- Email: [email protected]
A possible role of catecholamines and (Na+ + K+)ATPase in the ethanol withdrawal syndrome
181
Drug and Alcohol Dependence, Ei(1980) 181 - 184 @ Elsevier Sequoia S.A., Lausanne - Printed in the Netherlands
A POSSIBLE ROLE OF CATECHOLAMINES THE ETHANOL WITHDRAWAL SYNDROME
AND (Na++K+)ATPase
IN
H. ~HLIN*, R. HQRLIN, J. WADSTEIN and A. &TERLING Department (Sweden)
of Alcohol
Diseases,
University
of Lund, Malmii
General
Hospital,
Malmii
(Received April 26,1979)
Summary Chronic ethanol intoxication leads to an increase in the intracellular Na+/K+ ratio. It is suggested that this derangement is counteracted by catecholamines via an activation of (Na++K+)ATPase. This hypothesis is discussed in relation to the symptomatology of ethanol withdrawal.
In a previous article we have reported on hypokalemia in conjunction with delirium tremens [l] . In an attempt to explain this observation we propose the following pathogenetic model of the ethanol withdrawal syndrome. This model is based on our own observations and the reports of other authors. Although parts of the model are supported by experimental evidence, further research is necessary to verify it in toto. Thus, we want to stress its hypothetical character. During chronic ethanol intoxication inhibition of (Na++K+)ATPase takes place due to the direct effect of ethanol on the enzyme [ 21. After chronic ethanol administration an increase in the specific activity of brain (Na++K+)ATPase has been demonstrated in the rat [3], cat [4] and dog [ 51. Sun et al. [ 51 have shown in the dog that this is due to an increase in the synthesis of enzyme protein. They conclude that this seems to be an adaptive mechanism exhibited by the enzyme in order to compensate for the known inhibitory effect of ethanol. This impairment of the sodium-potassium pump might explain the increase of the intracellular Na+/K+ ratio after chronic ethanol ingestion shown in rat and man by Pierson et al. [6], who further demonstrated a decrease of total body K+ and an increase of total body exchangeable Na+, the total amount of cations being constant. How these electrolyte changes affect different types of cells within the organism remains to be shown.
*Requests for reprints should be addressed to Hans C)hlin, Department of Alcohol Diseases, Malmii General Hospital, MalmS S-214 01 Sweden.
182
What would be the effect of a high intracellular sodium concentration in the adrenergic neuron? The interaction of cations with the release of catecholamines is complex and intriguing, but some studies suggest an effect of sodium on the release of norepinephrine. De Champlain et al. [ 71 have demonstrated that sympathetic nervous tissue from rats given desoxycorticosterone and sodium chloride to induce hypertension, showed a defective capacity to retain norepinephrine in the microsomal storage granules. Recently Mattiassion et al. [8] have shown that on varying the concentration of sodium in the medium there is a changed efflux rate of norepinephrine from platelets. Higher concentrations of sodium resulted in faster efflux. These studies point to the increased intracellular sodium concentration as one possible cause of the adrenergic hyperactivity in ethanol withdrawal [9 - 111. Apart from this presumed direct effect of Na+ on the retention of norepinephrine in storage granules Na+ also effects the intracellular concentration of Ca2+. A high intracellular Na+ concentration increases the intracellular concentration of Ca2+ [ 121. Ca2+ plays a critical role in the transmittor release process at presynaptic terminals [ 13,141. Ca2+ also increases the activity of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis [ 151. Ross et al. have reported that chronic exposure of animals to ethanol results in an increased Ca2+ content of synaptosomal membrane as opposed to the lowered content seen after a single dose of ethanol [ 161. We assume that during the early phase of abstinence the activity of (Na++K+)ATPase is gradually restored and that, at the beginning of the second phase, delirium tremens, there is a hyperactivity of the enzyme due to a compensatory increase of enzyme protein (inferred from the animal experiments mentioned above), and to the effect of catecholamine stimulation. Clausen et al. [17] have shown that catecholamines increase the activity of (Na++K+)ATPase in rat striated muscle and that this activation is the result of j32-stimulation. The effect of f12-stimulation in man can be demonstrated by infusion of salbutamol, leading to a transient hypokalemia and tremor [ 181. This may be a parallel to our observation of hypokalemia during delirium tremens [l] . It seems likely that this activation also occurs in heart muscle [ 191, explaining why in a recent study with ECG recordings during delirium tremens we could not find the usual signs of hypokalemia 1291. There are indications of a catecholamine-mediated activation of (Na++ K+)ATPase also in the brain. Several workers report such activation of the enzyme in crude preparations from rat and cat brain [ 21-23 1. The catecholamines seem to exert their effect by reversal of divalent metal ion inhibition of (Na++K+)ATPase activity. The order of efficiency is stated to be isoproterenol > epinephrine = norepinephrine >phenylephrine, following the p-adrenergic “pattern”. The efficiency of dopamine is equal to that of norepinephrine [ 241. The activation of (Na++K+)ATPase by norepinephrine and dopamine can be blocked in vitro by propranolol [24] and chlorpromazine [ 251, respectively.
