Pharmacology 14: 227- 231 (1976)
The Reversal of Clonidine-Induced Hypotension by Protriptyline and Desipramine P.A. van Zwieten' With the technical assistance of Marion Pauer Division of Pharmacotherapy, Department of Pharmacy, University of Amsterdam, Amsterdam
Key Words. Drug interaction • Clonidine • Tricyclic antidepressants • Central a-adrenoreceptors • Desipramine • Protriptyline • Hypotensive effect • Vertebral artery Abstract. The present paper deals with further studies on the interaction between clonidine and tricyclic antidepressants. The pronounced central hypotensive action of 1 Mg clonidine/kg, administered into the left vertebral artery of chloralose-anaesthetized cats was readily reversed by protriptyline (300 Mg/kg) or desipramine (300 Mg/kg), infused via the same route shortly after the development of the maximum hypotensive effect of clonidine. In earlier studies it has been demonstrated that pretreatment with tricyclic antidepressants significantly diminishes the central hypotensive action of clonidine. This interaction has been presumed to occur at the level of central a-adrcnorcceptors, where clonidine would be the agonist and tricyclic antidepressants the antagonist. The present findings suggest that a competitive antagonism at the central level, which can occur in either sense, may be in volved.
In preceding communications (van Spanning and van Zwieten, 1973; van Zwieten, 1975 a, b) we have described how pretreatment of anaesthetized cats with various tricyclic antidepressants significantly reduces the central hypoten sive action of clonidine, but also that of a-methyl-dopa (van Spanning and van Zwieten, 1975; van Zwieten, 1975b). This finding has been interpreted in the sense of an antagonism at the level of the central »-adrenoreceptors, which are presumed to be the main sites of initiation of clonidine’s central hypotensive effect. This antagonism is probably competitive in nature, since the doseresponse curve for clonidine’s hypotensive effect was shifted to the right in a ' We are greatly indebted to the Dutch Heart Foundation (Nederlandse Hartstichting), The Hague, Netherlands, for the support of these studies.
Downloaded by: King's College London 137.73.144.138 - 3/6/2018 10:27:31 PM
Received: November 14, 1975.
van Zwieten
228
parallel fashion upon pretreatment with protriptyline (van Zwieten, 1975 a). Similarly, Schmitt et al. (1973) presumed that the amitriptyline-induced reduc tion of clonidine’s central hypotensive effect reflects a competitive antagonism at the level of central a-adrenoreceptors. In this connection it should be kept in mind that protriptyline, amitriptyline and various other tricyclic antidepressants possess considerable a-sympatholytic activity, at least in the peripheral circulato ry system. Clonidine may be regarded as a potent stimulator of central a-adrenergic receptors whereas a-sympatholytic drugs like yohimbine and piperoxan are known to block the central hypotensive action of clonidine (Hoefke and Kobinger, 1966; Schmitt et al., 1971). If a competitive antagonism on the cen tral a-adrenoreceptors is indeed involved in case of interaction between tricyclic antidepressants and clonidine, one should expect a diminishment of the already established hypotensive effect of clonidine by subsequently administered tricy clic antidepressants. This problem was investigated in the present study.
All experiments were carried out on mongrel cats of either sex, anaesthetized with a-glucochloralosc, administered intraperitoneally (60 mg/kg). The animals were subjected to artificial respiration, using a Braun Melsungcn pump. After left-sided thoracotomy, a can nula was introduced into the left subclavian artery and pushed forward until its tip was located 2 -3 mm distal from the ostium of the left vertebral artery. Small volumes (0.1 ml-kg"‘ body weight) of solutions infused at a rate of 0.1 m l-m in'1 arc thus intro duced into the left vertebral artery. Owing to the blood stream from the aortic arch and proximal left subclavian artery, drugs thus infused will reach the pontomedullary region of the brain. In the cat, brain centres higher than the pontomedullary are not substantially perfused with blood from the vertebral arteries, as demonstrated by means of radioactively labelled microsphcres (Reneman et al., 1974). The technique of drug administration into the cat’s left vertebral artery has been described previously in full detail (Henning and van Zwieten, 1968; van Zwieten, 1975b). Heparine was injected intravenously after the surgical intervention. Mean arterial blood pressure was recorded from a cannulated femoral artery by means of a Statliam pressure transducer connected to a Hellige HE 19 amplification and recording device. Cardiac frequency was obtained from the femoral pulse wave that was recorded at high speed of the recording paper. The mean arterial pressure before any drug treatment (apart from anaesthesia) had occurred amounted to 124.0+ 3.6mm Hg (m eant SEM, n= 24 for all cats, prior to treatment). All animals with a blood pressure lower than 100 mm Hg were discarded. All subsequent values for blood pressure were expressed as percentage of the initial value before drug treatment in each individual experiment. Mean values ± SEM were calculated for the number of 4 different cats. For statistical analysis Student’s t test was used. All drugs (apart from a-glucochloralose that was taken up in hot distilled water) were dissolved in saline. Clonidine hydrochloride was obtained front C.H. Boehringer Sohn, Ingelheim am Rhein (W. Germany); desipramine hydrochloride was provided by CIBAGeigy, Basel (Switzerland); protriptyline hydrochloride by Merck, Sharp and Dohme, Haarlem (The Netherlands); yohimbine and piperoxan (hydrochlorides) were kindly put at our disposal by Prof. Dr. H. Schmitt, Paris; a-glucochloralose was purchased from E. Merck A.G., Darmstadt (W. Germany).
