The influence of metiamide on ouabain cardiotoxicity

233

European Journal of Pharmacology, 34 (1975) 233--236

© North-Holland Publishing Company, Amsterdam -- Printed in The Netherlands Short communication THE INFLUENCE OF METIAMIDE ON OUABAIN CARDIOTOXICITY* JOHN SOMBERG, NORMAN A. CAGIN, JACK KLEID, HELENE BOUNOUS, BARRIE LEVITT and ROBERTO LEVI** Department of Medicine, New York Medical College, New York, 10029, and the Department of Pharmacology, Cornell University Medical College, New York, 10021, U.S.A.

Received 19 August 1975, accepted 4 September 1975

J. SOMBERG, N.A. CAGIN, J. KLEID, H. BOUNOUS, B. LEVITT and R. LEVI, The influence ofmetiamide on ouabain cardiotoxicity, European J. Pharmacol. 34 (1975) 233--236.

The effect of metiamide on the cardiotoxicity produced by ouabain was studied in pentobarbital-anesthetized cats. The onset of ouabain-induced ventricular tachycardia and fibrillation was significantly delayed in cats treated with metiamide as compared with cats that did not receive metiamide. Although the mechanism by which metiamide inhibits ouabain toxicity is speculative, the data suggest that histamine H2-receptor blocking agents may be useful as anti-arrhythmic drugs in digitalis cardiotoxicity. Ouabain (digitalis)

Metiamide

Antihistamine

1. I n t r o d u c t i o n H i s t a m i n e , w h e t h e r a d m i n i s t e r e d exogen o u s l y or released f r o m e n d o g e n o u s sources m a y cause p r o f o u n d changes in cardiac f u n c tion, altering c o n t r a c t i l i t y , a u t o m a t i c i t y , cardiac c o n d u c t i o n and c o r o n a r y f l o w ( H a r m e r and Harris, 1 9 2 6 ; Weiss et al., 1932; Levi and Giotti, 1967; Levi, 1972; C a p u r r o and Levi, 1975). T h e d e v e l o p m e n t o f n e w antihistam i n e s ( H 2 - r e c e p t o r antagonists; Black et al., 1 9 7 3 ) has b r o u g h t a n t a g o n i s m o f cardiac hist a m i n e e f f e c t s into t h e r e a l m o f possibility. S o m e o f t h e cardiac e f f e c t s o f h i s t a m i n e r e s e m b l e t h o s e o f digitalis: b o t h h i s t a m i n e and digitalis e n h a n c e cardiac c o n t r a c t i l e force, p r o l o n g a t r i o v e n t r i c u l a r c o n d u c t i o n t i m e and e n h a n c e cardiac a u t o m a t i c i t y . F u r t h e r m o r e ,

* Supported by a grant-in-aid from Whitehall Foundation and a grant-in-aid from the New York Heart Association. ** Supported by a grant-in-aid from the New York Heart Association by the John Polachek Foundation and by U.S.P.H.S. Grant ¢ GM 20091.

Histamine H2-receptor blocking agent

Digitalis toxicity

o u a b a i n p o t e n t i a t e s h i s t a m i n e - i n d u c e d cardiac a r r h y t h m i a s (Levi and C a p u r r o , 1975). Therefore, it is e n t i r e l y possible t h a t agents w h i c h inhibit t h e cardiac e f f e c t s o f h i s t a m i n e m a y also i n t e r f e r e w i t h t h e cardiac effects o f digitalis. In o r d e r to elucidate t h e influence histam i n e H 2 - b l o c k i n g agents o n digitalis t o x i c i t y , t h e c a p a c i t y o f m e t i a m i d e , an H 2 - h i s t a m i n e r e c e p t o r a n t a g o n i s t (Black et al., 1973), t o m o d i f y t h e d o s e o f o u a b a i n n e e d e d to prod u c e v e n t r i c u l a r a r r h y t h m i a s and d e a t h was investigated in t h e cat.

2. Materials a n d m e t h o d s All e x p e r i m e n t s w e r e p e r f o r m e d on cats o f e i t h e r sex weighing b e t w e e n 1.6 and 3.0 kg. Animals w e r e a n e s t h e t i z e d w i t h s o d i u m pent o b a r b i t a l 40 m g / k g injected i n t r a p e r i t o n e a l ly. T r a c h e a l c a n n u l a t i o n was p e r f o r m e d on all animals. B o d y t e m p e r a t u r e was m e a s u r e d b y m e a n s o f a rectal t h e r m o m e t e r and maintained b e t w e e n 36 ° and 37°C w i t h r a d i a n t heat. T h e f e m o r a l a r t e r y was c a n n u l a t e d f o r

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J. S O M B E R G ET AL.