183
The high incidence of epileptic fits in the first phase of ethanol withdrawal compared to the second, delirium tremens, has been explained by concomitant hypomagnesemia and respiratory alkalosis [ 261. In addition to these pathogenetic factors our hypothesis suggests a role for (Na++K+)ATPase: During the first phase the relatively hypoactive (Na’+K’)ATPase leaves the neuron in a state of partial depolarization leading to an increase of excitability. The activation of (Na++K+)ATPase during the second phase leads to a relative hyperpolarization, reducing the incidence of epileptic fits. In this respect the catecholamines play a protective role. This hypothesis is supported by the results of Goldstein [ 271, who found that drugs which decrease the activity of noradrenergic synapses aggravated ethanol withdrawal convulsions in mice. Our model emphasizes the role of catecholamines in ethanol withdrawal, as regulators of the electrolyte balance and the state of polarization in excitable cells such as neurons and muscles, including the heart [ 191. Probably, potassium is preferentially taken up by those catecholamine-activated cells. At the present state of knowledge it is impossible to predict the topographic pattern of (Na++K+)ATPase hyperactivity within the brain. Further we can only speculate about the connection between this enzyme activity and the psychic symptoms of delirium tremens such as confusion, hallucinations and psychomotor hyperactivity. During delirium tremens a progressive increase of adrenergic hyperactivity is indicated by the increase of pulse rate and blood pressure. We think that this could be explained by the following model: the hypokalemia during delirium tremens will decrease the activity of (Na++K+)ATPase [ 281, leading to an increase of intracellular sodium concentration and, as far as the adrenergic neuron is concerned, this possibly increases the release of norepinephrine. The impairment of (Na++K+)ATPase also decreases the reuptake of norepinephrine [ 291. This might create a vicious circle with catecholamine stimulation of (Na++K+)ATPase in striated muscle and parts of the brain, leading to an aggravation of hypokalemia and so forth. Our hypothesis connects in a new way the adrenergic activity and the deranged electrolyte balance during ethanol withdrawal, emphasizing, in a teleological sense, the usefulness of catecholamines. This may be of importance for future research concerning the pathogenesis and treatment of ethanol withdrawal.
References 1 2 3 4 5
J. Wadstein and G. Skude, Lance& ii (1978) 549. Y. Israel, H. Kalant and A. E. LeBlanc, Biochem. J., 100 (1966) 27. Y. Israel, et al., J. Pharmacol. Exp. Ther., 174 (1970) 330. W. H. Knox, R. G. Perrin and A. K. Sen, J. Neurochem., 19 (1971) 2881. A. Y. Sun, G. Y. Sun and C. C. Middleton, in F. A. Seixas (ed.), Currents in Alcoholism, Vol. 1, Grune and Stratton, New York, 1977, p. 81.
