Cardiac arrhythmias produced by bretylium in cats anesthetized with halothane

European Journal of Pharmacology, 55 (1979) 93-97 © Elsevier/North-Holland Biomedical Press

93

Short communication C A R D I A C A R R H Y T H M I A S P R O D U C E D BY B R E T Y L I U M I N C A T S A N E S T H E T I Z E D W I T H HALOTHANE GEORGE A. CONDOURIS, JOSEPHINA ORTIZ and WILLIAM LYNESS Department of Pharmacology, New Jersey Medical School (CMDNJ), Newark, New Jersey 07103, U.S.A.

Received 8 November 1978, accepted 31 January 1979

G.A. CONDOURIS, J. ORTIZ and W. LYNESS, Cardiac arrhthmias produced by bretylium in cats anesthetized with halothane, European J. Pharmacol. 55 (1979) 93--97. Bretylium given by rapid intravenous injection into cats anesthetized solely with halothane precipitates severe and unusually long-lasting ventricular arrhthymias. They are observed 20--70 sec following doses of bretylium ranging from 0.8 mg/kg to 15 mg/kg and last for 60 sec to just over half an hour. Bretylium also manifests signs of sympathetic involvement since it raises blood pressure and heart rate just prior to the onset of arrhythmias. Propranolol pretreatment prevents bretylium arrhythmias. From these results and from those of other investigations, it is concluded that bretylium arrhythmias are mediated through the release of endogenous noradrenaline stored in adrenergic neurons of the heart. These results call attention to the arrhythmogenic potential of bretylium in the presence of halothane anesthesia. Cardiac arrhythmias

Bretylium

Halothane

1. I n t r o d u c t i o n B r e t y l i u m is an adrenergic n e u r o n b l o c k i n g d r u g t h a t also possesses a n t i a r r h y t h m i c e f f e c t s in e x p e r i m e n t a l a n i m a l s a n d in h u m a n subjects (Bacaner, 1 9 6 8 ; Allen et a l . , 1 9 7 2 ; S a n n a a n d A r c i d i a c o n o , 1973). A p r o m i n e n t p h a r m a c o l o g i c f e a t u r e is its ability to p r o d u c e s y m p a t h o m i m e t i c e f f e c t s on t h e cardiovascular s y s t e m w h i c h result f r o m t h e release o f c a t e c h o l a m i n e s f r o m adrenergic storage sites. O u r i n t e r e s t in this d r u g arose o u t o f t h e obs e r v a t i o n t h a t in cats a n e s t h e t i z e d w i t h halothane, the acute intravenous administration o f b r e t y l i u m p r o v o k e s serious v e n t r i c u l a r arrhythmias of moderately long duration. This i n t e r a c t i o n b e t w e e n a h a l o g e n a t e d hyd r o c a r b o n a n e s t h e t i c a n d a d r u g releasing c a t e c h o l a m i n e s f r o m adrenergic stores has n o t been reported. The experiments presented here were designed t o s t u d y t h e p h a r m a c o l o g i c condit i o n s u n d e r l y i n g t h e d e v e l o p m e n t o f cardiac

Catecholamines

arrhythmias due to the combined actions of b r e t y l i u m t o s y l a t e and h a l o t h a n e in t h e cat.

2. Materials a n d m e t h o d s H a l o t h a n e was a d m i n i s t e r e d to cats o f e i t h e r sex ( 1 . 7 - - 3 . 1 kg) w i t h t h e use o f t h e m o d i f i e d B l o o m q u i s t i n f a n t circle a b s o r b e r a d a p t e d to a Foregger anesthesia machine. Anesthesia was i n d u c e d w i t h a m e t e r e d m i x t u r e o f 5 - - 7 % h a l o t h a n e a n d 9 3 - - 9 5 % o x y g e n and, f o l l o w i n g t r a c h e a l i n t u b a t i o n , a n e s t h e s i a was m a i n tained a t a s t a n d a r d d e p t h w i t h m e t e r e d concentrations of halothane varying between 1.5% a n d 2.5%. In s o m e a n i m a l s r e s p i r a t i o n was assisted f o r 2 or 3 r e s p i r a t i o n cycles each m i n u t e ; in o t h e r s , r e s p i r a t i o n was p u r p o s e l y p e r m i t t e d t o go unassisted at rates b e t w e e n 4 0 - - 5 0 p e r m i n t o p r o v i d e changes in t h e a c i d - - b a s e b a l a n c e so as t o e v a l u a t e t h e cont r i b u t i o n o f t h e s e changes t o t h e d e v e l o p m e n t of halothane--bretylium arrhythmias.