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Materials and Methods
Clonidine and Tricyclic Antidepressants
229
Clonidine (1 ng/kg) infused into the vertebral artery rapidly reduced mean arterial pressure by approximately 40 % of its initial value. Slow recovery of pressure started 5 10 min after the initial maximal effect (fig. 1). The infusion of saline (0.1 m l-k g '1 •m in '1) at the moment of the maximal decrease in pres sure into the vertebral artery did not influence the rate at which blood pressure regained normal values. Cardiac frequency was also depressed and showed a similar pattern of recovery. These data confirm earlier studies using the same technique (Sartler and van Zwieten, 1967) and are also in agreement with results obtained in other animal species where the drug was injected intravenously (Hoefke and Kobinger, 1966; Schmitt et ai, 1967; Kobinger, 1973). The fact that clonidine’s hypotensive effect is much more potent when injected into a vertebral artery than when administered intravenously, is one of the basic arguments leading to the assump tion that clonidine’s acute hypotensive action is of central nervous origin. In a second series of experiments protriptyline (300 ¡ig' kg"1) was injected into the vertebral artery shortly after the maximum hypotensive activity of clonidine was clearly established. Owing to the administration of protriptyline the hypotensive effect of clonidine was readily reversed and restored to normal values much more quickly, as shown in figure 1. One min after protriptyline administration and at all subsequent later moments blood pressure was significantly higher (at p < 0.01) than that in clonidine-treated animals which had not received the tricyclic antidepressant. After clonidine alone (fig. 1 a) residual blood pressure amounted to 82 % at 45 min following administration, whereas control values ( a, 100 %) were achieved already 10 min after clonidine injection followed by treatment with protriptyline. Qualitatively similar results were obtained when desipramine (300 /ctg-kg'1) was infused into the vertebral artery instead of protriptyline (fig. 2). Although significant, the influence of desipramine on the clonidine effect is less pro nounced than that of protriptyline. The initial level was not achieved. The bradycardie effect of clonidine was also diminished upon the infusion of the tricyclic antidepressant drugs. However, a quantitative determination proved un satisfactory, since the maximum of the negative chronotropic effect of clonidine not always coincided with the maximal hypotensive action. The present results suggest that protriptyline and desipramine applied via the vertebral artery readily reverse the already established central hypotensive effect of clonidine. If, however, protriptyline was given intravenously (300/ig/kg) no reversal of the clonidine effect was observed. Only when much higher doses (3 mg/kg) of protriptyline were given via the intravenous route could the already established hypotensive effect of clonidine be mitigated. This finding leads to the conclusion that the inhibition of the hypotensive effect by
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Results and Discussion
van Zwieten
230
protriptyline and desipramine occurs within the pontomedullary area of the CNS and not in the periphery. In view of our earlier results it seems likely that an antagonism at die level of the central a-adrenoreceptors is involved (see intro duction). Accordingly, the present results support the earlier interpretation of a com petitive interaction at the a-receptors within the CNS {van Zwieten, 1975 a). It is unlikely, that the cocaine-like properties of the tricyclic antidepressants play a part, since cocaine itself does not diminish the effect of clonidine. The present results are in accordance with die clinical observations by Briant et al. (1973), who described that low doses of desipramine may cause a dangerous rise in blood pressure in hypertensive patients who were well controlled by clonidine.