184 6 R. N. Pierson, J. Wang, W. Frank, G. Allen and A. Rayyes, in F. A. Seixas (ed.), Currents in Alcoholism, Vol. 1, Grune and Stratton, New York, 1977, p. 161. 7 J. de Champlain, L. Krakoff and J. Axehod, Circ. Res., XXIV, Suppl. 1 (1969) 75. 8 I. Mattiasson, B. Mattiasson and B. Hood, Life Sci., 24 (1979) 2265. 9 E. Giacobini, S. Izikowitz and A. Wegman, Experientia, 16 (1960) 467. 10 L. Ahtee and M. Svartstriim-Fraser, Acta Pharmocol., 36 (1975) 289. 11 W. A. Hunt and E. J. Majchrowicz,Neurochemistry, 23 (1974) 549. 12 M. P. Blaustein and J. 0. Carol, J. Physiol., 247 (1975) 657. 13 A. M. Harvey and F. C. MacIntosh,J. Physiol., 97 (1940) 408. 14 B. Katz and R. Miledi, J. Physiol., 203 (1969) 459. 15 V. H. Morgenroth,M. C. Broadle-Biber and R. H. Roth, Mol. Pharmacol., 11 (1975) 427. 16 D. H. Ross, H. L. Cardenas and S. C. Lynn, Trans. Am. Sot. Neurochem., 7 (1976) 150. 17 T. Clausen and J. A. Flatman,J. Physiol., 270 (1977) 383. 18 A. G. Leicht, L. J. Clancy, J. F. Costello and D. C. Flerdey, Br. Med. J., 1 (1976) 365. 19 B. F. Hoffman and D. H. Singer, Ann. N. Y. Acad. Sci., 139 (1967) 914. 20 R. Horlin, A. Gsterling, J. Wadstein and H. Ghlin, Abstract in Proceedings for the Annual Meeting of Swedish Medical Association, 1978. 21 A. Schaefer, G. Unyi and A. K. Pfeifer, Biochem. Pharmacol., 21 (1972) 2289. 22 K. Yoshimura, J. Biochem. (Tokyo), 74 (1973) 389. 23 P. Iwangoff, A. Enz and A. Chappius, Experientia, 30 (1974) 688. 24 T. D. Hexum, Biochem. Phormacol., 26 (1977) 1221. 25 A. Schaefer, A. Segeri and A. K. Pfeifer, Biochem. Pharmacol., 22 (1973) 2375. 26 S. M. Wolfe and M. Victor, in N. K. Mello and J. H. Mendelson (eds.), Recent Advances in Studies of Alcoholism, U.S. Govt. Printing Office, Washington, D.C., 1972, p. 188. 27 D. B. Goldstein, J. Pharmacol. Exp. Ther., 186 (1973) 1. 28 E. Heinz, P. Geck and C. Pietrzyk,Ann. N. Y. Acad. Sci., 264 (1976) 428. 29 A. H. Tissari, P. S. ScMnhSfer, D. F. Bogdanski and B. B. Brodie, Mol. Pharmacol., 5 (1969) 993.
Drug and Alcohol Dependence, Ei(1980) 181 - 184 @ Elsevier Sequoia S.A., Lausanne - Printed in the Netherlands
A POSSIBLE ROLE OF CATECHOLAMINES THE ETHANOL WITHDRAWAL SYNDROME
AND (Na++K+)ATPase
IN
H. ~HLIN*, R. HQRLIN, J. WADSTEIN and A. &TERLING Department (Sweden)
of Alcohol
Diseases,
University
of Lund, Malmii
General
Hospital,
Malmii
(Received April 26,1979)
Summary Chronic ethanol intoxication leads to an increase in the intracellular Na+/K+ ratio. It is suggested that this derangement is counteracted by catecholamines via an activation of (Na++K+)ATPase. This hypothesis is discussed in relation to the symptomatology of ethanol withdrawal.
In a previous article we have reported on hypokalemia in conjunction with delirium tremens [l] . In an attempt to explain this observation we propose the following pathogenetic model of the ethanol withdrawal syndrome. This model is based on our own observations and the reports of other authors. Although parts of the model are supported by experimental evidence, further research is necessary to verify it in toto. Thus, we want to stress its hypothetical character. During chronic ethanol intoxication inhibition of (Na++K+)ATPase takes place due to the direct effect of ethanol on the enzyme [ 21. After chronic ethanol administration an increase in the specific activity of brain (Na++K+)ATPase has been demonstrated in the rat [3], cat [4] and dog [ 51. Sun et al. [ 51 have shown in the dog that this is due to an increase in the synthesis of enzyme protein. They conclude that this seems to be an adaptive mechanism exhibited by the enzyme in order to compensate for the known inhibitory effect of ethanol. This impairment of the sodium-potassium pump might explain the increase of the intracellular Na+/K+ ratio after chronic ethanol ingestion shown in rat and man by Pierson et al. [6], who further demonstrated a decrease of total body K+ and an increase of total body exchangeable Na+, the total amount of cations being constant. How these electrolyte changes affect different types of cells within the organism remains to be shown.
*Requests for reprints should be addressed to Hans C)hlin, Department of Alcohol Diseases, Malmii General Hospital, MalmS S-214 01 Sweden.