the withdrawal of blood samples to measure pH, pCO2 and pO2. A bipolar catheter was inserted in the jugular vein and advanced to record the inta-atrial electrogram. The bracheal artery was cannulated to measure arterial blood pressure using a Statham P-50 transducer. Both femoral veins were exposed and catheterized. Polyethylene catheters were connected to a twochannel Harvard model continuous infusion pump. A four lead surface electrocardiogram, the intra-atrial electrogram and arterial blood pressure were recorded continuously on a Beckman 411 Dynograph recorder. Bilateral vagal section was performed on all cats by crushing and dividing the vagus nerve in the neck. Mechanical ventilation with room air when needed was provided by means of a constant volume pump (Harvard small animal model). Respiratory rate and tidal volume were adjusted to maintain arterial blood pH, pO2 and pCO2 within normal limits for the cat (Fink and Schoolman, 1963). These were measured by means of a Radiometer pH meter No. 27 equipped with microelectrodes for measurement of pO2 and pCO2. Ouabain injection USP (Eli Lilly and Company, Indianapolis, Ind.) was diluted with normal saline so that 1 pg/kg (as the octahydrate) could be delivered in 0.2 ml each minute by continuous infusion to all cats. One

group (control) received only ouabain. The other group received metiamide (a gift of Smith, Kline and French Laboratories, Philadelphia, Pa.) 12.2 pg/kg/min or 25 pg/kg/min. Metiamide and ouabain were infused simultaneously but each into a separate vein. The dose of ouabain associated with the induction of ventricular tachycardia and death was noted. The significance of the differences between means was determined with Student's t-test.

3. Results The present study indicates that the dose of ouabain associated with ventricular tachycardia and death in animals simultaneously treated with metiamide is significantly higher than in cats that did not receive metiamide. Thus, the dose of ouabain needed to produce ventricular tachycardia was 57.0 + 0.92 pg/kg while the dose of ouabain needed to produce ventricular tachycardia in cats that received metiamide 12.2 pg/kg/min was 75.4 + 4.6 pg/kg/min (p < 0.01) (table 1). In cats receiving metiamide 25 pg/kg/min the dose of ouabain needed to produce ventricular tachycardia was 85.2 -+ 5.6 pg/kg (p <: 0.001) (table 1). Moreover, the dose of ouabain required to produce death was increased from 66.9 + 1.2 pg/kg to 95.2 + 5.8 pg/kg and 107.2 + 5.2

TABLE 1 The influence o f m e t i a m i d e on the dose (pg/kg) o f o u a b a i n associated with the i n d u c t i o n o f cardiac r h y t h m disorders ( m e a n -+ S.E.). Ventricular t a c h y c a r d i a

Death

Ouabain (11) a

57.9 -+ 0.92

66.9 -+ 1.2

Ouabain & m e t i a m i d e 12.2 pg/kg/min (6)

75.4 -+ 4.65

95.2 -+ 5.8 c

Ouabain & m e t i a m i d e 25 pg/kg/min (6)

85.2 -+ 5.6 c

107.2 +- 5.2 c

a The n u m b e r s in p a r e n t h e s e s indicate t h e n u m b e r o f animals in each group. b Significantly d i f f e r e n t f r o m c o n t r o l , p < 0.01. c Significantly d i f f e r e n t f r o m c o n t r o l , p < 0.001.

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I N F L U E N C E O F M E T I A M I D E ON O U A B A I N T O X I C I T Y TABLE 2 The influence o f ouabain o n h e a r t rate and b l o o d pressure in cats given m e t i a m i d e . Control

1 rain b e f o r e ventricular tachycardia

1 min after ventricular tachycardia

Heart rate (beats/rain) Ouabain (11) a

208.1 ±

7.7

202.3 -+ 4.4

211.6 ± 14.0

Ouabain & m e t i a m i d e (12.2 pg/kg/min (6))

193.6 ±

9.9

188.8 ± 17.5

196.5 ± 22.5

Ouabain & m e t i a m i d e (25/~lg/kg/min (6))

207.8 ±

7.3

181.8 ± 14.0

193.2 ± 13.3

Ouabain

116.3±

7.5

1 0 9 . 6 ± 13.9

100.1 ± 17.3

Ouabain & m e t i a m i d e (12.2 pg/kg/min)

139.0 ±

2.0

112.5 ±

9.0

105.8 ±

Ouabain & m e t i a m i d e (25 pg/kg/min)

133.2 ± 13.6

109.6 ±

5.4

94.5 ± 11.6

Systolic b l o o d pressure ( m m Hg)

6.0

Diastolic b l o o d pressure (ram Hg) Ouabain

87.7 ±

9.5

70.0 ± 14.1

65.4 ± 13.8

Ouabain & m e t i a m i d e (12.2 pg/kg/min)

117.5 ±

6.4

73.7 ± 10.7

63.5 ±

9.2

Ouabain & m e t i a m i d e (25 pg/kg/min)

104.2 ±

8.9

63.2 ±

55.3 ±

6.9

3.2

a The n u m b e r s in p a r e n t h e s e s indicate t h e n u m b e r o f animals in each group.

pg/kg in cats treated with 12.2 and 25 pg/kg/ min of metiamide respectively {p < 0.001) (table 1). There was no significant difference in heart rate or blood pressure between cats treated with ouabain only and cats treated with ouabain and metiamide (see table 2).