94 Blood samples for pH and gas analysis were obtained anaerobically just prior to the provocation of arrhythmias or immediately following their disappearance. The heparinized sample was kept on ice until the chemical determinations were made within one hour. The instrument used for the pH, Po2 and Pco2 determinations were: Corning Analyzer Model 165 or Instrumentation Lab Analyzer, Model 113. The parameters measured or calculated were pH, Pco2, total CO2 and HCO3. The cat's temperature was maintained at 37 ° C + 0.5 ° C by means of a heat lamp controlled through a rectal thermometer and temperature-control relay. Drugs were dissolved in 0.9% saline and were injected intravenously into the cannulated saphenous or femoral vein and were always followed immediately by a 2 ml wash with 0.9% saline. Arterial blood pressure was recorded from the femoral artery in the contralateral leg through a polyethylene cannula connected to a Statham pressure transducer whose signals were transmitted to a Grass Model 7 Polygraph. Standard lead II was used in the electrocardiographic recordings. Following the cannulation of the vein and artery, the cat was allowed to remain quiet for 10 min before the administration of the first dose of noradrenaline or experimental drug. Bretylium and noradrenaline were given by rapid i.v. injection; propranolol hydrochloride was given i.v. slowly. The significance of mean difference in measured parameters was established with the use of the paired Student's t-test; the significance level selected was P < 0.05.

3. Results

Bretylium tosylate was administered by rapid i.v. injection into a total of 17 cats anesthetized with halothane as the only anesthetic. The doses of bretylium ranged from 0.8 mg/kg to 15 mg/kg (0.8, 1.6, 5.0, 10.0, 15.0 mg/kg) and ventricular arrhythmias were

G.A. CONDOURIS ET AL. seen in each animal receiving a dose within this range. The bulk of experiments, however, involved the use of a standard dose of 10 mg/kg which has been widely used by others in various types of investigations in cats and dogs. The ECG record in fig. 1 illustrates the time-course of the bretylium arrhythmias as well as the component types of arrhythmic patterns. A dose of 10 mg/kg evoked a chaotic ECG displaying an array of arrhythmias including nodal rhythm, premature ventriculax excitations (PVE), ventricular tachycardia (VT), multifocal r h y t h m (MF), bigeminy and trigeminy. Results from experiments involving a variety of doses show that the first sign of ventricular arrhythmia occurred in 20--70 sec, and that the duration of arrhythmias was as long as 33 min and as short as 60 sec. In 13 cats receiving a standard dose of 10 mg/kg bretylium tosylate, the mean onset time (+ S.E.) for arrhythmias was 32 + 5 sec (range: 20--70 sec); the mean duration (+S.E.) was 10.0 + 2.6 min (range: 4--33 min). Onset time was measured from the time of injection to the first PVE: duration was measured from the time of the first PVE to the time of the last PVE. (Duration time excludes the time required for conversion of nodal r h y t h m to normal sinus r h y t h m which often took an additional 10--30 min). Just prior to the appearance of the first PVE there was a rise in heart rate and in both systolic and diastolic blood pressure (table 1). These cardiovascular parameters generally remained elevated even during the arrhythmias except for a transient fall in blood pressure during brief runs of VT. If the injection of bretylium was repeated within one hour of the first dose, arrhthmias could be elicited again in only some cats suggesting that the drug demonstrates some tachyphylaxis with respect to its arrhythmogenic effect. Whenever the second injection of bretylium failed to produce arrhythmias, noradrenaline was always effective in causing arrhythmias. This latter result also indicates that bretylium does not exert any antiadren-

95

BRETYLIUM--HALOTHANE ARRHYTHMIAS

TABLE 1 Heart rate and blood pressure changes in response to bretylium. Data represent means + S.E. derived from 13 cats treated with 10 mg/kg of bretylium in the manner described in Methods. All contrasts between control values and the values prior to and during the arrhythmias are statistically highly significant when tested by Student's paired t-test. (P-values ranged from <0.0001 to <0.005).