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Fig. I. Influence of clonidine (1 uglkg) alone and that of clonidine (I Mg/kg) followed by protriptyline t300 jag/kg) on mean arterial blood pressure in the anaesthetized cat. Both drugs were administered into the left vertebral artery. Blood pressure has been expressed as percentage of the initial control value (± SEM, n = 9 different cats for both series of experiments). Protriptyline was injected as soon as the maximal hypotensive effect of clonidine was clearly established, a Clonidine alone; b clonidine, followed by protriptyline. Fig. 2. Influence of clonidine (1 Mg/kg) alone and that of clonidine (1 ug/kg) followed by desipramine on mean arterial blood pressure in the anaesthetized cat. Details as in legend to figure 1, although n = 5 for each series, a Clonidine alone; b clonidine, followed by desipramine.
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References
Prof. Dr. P.A. van Zwieten. Division of Pharmacotherapy, Department of Pharmacy, Plantage Muidergracht 24, A msterdam-C (The Netherlands)
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Briant, R.H.: Reid, J.L., and Dollery, C.T.: Interaction between elonidinc and desipramine in man. Br. med. J. iV 522 526 (1973). Henning, M, and Zwieten, P.A. van: Central hypotensive action of a-methyl-dopa. J. Pharm. Pharmac. 20: 409 417 (1968). Hoefke, W. and Kobinger, W.: Pharmakologische Wirkungen des 2-(2,6-Dichlorphcnylamino)-2-imidazolinhydrochlorids, einer neuen antihypertensiven Substanz. Arznei mittel-Forsch. 16: 1038 1050(1966). Kobinger, W.: Pharmacological basis of the cardiovascular actions of clonidine; in Hyper tension: mechanisms and management, pp. 369-380 (1973). Reneman, R.S.: Weliens, D.; Jageneau, A.H.M., and Stynen, I..: Vertebral and carotid blood of the dog and the cat. Cardiovasc. Res. 8: 65 72 (1974). Sattler, R. W. and Zwieten, P.A. van: Acute hypotensive action of 2-(2.6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155) after infusion into the cat’s vertebral artery. Eur. J. Pharmacol. 2: 9-13 (1967). Schmitt, H.: Schmitt, H.; Boissier, J.R., and Giudiceili, J.F.: (1967): Centrally mediated decrease in sympathetic tone induced by 2-(2,6-dichlorophenylamino)-2-imidazoline (St 155, Catapresan®). Eur. J. Pharmacol. 2: 147 148 (1967). Schmitt. //., Schmitt, H.. and Fenard, S.: Evidence for an a-sympathomimctic component in the effects of catapresan on vasomotor centres: antagonism by piperoxan. Eur. J. Pharmacol. 14: 98-100(1971). Schmitt, H.: Schmitt, //., and Fenard, S.: Action of a-adrencrgic blocking drugs on the sympathetic centres and their interactions with the central sympatho-inhibitory effect of clonidine. Arzneimittel-Eorsch. 23: 40 44 (1973). Spanning, H. W. van and Zwieten, P.A. van: The interaction between a-methyl-dopa and tricyclic antidepressants. Int. J. clin. Pharmacol. 11: 65-67 (1975). Spanning, H. W. van and Zwieten, P.A. van: The interference of tricyclic antidepressants with the central hypotensive effect of clonidine. Eur. J. Pharmacol. 24: 402 404 (1973). Zwieten, P.A. van: The interaction between centrally acting hypotensive drugs and tricyclic antidepressants. Archs int. Pharmacodyn. Thcr. 214: 12-30 (1975a). Zwieten, P.A. van: Antihypertensive drugs with a central action. Prog. Pharmacol., vol. I, pp. 1-63 (Fischer, Stuttgart 1975 b).
The Reversal of Clonidine-Induced Hypotension by Protriptyline and Desipramine P.A. van Zwieten' With the technical assistance of Marion Pauer Division of Pharmacotherapy, Department of Pharmacy, University of Amsterdam, Amsterdam
Key Words. Drug interaction • Clonidine • Tricyclic antidepressants • Central a-adrenoreceptors • Desipramine • Protriptyline • Hypotensive effect • Vertebral artery Abstract. The present paper deals with further studies on the interaction between clonidine and tricyclic antidepressants. The pronounced central hypotensive action of 1 Mg clonidine/kg, administered into the left vertebral artery of chloralose-anaesthetized cats was readily reversed by protriptyline (300 Mg/kg) or desipramine (300 Mg/kg), infused via the same route shortly after the development of the maximum hypotensive effect of clonidine. In earlier studies it has been demonstrated that pretreatment with tricyclic antidepressants significantly diminishes the central hypotensive action of clonidine. This interaction has been presumed to occur at the level of central a-adrcnorcceptors, where clonidine would be the agonist and tricyclic antidepressants the antagonist. The present findings suggest that a competitive antagonism at the central level, which can occur in either sense, may be in volved.
