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Observations on the hypotensive response to dehydroemetine
EUROPEAN JOURNAL OF PHARMACOLOGY 14 (1971) 200-203. NORTH-HOLLAND PUBLISHING COMPANY
S h o r t communication
OBSERVATIONS
ON THE HYPOTENSIVE
RESPONSE
TO DEHYDROEMETINE L.A. SALAKO * Pharmacology Department, University of lbadan, Ibadan, Nigeria and A.O. DUROTOYE Physiology Department, University of Ibadan, Ibadan, Nigeria
Received 19 January 1971
Accepted 9 February 1971
L.A. SALAKO and A.O. DUROTOYE, Observations on the hypotensive response to dehydroemetine, European J. Pharmacol. 14 (1971)200-203. Dehydroemetine reduced blood pressure and produced adrenergic neurone block in the anaesthetised cat but the time courses of the two effects were different. Dehydroemetine also increased the venous outflow in the isolated perfused rabbit ear and decreased the rate and force of contraction of the isolated perfused rabbit heart. Dehydroemetine Perfused rabbit ear
Cat nictitating membrane Perfused rabbit heart
Adrenergic nettrone block Blood pressure, cat
1. INTRODUCTION
2. METHODS
Dehydroemetine is a recently introduced antiamoebic drug (Herrero, Brossi, Faust and Frey, 1960) which is rapidly replacing emetine as the drug of choice in the treatment of acute intestinal and systemic amoebiasis (Wilmot, 1969). The drug is generally believed to be better tolerated than emetine, but transient hypotension and tachycardia occur after an injection of dehydroemetine as it does after emetine. (Dempsey and Salem, 1966; Salem and Abd-Rabbo, 1964). Ng and Ng (1970) showed that dehydroemetine had an adrenergic neurone blocking action in vitro and suggested that the transient hypotension produced by the drug might be due to this action. The nature of the hypotensive effect of dehydroemetine was further examined in this study.
6 cats were anaesthetised with intravenous chloralose (80 mg/kg) to which sodium pentobarbitone (5 mg/kg) was added. The pre- or post-ganglionic trunk of the cervical sympathetic nerve was stimulated through a pair of platinum electrodes with square pulses of 20 V and 0.5 msec and the resulting contractions of the nictitating membrane were recorded on smoked paper. Blood pressure was measured from a femoral artery either with a Statham P23 transducer and recorded on a Schwatzer physiograph or with a mercury manometer and recorded on smoked paper. Hearts isolated from six rabbits were mounted and perfused by the Langendorff technique (Burn, 1952). The perfusion fluid was oxygenated Locke's solution at 38°C. Contractions of the heart were recorded on smoked paper. 12 ears detached from 6 freshly killed rabbits were kept in a refrigerator for 1 8 - 2 4 hr after cannulating
* Address to which all communications are to be sent.
L.A.Salako, A.O.Durotoye, Dehydroemetine and the cardiovascular system
201
above caused a more prolonged fall in blood pressure associated with bradycardia and sometimes irregular heart beat. Recovery was slow, lasting 30 rnin to 1 hr, but usually complete. The effect on blood pressure was not affected by vagotomy, atropine (1 mg/kg) propranolol 1-2.5 mg/kg, phenoxybenzamine ( l m g / k g ) mepyrarnine 0 . 5 - 1 m g / k g and hexamethonium 1 mg/kg. Contractions of the nictitating membrane elicited by preganglionic or postganglionic stimulation of the cervical sympathetic nerve were not affected by 0.5, 1.0 and 2.0 mg/kg dehydroemetine, but were inhibited by doses of dehydroemetine of 5 mg/kg and above. Doses of 3 mg/kg repeated 2 - 3 times at 10-15 min intervals also inhibited the contractions. The effect on nictitating membrane contractions had a latent period of 10-20 min and was not reversible after 4 hr observation. The effect was also not reversed by giving-cocaine 0.5 mg/kg i.v. Contractions of the nictitating membrane elicited by giving 50 lag
the central artery. Storage for 24 hr is said to increase the sensitivity of the ear (Andrew, 1965). The ears were then mounted and perfused as described by Burn (1952), the technique being modified to keep both the perfusion fluid (oxygenated Locke's solution) and the ear at the same constant temperature of 30°C (Green and Boura, 1964). The venous outflow from the perfused ear was passed through a photoelectric drop counter and recorded on smoked paper using a Thorp impulse recorder.