4. Discussion Our data clearly indicate that metiamide delays the onset of ventricular rhythm disorders induced by ouabain and increases lethal dose of ouabain in the cat. Since metiamide is a histamine H:-receptor antagonist (Black et al., 1973), the most facile explanation is that histamine might play a role in the induction

of cardiotoxicity by ouabain, and that metiamide prevents some of these toxic effects by antagonizing some cardiac effects of histamine. A ouabain--histamine interaction leading to severe cardiac dysfunction has been demonstrated in the isolated heart of the guinea pig (Levi and Capurro, 1975). However metiamide could prevent ouabain toxicity b y mechanisms other than its capacity to block histamine H2-receptors. It may be that this antiarrhythmic action is peculiar to metiamide and not shared by other histamine H2-receptor blocking agents. Metiamide might inhibit digitalis toxicity by interfering with the autonomic nervous system and particularly by decreasing adrenergic influences. Elimination of the adrenergic nervous system by surgical ablation (Levitt et al., 1973; Cagin et

236

al., 1974) and by antiadrenergic drugs (Levitt and Roberts, 1965; Standaert et al., 1966; Ciofalo et al., 1967; Raines et al., 1968; Levitt et al., 1969; Kelliher et al., 1971) has been shown to decrease the capacity of digitalis to cause toxicity. However, an antiadrenergic effect is unlikely because metiamide did not change heart rate or blood pressure. Furthermore, metiamide could inhibit the uptake of ouabain by the myocardium. Inhibition of ouabain uptake by propranolol protects the heart against ouabain toxicity in vitro (Cagin et al., 1973). On the other hand, metiamide may display local anesthetic effects, or even enhance the renal elimination of ouabain. Clearly, further investigation is needed to elucidate metiamide's ability to diminish ouabain toxicity in the cat. This study reveals not only a new use for histamine H 2-receptor antagonists but also introduces a new approach to the prevention of digitalis toxicity.

References Black, J.W., W.A.M. Duncan, J.C. Emmet, C.R. Ganellin, T. Hesselbo, M.E. Parsons and J.H. Wyllie, 1973, Metiamide- an orally active histamine H2receptor antagonist, Agents and Actions 3,133. Cagin, N., E. Freeman~ J. Somberg, H. Bounous, T. Mittage, R. Diaz and B. Levitt, 1973, The influence of propranolol on ouabain uptake by the guinea pig heart, European J. Pharmacol. 24, 3. Cagin, N., J. Somberg, H. Bounous, T. Mittage, A. Raines and B. Levitt, 1974, The influence of spinal cord transection on the capacity of digitoxin to induce cardiotoxicity, Arch. Int. Pharmacodyn. Ther. 207,340. Capurro, N. and R. Levi, 1975, The heart as a target organ in systemic allergic reactions: comparison of anaphylaxis in vivo and in vitro, Circulat. Res. 36, 520.

J. SOMBERG ET AL. Ciofalo, F., B. Levitt and J. Roberts, 1967, Some factors affecting ouabain-induced ventricular arrhythmia in the reserpine-treated cat, Brit. J. Pharmacol. 30, 143. Fink, B. and A. Schoolman, 1963, Arterial blood acid-base balance in unrestrained waking cats, Proc. Soc. Exp. Biol. Med. 112, 328. Harmer, I. and K. Harris, 1926, Observations on the vascular reactions in man in response to histamine, Heart 13, 381. Kelliher, G., B. Levitt, A. Raines and J. Roberts, 1971, The influence of practolol on cardiotoxicity induced by ouabain and digoxin, Pharmacologist 13, 301. Levi, R. and A. Giotti, 1967, Effects of histamine on Sino-atrial node cells of rabit heart, Experientia 23, 66. Levi, R., 1972, Effects of exogenous and immunologically released histamine on the isolated heart; a quantitative comparison, J. Pharmacol. Exp. Ther. 182, 227. Levi, R. and N. Capurro, 1975, Cardiac histamine-ouabain interaction: potentiation by ouabain of the arrhythmogenic effects of histamine, J. Pharmacol. Exp. Ther. 192, 113. Levitt, B. and J. Roberts, 1965, Depression of digitalis-induced ventricular arrhythmia by reserpine, Pharmacologist 7,176. Levitt, B., A. Raines, D. Moros and F. Standaert, 1969, The capacity of N-isopropyl-p-nitro-phenylethanolamine (INPEA) to influence the course of ouabain induced cardiotoxicity in the cat, European J. Pharmacol. 6, 217. Levitt, B., M. Cagin, J. Somberg, H. Bounous, T. Mittage and A. Raines, 1973, Alteration of the effects and distribution of ouabain by spinal cord transection in the cat, J. Pharmacol. Exp. Ther. 185, 24. Raines, A., D. Moros and B. Levitt, 1968, The effect of guanethidine on ouabain-induced ventricular ar o rhythmia in the cat, Arch. Int. Pharmacodyn. Ther. 174, 373. Standaert, F., B. Levitt and J. Roberts, 1966, Antagonism of digitalis arrhythmia by pronethalol, a neural phenomenon? Nature 210, 742. Weiss, S., G. Robb and L. Ellis, 1932, The systemic effects of histamine in man; with special reference to the response of the. cardiovascular system, Arch. Intern. Med. 49, 360.