CONTROL

0.5 rnin

Control

Prior to first PVE

During arrhytmia

118 + 7

148 + 8

159 + 10

101 + 5

134 + 7

172 + 8

62 -+ 6

95 + 7

123 + 7

I rain

Heart rate (beats/rain) Systolic blood pressure (mmHg) Diastolic blood pressure (mmHg)

5 rain

7 rain

I0 rnin ~

~

~

,

~

17 rain I

I I ae¢

Fig. 1. Temporal course of development of cardiac arrhythmias following the rapid i.v. administration of bretylium tosylate, 10 mg/kg, into a cat at zero time. Note the display of PVE, multifocal PVE, VT, trigeminy and nodal rhythm. Halothane anesthesia. ergic or a n t i a r r h y t h m i c e f f e c t against catecholamine arrhythmias during these periods of tachyphylaxis. Experiments were done with dl-propranolol (0.5 m g / k g ) in 4 cats t o a s c e r t a i n w h e t h e r

~-adrenergic b l o c k a d e c o u l d p r e v e n t or m o d ify b r e t y l i u m a r r h y t h m i a s . In 2 cats t h e o r d e r o f d r u g a d m i n i s t r a t i o n was n o r a d r e n a l i n e bretylium-propranolol-noradrenaline-bretyliu m . T o a c c o u n t f o r t h e possibility o f t a c h y phylaxis to the second dose of bretylium, the o r d e r in 2 o t h e r cats was n o r a d r e n a l i n e propranolol-noradrenaline-bretylium. Propranolol prevented noradrenaline and bretylium v e n t r i c u l a r a r r h y t h m i a s in all cats. (A b r i e f epis o d e o f b r a d y c a r d i a w i t h 1 P V E o c c u r r e d in 1 cat). P r o p r a n o l o l itself p r o d u c e a fall in h e a r t r a t e a n d b l o o d p r e s s u r e as e x p e c t e d f r o m its b l o c k of/3-adrenergic r e c e p t o r s in t h e heart. A r r h y t h m i a s w e r e o b s e r v e d in cats having w i d e ranges o f values o f arterial p H , Pco2, t o t a l CO2 and b i c a r b o n a t e . T h e s e values, summ a r i z e d in t a b l e 2 , c o m p a r e closely w i t h values p r e v i o u s l y r e p o r t e d f o r " a n e s t h e t i z e d " cats: p H 7 . 2 8 (range: 7 . 1 8 - - 7 . 3 5 ) ; Pco2 45 m m Hg (range: 3 4 - - 5 2 ) ; t o t a l CO2 2 1 . 8 ram/1 {range: 1 9 - - 2 5 ) ; ( A l t m a n a n d D i t t m e r , 1961). Since a r r h t h m i a s w e r e o b s e r v e d u n d e r t h e s e diverse c o n d i t i o n s o f p H a n d Pco2, changes in

96

G.A. CONDOURIS ET AL.

TABLE 2 Summary of acid--base statistics 1 Mean + S.E. pH Pco 2 (mmHg) Total CO2 (mm/l) Bicarb. (meq/1)

7.28 33.7 18.1 16.8

Rangeof values

0 . 0 3 7.13-- 7.54 2.2 19 --49 0.9 14.5 --25.0 0.8 14.0 --23.0

I The statistics were derived from blood samples taken from 13 cats (see Methods).

blood chemistry were n o t important determinants for the pharmacological effect.

4. Discussion The results reported here demonstrate apparently for the first time the severe ventricular arrhythmias caused by the combined interaction of halothane and bretylium. The apparent paradox in which bretylium, an adrenergic blocking drug and antiarrhythmic drug, provokes severe cardiac arrhythmias in the presence of halothane is readily explained by invoking one of the several actions of bretylium at the terminal of adrenergic nerves, namely, the liberation of catecholamines that are stored in nerve terminals of the heart, an action that precedes the more well-known paralysis of adrenergic nerves (Boura and Green, 1965). Direct evidence for bretylium's release of catecholamines from cardiac tissues was obtained in the dog under pentobarbital anesthesia (Gilmore and Siegel, 1962). The investigators reported a significant rise in coronary venous levels for a period of 15 min and simultaneous cardiodynamic changes consistent with adrenergic amine effects. These facts support the earlier work of Yelnosky and Mortimer (1961) who first suggested that the cardiovascular effects of bretylium in the dog were due to the release of catecholamines from cardiac tissues stores. The prolonged release of cateqholamines reported above fits in well with the relatively