3. RESULTS 3.1. Cat blood pressure and nictitating membrane Intravenous injection of dehydroemetine in doses between 0.5 and 3 mg/kg caused an immediate fall in blood pressure. The effect was short-lived lasting only 30 sec-2 min, and was not accompanied by any change in heart rate (fig. 1). Doses of 5 mg/kg and
ISO-
E 100-
so
•
0 1
•
A
•
A
m011
Fig. 1. Cat 2.1 kg under chloralose anaesthesia. Effect of dehydroemetine on blood pressure. At • from left to fight dehydroemetine, 1, 2 and 3 mg/kg successivelyi.v. At A, the paper speed was increased 10-fold to show effect on heart rate.
\
\ L..---J
30rain
L-.d
60 vnin
Fig. 2. Cat 2.1 kg under chloralose anaesthesia. Effect of dehydroemetine on contractions of the nictitating membrane elicited by preganglionic stimulation of the cervical sympathetic nerve. Dehydroemetine 5 mg/kg was given i.v. at the end of the first panel. Contractions of the nictitating membrane elicited by intravenous injection of noradrenaline (50 ~g) were unaffected by the drug.
202
L.A.Salako, A.O.Durotoye, Dehydroemetine and the cardiovascular system
noradrenaline i.v. were not affected by dehydroemetine (fig. 2). 2.2. Isolated rabbit heart
Dehydroemetine, in doses of 10~g and above, injected into the perfusion fluid close to the aortic cannula caused a fall in the force and rate of contraction of the heart. In 6 experiments 10#g dehydroemetine caused a mean decrease of 22 + 2.4% (S.D.) in the amplitude of contraction and 12 -+ 2.1% (S.D.) in the rate of contraction 10 min after injecting the drug into the perfusion tubing. 3.3. Isolated rabbit ear
Dehydroemetine injected into the perfusion tubing close to the arterial cannula increased the venous outflow from the ear. The effect was slight and transient (lasting 1-3 rain), and relatively large doses of dehydroemetine (above 0.1 mg) were required. Maximal effect was produced by 1 mg and above, and this averaged 10 -+ 2.1% (S.D.) increase over control outflow in 12 experiments. The effect persisted in the presence of propranolol (1 #g/ml) in the perfusion fluid.
4. DISCUSSION The results of this study show that dehydroemetine inhibits contractions of the cat nictitating membrane elicited by pre- or post-ganglionic stimulation of the cervical sympathetic nerve without affecting contractions elicited by intravenous noradrenalinc. The drug thus has an adrenergic neurone blocking action in vivo similarly to that previously demonstrated in vitro (Ng and Ng, 1970). The adrenergic neurone blocking action of dehydroemetine however differs from that of bretylium and guanethidine in that it cannot be reversed by cocaine (Day, 1962). The hypotension produced by dehydroemetine is immediate and reversible, either rapidly (0.5-3 mg/kg dehydroemetine, 0.5 to 2 min) or slowly ( 5 - 1 0 mg/kg dehydroemetine, 30 min to 1 hr). On the other hand the adrenergic neurone blocking action has a latent period of 10-20 rain and is not reversible. It therefore follows from this study that the hypotensive effect of dehydroemetine cannot be explained on the basis of adrenergic neurone blockade.
The observation that the transient fall in blood pressure produced by 0.5-3 mg/kg dehydroemetine is not accompanied by any change in pulse rate or pulse pressure suggests that this effect is due to a fall in peripheral resistance rather than in cardiac output. Any peripheral vasodilation effect by dehydroemetine cannot be due to histamine release since the hypotension is not prevented by the antihistamine mepyramine. Similarly it cannot be due to/~-adrenergic action on the peripheral blood vessels since it is not antagonised by propranolol. The increase in venous outflow from the perfused rabbit ear by dehydroemetine provides a direct evidence for peripheral vasodilation by the drug. The time course for this in vitro effect is similar to the time course of the hypotension produced by small doses of dehydroemetine. The observation that relatively large doses of the drug were needed to produce the vasodilation effect in vitro is not surprising since the rabbit ear preparation is well known to be relatively insensitive to vasodilating drugs (Andrew, 1965). In spite of this, the demonstration of a vasodilation effect in vitro and the identity of the time course of this effect with that of the hypotension produced by the lower doses of dehydroemetine suggest that the hypotension might be due to peripheral vasodilatation. The peripheral vasodilatation observed in vitro is probably due to direct relaxation of vascular smooth muscle since it is not abolished by the presence of propranolol in the perfusing fluid. A similar relaxation of intestinal smooth muscle is also produced by dehydroemetine (Salako, 1970). Finally, the reduction of the rate and force of contraction of the isolated perfused rabbit heart by dehydroemetine shows that the drug has an inhibitory action on myocardial activity and this action would explain the bradycardia and other arrhythmias which follow injections of larger doses of the drug in the anaesthetised cat.
