after Injection
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The current study was conducted to determine the effects of verapamil injection on ECG parameters in healthy donkeys. Calcium channel blockers are a major class of drugs that are used in treatment of cardiac arrhythmias. Calcium channel blockers are broadly divided into dihydropyridines (eg, nifedipine) and non-dihydropyridines (eg, verapamil). Verapamil suppresses conduction through the atrioventricular node; it is effective on both AV reciprocating tachycardia and AV nodal reentrant tachycardia. It is also useful to reduce ventricular response during atrial fibrillation/flutter.1,4 This agent inhibits the voltage-dependent calcium channel in vascular smooth muscle and also myocardial slow calcium channels.5 As previously reported, verapamil significantly suppressed AV node conduction and slightly decreased mean blood pressure. Although no significant changes occurred in the filling pressure and contractility of the left ventricle, sinus automaticity, cardiac output, intraventricular conduction, ventricular repolarization phase, and refractoriness,10 these findings showed the benefit of verapamil for treatment of supraventricular arrhythmias such as atrial fibrillation/flutter.2 Verapamil’s antiarrhythmic effects are believed to be brought about largely by its action on the sinoatrial (SA) and atrioventricular (AV) nodes. This was confirmed in this study based on recording AV block and longer P-R interval after injection. Verapamil is also a potent smooth muscle relaxant with vasodilatory properties, as well as a depressant of myocardial contractility, and these effects are largely independent of autonomic influences. Tachycardia that was observed after verapamil injection in our cases could be attributable to hypotension induced by the drug rather than excitement. Using calcium channel blocker in normal horses produced arterial vasodilation and depressing effects on the myocardium and nodal tissues.8 In the current study, some arrhythmias such as sinus arrest stabilized after verapamil injection. In addition, a new case of wandering pacemaker at 20 minutes after treatment was observed. These may be related to decreasing effect of verapamil on the rate of depolarization and automaticity in the SA node. The occurrence of sinus tachycardia may be a reflex attributable to hypotension caused by verapamil injection, which disappeared at 10 minutes after injection. First-degree AV block was recognized during and at 10 minutes after verapamil injection. The second-degree AV block was recorded at the time of injection and stabilized in all times after injection (except at 20 minutes). These two arrhythmias are considered normal variations.11 These
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conduction disorders often are associated with high vagal tone and may occur with sinus bradycardia or sinus arrhythmia.12,13 At the time of verapamil injection, hypotension and sympathetic activity led to tachycardia. Because of the physiologic response, and intervention of parasympathetic activity, heart rate was decreased by sluggish depolarization of the SA node and an increase of refractory period in the AV node cells. It is known that vagal activity is generally a depressant to heart rate, atrioventricular conduction, excitability, and myocardial inotropic (contractile) state. However, because vagotonia shortens the action potential and refractory period of atrial myocytes, high vagal activity may be predisposing factors in the development of atrial fibrillation.13 Conversely, calcium channel blockers such as verapamil bind to slow Ca2þ channels and prevent them from opening, which decreases the entry of calcium into cardiac muscle cells during an action potential. Because Ca2þ entry is the primary depolarizing event during the plateau (phase 2) of the cardiac action potential, one major effect of a Ca2þ channel blocker is to lower the plateau. A secondary consequence is to lengthen the action potential. The action potential is longer because of a complicated effect of the height of the plateau on Kþ channels that close at the beginning of a cardiac action potential and then, after a period, reopen. Kþ channel reopening helps repolarization of the cell to a resting state at the end of the action potential. The length of period before Kþ channels reopen depends on the membrane voltage during the action potential. Specifically, when the plateau is lower than normal, the Kþ channels stay closed for a longer time. This prolongs the action potential and postpones repolarization. Drugs that lengthen the cardiac action potential also lengthen the refractory period. Therefore, it is less likely that those early extra action potentials form in ectopic pacemakers or that they do not propagate even if they are formed. The SA and AV nodes do not have fast Naþ channels; instead, Ca2þ entry through slow Ca2þ channels is the main event in the slow action potentials of these cells. These action potentials are also lengthened. Low-amplitude, long action potentials propagate very slowly from cell to cell, which decreases the likelihood that early extra action potentials form or propagate in SA or AV node cells. By increasing the refractoriness and decreasing the conductive velocity of AV node cells, Ca2þ channel blockers induce most of the atrial action potentials that are dissipated in the AV node and not to be conducted to the ventricular bundle branches.12
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Calcium channel blockers can affect blood pressure and influence the cardiac rhythm. Therefore, cases with sinus tachycardia in this study could be attributable to low blood pressure as a result of verapamil. Blood pressure was not recorded in this study because of technical limitations, so it would be difficult to disregard the effect of blood pressure on the cardiac rhythm and consequently on the ECG intervals.
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