182
What would be the effect of a high intracellular sodium concentration in the adrenergic neuron? The interaction of cations with the release of catecholamines is complex and intriguing, but some studies suggest an effect of sodium on the release of norepinephrine. De Champlain et al. [ 71 have demonstrated that sympathetic nervous tissue from rats given desoxycorticosterone and sodium chloride to induce hypertension, showed a defective capacity to retain norepinephrine in the microsomal storage granules. Recently Mattiassion et al. [8] have shown that on varying the concentration of sodium in the medium there is a changed efflux rate of norepinephrine from platelets. Higher concentrations of sodium resulted in faster efflux. These studies point to the increased intracellular sodium concentration as one possible cause of the adrenergic hyperactivity in ethanol withdrawal [9 - 111. Apart from this presumed direct effect of Na+ on the retention of norepinephrine in storage granules Na+ also effects the intracellular concentration of Ca2+. A high intracellular Na+ concentration increases the intracellular concentration of Ca2+ [ 121. Ca2+ plays a critical role in the transmittor release process at presynaptic terminals [ 13,141. Ca2+ also increases the activity of tyrosine hydroxylase, the rate-limiting enzyme of catecholamine synthesis [ 151. Ross et al. have reported that chronic exposure of animals to ethanol results in an increased Ca2+ content of synaptosomal membrane as opposed to the lowered content seen after a single dose of ethanol [ 161. We assume that during the early phase of abstinence the activity of (Na++K+)ATPase is gradually restored and that, at the beginning of the second phase, delirium tremens, there is a hyperactivity of the enzyme due to a compensatory increase of enzyme protein (inferred from the animal experiments mentioned above), and to the effect of catecholamine stimulation. Clausen et al. [17] have shown that catecholamines increase the activity of (Na++K+)ATPase in rat striated muscle and that this activation is the result of j32-stimulation. The effect of f12-stimulation in man can be demonstrated by infusion of salbutamol, leading to a transient hypokalemia and tremor [ 181. This may be a parallel to our observation of hypokalemia during delirium tremens [l] . It seems likely that this activation also occurs in heart muscle [ 191, explaining why in a recent study with ECG recordings during delirium tremens we could not find the usual signs of hypokalemia 1291. There are indications of a catecholamine-mediated activation of (Na++ K+)ATPase also in the brain. Several workers report such activation of the enzyme in crude preparations from rat and cat brain [ 21-23 1. The catecholamines seem to exert their effect by reversal of divalent metal ion inhibition of (Na++K+)ATPase activity. The order of efficiency is stated to be isoproterenol > epinephrine = norepinephrine >phenylephrine, following the p-adrenergic “pattern”. The efficiency of dopamine is equal to that of norepinephrine [ 241. The activation of (Na++K+)ATPase by norepinephrine and dopamine can be blocked in vitro by propranolol [24] and chlorpromazine [ 251, respectively.
183
The high incidence of epileptic fits in the first phase of ethanol withdrawal compared to the second, delirium tremens, has been explained by concomitant hypomagnesemia and respiratory alkalosis [ 261. In addition to these pathogenetic factors our hypothesis suggests a role for (Na++K+)ATPase: During the first phase the relatively hypoactive (Na’+K’)ATPase leaves the neuron in a state of partial depolarization leading to an increase of excitability. The activation of (Na++K+)ATPase during the second phase leads to a relative hyperpolarization, reducing the incidence of epileptic fits. In this respect the catecholamines play a protective role. This hypothesis is supported by the results of Goldstein [ 271, who found that drugs which decrease the activity of noradrenergic synapses aggravated ethanol withdrawal convulsions in mice. Our model emphasizes the role of catecholamines in ethanol withdrawal, as regulators of the electrolyte balance and the state of polarization in excitable cells such as neurons and muscles, including the heart [ 191. Probably, potassium is preferentially taken up by those catecholamine-activated cells. At the present state of knowledge it is impossible to predict the topographic pattern of (Na++K+)ATPase hyperactivity within the brain. Further we can only speculate about the connection between this enzyme activity and the psychic symptoms of delirium tremens such as confusion, hallucinations and psychomotor hyperactivity. During delirium tremens a progressive increase of adrenergic hyperactivity is indicated by the increase of pulse rate and blood pressure. We think that this could be explained by the following model: the hypokalemia during delirium tremens will decrease the activity of (Na++K+)ATPase [ 281, leading to an increase of intracellular sodium concentration and, as far as the adrenergic neuron is concerned, this possibly increases the release of norepinephrine. The impairment of (Na++K+)ATPase also decreases the reuptake of norepinephrine [ 291. This might create a vicious circle with catecholamine stimulation of (Na++K+)ATPase in striated muscle and parts of the brain, leading to an aggravation of hypokalemia and so forth. Our hypothesis connects in a new way the adrenergic activity and the deranged electrolyte balance during ethanol withdrawal, emphasizing, in a teleological sense, the usefulness of catecholamines. This may be of importance for future research concerning the pathogenesis and treatment of ethanol withdrawal.