REFERENCES Andrew, B.L., 1965, Experimental Physiology (Livingstone, London) pp. 31-32. Burn, J.H., 1952, Practical Pharmacology (Blackwell, Oxford) pp. 25-69. Day, M.D., 1962, Effect of sympathomirnetic amines on the blocking action of guanethidine, bretylium and xylocaine, Brit. J. Pharmacol. 18,421.
L.A.Salako, A.O.Durotoye, Dehydroemetine and the cardiovascular system Dempsey, J.J. and H.H. Salem, 1966, An enzymatic and electrocardiographic study on toxicity of dehydroemetine, Brit. Heart J. 28,505. Green, A.F. and A.L.A. Boura, 1964, Depressants of peripheral sympathetic nerve function, in: Evaluation of Drug Activities: Vol. 1. Pharmacometrics, eds. D.R. Laurence and A.L. Bacharach (Academic Press, London), pp. 407 -409. Herrero, J., A. Brossi, M. Faust and J.R. Frey, 1960, Preliminary experimental and clinical results with a new
203
emetineqike compound, Ann. Biochem. Exptl. Med. 20, 475. Ng, K.K.F. and Y.T. Ng, 1970, Adtenergic neurone blocking action of dehydroemetine, J. Pharm. PharmacoL 22, 787. Salako, L.A., 1970, Blockade of adrenergic transmission by dehydroemetine, J. Phann. Pharmacol. 22, 938. Salem, H.N. and H. Abd-Rabbo, 1964, Dehydroemetine in acute amoebiasis, Trans. Roy Soc. Trop. Med. Hygiene 58, 539. Wilmot, A.J., 1969, The Practitioner 203,634.
S h o r t communication
OBSERVATIONS
ON THE HYPOTENSIVE
RESPONSE
TO DEHYDROEMETINE L.A. SALAKO * Pharmacology Department, University of lbadan, Ibadan, Nigeria and A.O. DUROTOYE Physiology Department, University of Ibadan, Ibadan, Nigeria
Received 19 January 1971
Accepted 9 February 1971
L.A. SALAKO and A.O. DUROTOYE, Observations on the hypotensive response to dehydroemetine, European J. Pharmacol. 14 (1971)200-203. Dehydroemetine reduced blood pressure and produced adrenergic neurone block in the anaesthetised cat but the time courses of the two effects were different. Dehydroemetine also increased the venous outflow in the isolated perfused rabbit ear and decreased the rate and force of contraction of the isolated perfused rabbit heart. Dehydroemetine Perfused rabbit ear
Cat nictitating membrane Perfused rabbit heart
Adrenergic nettrone block Blood pressure, cat
1. INTRODUCTION
2. METHODS
Dehydroemetine is a recently introduced antiamoebic drug (Herrero, Brossi, Faust and Frey, 1960) which is rapidly replacing emetine as the drug of choice in the treatment of acute intestinal and systemic amoebiasis (Wilmot, 1969). The drug is generally believed to be better tolerated than emetine, but transient hypotension and tachycardia occur after an injection of dehydroemetine as it does after emetine. (Dempsey and Salem, 1966; Salem and Abd-Rabbo, 1964). Ng and Ng (1970) showed that dehydroemetine had an adrenergic neurone blocking action in vitro and suggested that the transient hypotension produced by the drug might be due to this action. The nature of the hypotensive effect of dehydroemetine was further examined in this study.