In preceding communications (van Spanning and van Zwieten, 1973; van Zwieten, 1975 a, b) we have described how pretreatment of anaesthetized cats with various tricyclic antidepressants significantly reduces the central hypoten sive action of clonidine, but also that of a-methyl-dopa (van Spanning and van Zwieten, 1975; van Zwieten, 1975b). This finding has been interpreted in the sense of an antagonism at the level of the central »-adrenoreceptors, which are presumed to be the main sites of initiation of clonidine’s central hypotensive effect. This antagonism is probably competitive in nature, since the doseresponse curve for clonidine’s hypotensive effect was shifted to the right in a ' We are greatly indebted to the Dutch Heart Foundation (Nederlandse Hartstichting), The Hague, Netherlands, for the support of these studies.
Downloaded by: King's College London 137.73.144.138 - 3/6/2018 10:27:31 PM
Received: November 14, 1975.
van Zwieten
228
parallel fashion upon pretreatment with protriptyline (van Zwieten, 1975 a). Similarly, Schmitt et al. (1973) presumed that the amitriptyline-induced reduc tion of clonidine’s central hypotensive effect reflects a competitive antagonism at the level of central a-adrenoreceptors. In this connection it should be kept in mind that protriptyline, amitriptyline and various other tricyclic antidepressants possess considerable a-sympatholytic activity, at least in the peripheral circulato ry system. Clonidine may be regarded as a potent stimulator of central a-adrenergic receptors whereas a-sympatholytic drugs like yohimbine and piperoxan are known to block the central hypotensive action of clonidine (Hoefke and Kobinger, 1966; Schmitt et al., 1971). If a competitive antagonism on the cen tral a-adrenoreceptors is indeed involved in case of interaction between tricyclic antidepressants and clonidine, one should expect a diminishment of the already established hypotensive effect of clonidine by subsequently administered tricy clic antidepressants. This problem was investigated in the present study.
All experiments were carried out on mongrel cats of either sex, anaesthetized with a-glucochloralosc, administered intraperitoneally (60 mg/kg). The animals were subjected to artificial respiration, using a Braun Melsungcn pump. After left-sided thoracotomy, a can nula was introduced into the left subclavian artery and pushed forward until its tip was located 2 -3 mm distal from the ostium of the left vertebral artery. Small volumes (0.1 ml-kg"‘ body weight) of solutions infused at a rate of 0.1 m l-m in'1 arc thus intro duced into the left vertebral artery. Owing to the blood stream from the aortic arch and proximal left subclavian artery, drugs thus infused will reach the pontomedullary region of the brain. In the cat, brain centres higher than the pontomedullary are not substantially perfused with blood from the vertebral arteries, as demonstrated by means of radioactively labelled microsphcres (Reneman et al., 1974). The technique of drug administration into the cat’s left vertebral artery has been described previously in full detail (Henning and van Zwieten, 1968; van Zwieten, 1975b). Heparine was injected intravenously after the surgical intervention. Mean arterial blood pressure was recorded from a cannulated femoral artery by means of a Statliam pressure transducer connected to a Hellige HE 19 amplification and recording device. Cardiac frequency was obtained from the femoral pulse wave that was recorded at high speed of the recording paper. The mean arterial pressure before any drug treatment (apart from anaesthesia) had occurred amounted to 124.0+ 3.6mm Hg (m eant SEM, n= 24 for all cats, prior to treatment). All animals with a blood pressure lower than 100 mm Hg were discarded. All subsequent values for blood pressure were expressed as percentage of the initial value before drug treatment in each individual experiment. Mean values ± SEM were calculated for the number of 4 different cats. For statistical analysis Student’s t test was used. All drugs (apart from a-glucochloralose that was taken up in hot distilled water) were dissolved in saline. Clonidine hydrochloride was obtained front C.H. Boehringer Sohn, Ingelheim am Rhein (W. Germany); desipramine hydrochloride was provided by CIBAGeigy, Basel (Switzerland); protriptyline hydrochloride by Merck, Sharp and Dohme, Haarlem (The Netherlands); yohimbine and piperoxan (hydrochlorides) were kindly put at our disposal by Prof. Dr. H. Schmitt, Paris; a-glucochloralose was purchased from E. Merck A.G., Darmstadt (W. Germany).