References 1 2 3 4 5
J. Wadstein and G. Skude, Lance& ii (1978) 549. Y. Israel, H. Kalant and A. E. LeBlanc, Biochem. J., 100 (1966) 27. Y. Israel, et al., J. Pharmacol. Exp. Ther., 174 (1970) 330. W. H. Knox, R. G. Perrin and A. K. Sen, J. Neurochem., 19 (1971) 2881. A. Y. Sun, G. Y. Sun and C. C. Middleton, in F. A. Seixas (ed.), Currents in Alcoholism, Vol. 1, Grune and Stratton, New York, 1977, p. 81.
184 6 R. N. Pierson, J. Wang, W. Frank, G. Allen and A. Rayyes, in F. A. Seixas (ed.), Currents in Alcoholism, Vol. 1, Grune and Stratton, New York, 1977, p. 161. 7 J. de Champlain, L. Krakoff and J. Axehod, Circ. Res., XXIV, Suppl. 1 (1969) 75. 8 I. Mattiasson, B. Mattiasson and B. Hood, Life Sci., 24 (1979) 2265. 9 E. Giacobini, S. Izikowitz and A. Wegman, Experientia, 16 (1960) 467. 10 L. Ahtee and M. Svartstriim-Fraser, Acta Pharmocol., 36 (1975) 289. 11 W. A. Hunt and E. J. Majchrowicz,Neurochemistry, 23 (1974) 549. 12 M. P. Blaustein and J. 0. Carol, J. Physiol., 247 (1975) 657. 13 A. M. Harvey and F. C. MacIntosh,J. Physiol., 97 (1940) 408. 14 B. Katz and R. Miledi, J. Physiol., 203 (1969) 459. 15 V. H. Morgenroth,M. C. Broadle-Biber and R. H. Roth, Mol. Pharmacol., 11 (1975) 427. 16 D. H. Ross, H. L. Cardenas and S. C. Lynn, Trans. Am. Sot. Neurochem., 7 (1976) 150. 17 T. Clausen and J. A. Flatman,J. Physiol., 270 (1977) 383. 18 A. G. Leicht, L. J. Clancy, J. F. Costello and D. C. Flerdey, Br. Med. J., 1 (1976) 365. 19 B. F. Hoffman and D. H. Singer, Ann. N. Y. Acad. Sci., 139 (1967) 914. 20 R. Horlin, A. Gsterling, J. Wadstein and H. Ghlin, Abstract in Proceedings for the Annual Meeting of Swedish Medical Association, 1978. 21 A. Schaefer, G. Unyi and A. K. Pfeifer, Biochem. Pharmacol., 21 (1972) 2289. 22 K. Yoshimura, J. Biochem. (Tokyo), 74 (1973) 389. 23 P. Iwangoff, A. Enz and A. Chappius, Experientia, 30 (1974) 688. 24 T. D. Hexum, Biochem. Phormacol., 26 (1977) 1221. 25 A. Schaefer, A. Segeri and A. K. Pfeifer, Biochem. Pharmacol., 22 (1973) 2375. 26 S. M. Wolfe and M. Victor, in N. K. Mello and J. H. Mendelson (eds.), Recent Advances in Studies of Alcoholism, U.S. Govt. Printing Office, Washington, D.C., 1972, p. 188. 27 D. B. Goldstein, J. Pharmacol. Exp. Ther., 186 (1973) 1. 28 E. Heinz, P. Geck and C. Pietrzyk,Ann. N. Y. Acad. Sci., 264 (1976) 428. 29 A. H. Tissari, P. S. ScMnhSfer, D. F. Bogdanski and B. B. Brodie, Mol. Pharmacol., 5 (1969) 993.