6 cats were anaesthetised with intravenous chloralose (80 mg/kg) to which sodium pentobarbitone (5 mg/kg) was added. The pre- or post-ganglionic trunk of the cervical sympathetic nerve was stimulated through a pair of platinum electrodes with square pulses of 20 V and 0.5 msec and the resulting contractions of the nictitating membrane were recorded on smoked paper. Blood pressure was measured from a femoral artery either with a Statham P23 transducer and recorded on a Schwatzer physiograph or with a mercury manometer and recorded on smoked paper. Hearts isolated from six rabbits were mounted and perfused by the Langendorff technique (Burn, 1952). The perfusion fluid was oxygenated Locke's solution at 38°C. Contractions of the heart were recorded on smoked paper. 12 ears detached from 6 freshly killed rabbits were kept in a refrigerator for 1 8 - 2 4 hr after cannulating
* Address to which all communications are to be sent.
L.A.Salako, A.O.Durotoye, Dehydroemetine and the cardiovascular system
201
above caused a more prolonged fall in blood pressure associated with bradycardia and sometimes irregular heart beat. Recovery was slow, lasting 30 rnin to 1 hr, but usually complete. The effect on blood pressure was not affected by vagotomy, atropine (1 mg/kg) propranolol 1-2.5 mg/kg, phenoxybenzamine ( l m g / k g ) mepyrarnine 0 . 5 - 1 m g / k g and hexamethonium 1 mg/kg. Contractions of the nictitating membrane elicited by preganglionic or postganglionic stimulation of the cervical sympathetic nerve were not affected by 0.5, 1.0 and 2.0 mg/kg dehydroemetine, but were inhibited by doses of dehydroemetine of 5 mg/kg and above. Doses of 3 mg/kg repeated 2 - 3 times at 10-15 min intervals also inhibited the contractions. The effect on nictitating membrane contractions had a latent period of 10-20 min and was not reversible after 4 hr observation. The effect was also not reversed by giving-cocaine 0.5 mg/kg i.v. Contractions of the nictitating membrane elicited by giving 50 lag
the central artery. Storage for 24 hr is said to increase the sensitivity of the ear (Andrew, 1965). The ears were then mounted and perfused as described by Burn (1952), the technique being modified to keep both the perfusion fluid (oxygenated Locke's solution) and the ear at the same constant temperature of 30°C (Green and Boura, 1964). The venous outflow from the perfused ear was passed through a photoelectric drop counter and recorded on smoked paper using a Thorp impulse recorder.
3. RESULTS 3.1. Cat blood pressure and nictitating membrane Intravenous injection of dehydroemetine in doses between 0.5 and 3 mg/kg caused an immediate fall in blood pressure. The effect was short-lived lasting only 30 sec-2 min, and was not accompanied by any change in heart rate (fig. 1). Doses of 5 mg/kg and
ISO-
E 100-
so
•
0 1
•
A
•
A
m011
Fig. 1. Cat 2.1 kg under chloralose anaesthesia. Effect of dehydroemetine on blood pressure. At • from left to fight dehydroemetine, 1, 2 and 3 mg/kg successivelyi.v. At A, the paper speed was increased 10-fold to show effect on heart rate.
\
\ L..---J
30rain
L-.d
60 vnin
Fig. 2. Cat 2.1 kg under chloralose anaesthesia. Effect of dehydroemetine on contractions of the nictitating membrane elicited by preganglionic stimulation of the cervical sympathetic nerve. Dehydroemetine 5 mg/kg was given i.v. at the end of the first panel. Contractions of the nictitating membrane elicited by intravenous injection of noradrenaline (50 ~g) were unaffected by the drug.
202
L.A.Salako, A.O.Durotoye, Dehydroemetine and the cardiovascular system
noradrenaline i.v. were not affected by dehydroemetine (fig. 2). 2.2. Isolated rabbit heart
Dehydroemetine, in doses of 10~g and above, injected into the perfusion fluid close to the aortic cannula caused a fall in the force and rate of contraction of the heart. In 6 experiments 10#g dehydroemetine caused a mean decrease of 22 + 2.4% (S.D.) in the amplitude of contraction and 12 -+ 2.1% (S.D.) in the rate of contraction 10 min after injecting the drug into the perfusion tubing. 3.3. Isolated rabbit ear
Dehydroemetine injected into the perfusion tubing close to the arterial cannula increased the venous outflow from the ear. The effect was slight and transient (lasting 1-3 rain), and relatively large doses of dehydroemetine (above 0.1 mg) were required. Maximal effect was produced by 1 mg and above, and this averaged 10 -+ 2.1% (S.D.) increase over control outflow in 12 experiments. The effect persisted in the presence of propranolol (1 #g/ml) in the perfusion fluid.