long duration of bretylium-induced arrhythmias in our experiments. Single injections of noradrenaline, on the other hand, rarely produce arrhythmias lasting longer than 120 sec. The unequivocal block of bretylium arrhythmias with propranolol further substantiates the conclusion that bretylium's arrhythmias are mediated through released catecholamines, most probably noradrenaline. It is unlikely that bretylium produces the arrhythmias by acting directly on the myocardium since bretylium causes minimal effects on the electrophysiologic properties of isolated canine papillary muscle and Purkinje fibers, although it increases the rate of spontaneous excitation of Purkinje cells and the rate of phase 4 depolarization, effects which the authors feel are due to the release of catecholamines (Bigger and Jaffe, 1971). The aggregate evidence favors the view that bretylium arrhythmias in cats anesthetized with halothane are, in reality, the classical catecholamine-hydrocarbon arrhythmias. There is no ready explanation for the apparent tachyphylaxis to bretylium's arrhythmogenic effect. It does not deplete cardiac catecholamines as do tyramine and guanethidine (Boura and Green, 1965). And, as shown in the present experiments it does not have an antiadrenergic effect. There is a remote possibility that the drug may interfere with its own uptake mechanism, but there is no evidence available for this conjecture. The question arises whether or not bretylium can cause arrhythmias in animals anesthetized with other anesthetics. We examined this in 3 cats under Dial--urethane anesthesia, but observed no arrhythmias with 10 mg/kg bretylium. On the other hand, others did observe "ventricular ectopic beats" in dogs given bretylium (20 mg/kg) under anesthesia with a combination of morphine, thialbarbitone and chloralose {Allen et al., 1972). In cats under Dial--urethane anesthesia bretylium intensifies ventricular arrhythmias caused by digitalis (Gillis et al., 1973). These investigators concluded that the effect was a consequence of catecholamine liberation. These findings col-

BRETYLIUM--HALOTHANE ARRHYTHMIAS lectively s u p p o r t the c o n c l u s i o n t h a t bretyliu m is, in fact, an a r r h y t h m o g e n i c d r u g t h a t p r o d u c e s t h e e f f e c t indirectly t h r o u g h t h e release o f tissue c a t e c h o l a m i n e s . T h e unm a s k i n g o f this l a t e n t a c t i o n d e p e n d s o n t h e presence o f a p r o p e r p h a r m a c o l o g i c substrate and o n t h e p h y s i o l o g i c state o f the animal. H a l o t h a n e anesthesia or digitalis p r e t r e a t m e n t are t w o c o n d i t i o n s t h a t allow t h e manifestat i o n o f t h e a r r h y t h m o g e n i c effect. Preliminary investigations indicate t h a t b r e t y l i u m shares this a r r h y t h m o g e n i c p r o p e n s i t y with guanet h i d i n e ( K o p i a a n d C o n d o u r i s , 1977).

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97 Bacaner, M., 1968, Treatment of ventricular fibrillation and other acute arrhythmias with bretylium tosylate, Amer. J. Cardiol. 21,530. Bigger, J.T. and C.C. Jaffe, 1971, The effect of bretylium tosylate on the electrophysiologic properties of ventricular muscle and purkinje fibers, Amer. J. Cardiol. 27, 82. Boura, A.L.A. and A.F. Green, 1965, Adrenergic neurone blocking agents, Ann. Rev. Pharmacol. 5, 183. Gillis, R.A., M.M. Clancy and R.J. Anderson, 1973, Deleterious effects of bretylium in cats with digitalis-induced ventricular tachycardia, Circulation 47,947. Gilmore, J.P. and J.H. Siegel, 1962, Mechanism of myocardial effects of bretylium, Circulation Res. 10, 347. Kopia, G. and G. Condouris, 1977, Guanethidineinduced cardiac arrhythmias in cats anesthetized with halothane, Federation Proc. 36, 1013. Sanna, G. and R. Arcidiacono, 1973, Chemical ventricular defibrillation of the human heart with bretylium tosylate, Amer. J. Cardiol. 32, 982. Yelnosky, J. and L.C. Mortimer, 1961, A brief study of the sympathomimetic cardiovascular effects of bretlyium, Arch. Inter. Pharmacodyn. 130,200.