4. DISCUSSION The results of this study show that dehydroemetine inhibits contractions of the cat nictitating membrane elicited by pre- or post-ganglionic stimulation of the cervical sympathetic nerve without affecting contractions elicited by intravenous noradrenalinc. The drug thus has an adrenergic neurone blocking action in vivo similarly to that previously demonstrated in vitro (Ng and Ng, 1970). The adrenergic neurone blocking action of dehydroemetine however differs from that of bretylium and guanethidine in that it cannot be reversed by cocaine (Day, 1962). The hypotension produced by dehydroemetine is immediate and reversible, either rapidly (0.5-3 mg/kg dehydroemetine, 0.5 to 2 min) or slowly ( 5 - 1 0 mg/kg dehydroemetine, 30 min to 1 hr). On the other hand the adrenergic neurone blocking action has a latent period of 10-20 rain and is not reversible. It therefore follows from this study that the hypotensive effect of dehydroemetine cannot be explained on the basis of adrenergic neurone blockade.
The observation that the transient fall in blood pressure produced by 0.5-3 mg/kg dehydroemetine is not accompanied by any change in pulse rate or pulse pressure suggests that this effect is due to a fall in peripheral resistance rather than in cardiac output. Any peripheral vasodilation effect by dehydroemetine cannot be due to histamine release since the hypotension is not prevented by the antihistamine mepyramine. Similarly it cannot be due to/~-adrenergic action on the peripheral blood vessels since it is not antagonised by propranolol. The increase in venous outflow from the perfused rabbit ear by dehydroemetine provides a direct evidence for peripheral vasodilation by the drug. The time course for this in vitro effect is similar to the time course of the hypotension produced by small doses of dehydroemetine. The observation that relatively large doses of the drug were needed to produce the vasodilation effect in vitro is not surprising since the rabbit ear preparation is well known to be relatively insensitive to vasodilating drugs (Andrew, 1965). In spite of this, the demonstration of a vasodilation effect in vitro and the identity of the time course of this effect with that of the hypotension produced by the lower doses of dehydroemetine suggest that the hypotension might be due to peripheral vasodilatation. The peripheral vasodilatation observed in vitro is probably due to direct relaxation of vascular smooth muscle since it is not abolished by the presence of propranolol in the perfusing fluid. A similar relaxation of intestinal smooth muscle is also produced by dehydroemetine (Salako, 1970). Finally, the reduction of the rate and force of contraction of the isolated perfused rabbit heart by dehydroemetine shows that the drug has an inhibitory action on myocardial activity and this action would explain the bradycardia and other arrhythmias which follow injections of larger doses of the drug in the anaesthetised cat.
REFERENCES Andrew, B.L., 1965, Experimental Physiology (Livingstone, London) pp. 31-32. Burn, J.H., 1952, Practical Pharmacology (Blackwell, Oxford) pp. 25-69. Day, M.D., 1962, Effect of sympathomirnetic amines on the blocking action of guanethidine, bretylium and xylocaine, Brit. J. Pharmacol. 18,421.
L.A.Salako, A.O.Durotoye, Dehydroemetine and the cardiovascular system Dempsey, J.J. and H.H. Salem, 1966, An enzymatic and electrocardiographic study on toxicity of dehydroemetine, Brit. Heart J. 28,505. Green, A.F. and A.L.A. Boura, 1964, Depressants of peripheral sympathetic nerve function, in: Evaluation of Drug Activities: Vol. 1. Pharmacometrics, eds. D.R. Laurence and A.L. Bacharach (Academic Press, London), pp. 407 -409. Herrero, J., A. Brossi, M. Faust and J.R. Frey, 1960, Preliminary experimental and clinical results with a new
203
emetineqike compound, Ann. Biochem. Exptl. Med. 20, 475. Ng, K.K.F. and Y.T. Ng, 1970, Adtenergic neurone blocking action of dehydroemetine, J. Pharm. PharmacoL 22, 787. Salako, L.A., 1970, Blockade of adrenergic transmission by dehydroemetine, J. Phann. Pharmacol. 22, 938. Salem, H.N. and H. Abd-Rabbo, 1964, Dehydroemetine in acute amoebiasis, Trans. Roy Soc. Trop. Med. Hygiene 58, 539. Wilmot, A.J., 1969, The Practitioner 203,634.