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Materials and Methods
Clonidine and Tricyclic Antidepressants
229
Clonidine (1 ng/kg) infused into the vertebral artery rapidly reduced mean arterial pressure by approximately 40 % of its initial value. Slow recovery of pressure started 5 10 min after the initial maximal effect (fig. 1). The infusion of saline (0.1 m l-k g '1 •m in '1) at the moment of the maximal decrease in pres sure into the vertebral artery did not influence the rate at which blood pressure regained normal values. Cardiac frequency was also depressed and showed a similar pattern of recovery. These data confirm earlier studies using the same technique (Sartler and van Zwieten, 1967) and are also in agreement with results obtained in other animal species where the drug was injected intravenously (Hoefke and Kobinger, 1966; Schmitt et ai, 1967; Kobinger, 1973). The fact that clonidine’s hypotensive effect is much more potent when injected into a vertebral artery than when administered intravenously, is one of the basic arguments leading to the assump tion that clonidine’s acute hypotensive action is of central nervous origin. In a second series of experiments protriptyline (300 ¡ig' kg"1) was injected into the vertebral artery shortly after the maximum hypotensive activity of clonidine was clearly established. Owing to the administration of protriptyline the hypotensive effect of clonidine was readily reversed and restored to normal values much more quickly, as shown in figure 1. One min after protriptyline administration and at all subsequent later moments blood pressure was significantly higher (at p < 0.01) than that in clonidine-treated animals which had not received the tricyclic antidepressant. After clonidine alone (fig. 1 a) residual blood pressure amounted to 82 % at 45 min following administration, whereas control values ( a, 100 %) were achieved already 10 min after clonidine injection followed by treatment with protriptyline. Qualitatively similar results were obtained when desipramine (300 /ctg-kg'1) was infused into the vertebral artery instead of protriptyline (fig. 2). Although significant, the influence of desipramine on the clonidine effect is less pro nounced than that of protriptyline. The initial level was not achieved. The bradycardie effect of clonidine was also diminished upon the infusion of the tricyclic antidepressant drugs. However, a quantitative determination proved un satisfactory, since the maximum of the negative chronotropic effect of clonidine not always coincided with the maximal hypotensive action. The present results suggest that protriptyline and desipramine applied via the vertebral artery readily reverse the already established central hypotensive effect of clonidine. If, however, protriptyline was given intravenously (300/ig/kg) no reversal of the clonidine effect was observed. Only when much higher doses (3 mg/kg) of protriptyline were given via the intravenous route could the already established hypotensive effect of clonidine be mitigated. This finding leads to the conclusion that the inhibition of the hypotensive effect by
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Results and Discussion
van Zwieten
230
protriptyline and desipramine occurs within the pontomedullary area of the CNS and not in the periphery. In view of our earlier results it seems likely that an antagonism at die level of the central a-adrenoreceptors is involved (see intro duction). Accordingly, the present results support the earlier interpretation of a com petitive interaction at the a-receptors within the CNS {van Zwieten, 1975 a). It is unlikely, that the cocaine-like properties of the tricyclic antidepressants play a part, since cocaine itself does not diminish the effect of clonidine. The present results are in accordance with die clinical observations by Briant et al. (1973), who described that low doses of desipramine may cause a dangerous rise in blood pressure in hypertensive patients who were well controlled by clonidine.
Downloaded by: King's College London 137.73.144.138 - 3/6/2018 10:27:31 PM
Fig. I. Influence of clonidine (1 uglkg) alone and that of clonidine (I Mg/kg) followed by protriptyline t300 jag/kg) on mean arterial blood pressure in the anaesthetized cat. Both drugs were administered into the left vertebral artery. Blood pressure has been expressed as percentage of the initial control value (± SEM, n = 9 different cats for both series of experiments). Protriptyline was injected as soon as the maximal hypotensive effect of clonidine was clearly established, a Clonidine alone; b clonidine, followed by protriptyline. Fig. 2. Influence of clonidine (1 Mg/kg) alone and that of clonidine (1 ug/kg) followed by desipramine on mean arterial blood pressure in the anaesthetized cat. Details as in legend to figure 1, although n = 5 for each series, a Clonidine alone; b clonidine, followed by desipramine.
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231
References
Prof. Dr. P.A. van Zwieten. Division of Pharmacotherapy, Department of Pharmacy, Plantage Muidergracht 24, A msterdam-C (The Netherlands)
Downloaded by: King's College London 137.73.144.138 - 3/6/2018 10:27:31 PM
Briant, R.H.: Reid, J.L., and Dollery, C.T.: Interaction between elonidinc and desipramine in man. Br. med. J. iV 522 526 (1973). Henning, M, and Zwieten, P.A. van: Central hypotensive action of a-methyl-dopa. J. Pharm. Pharmac. 20: 409 417 (1968). Hoefke, W. and Kobinger, W.: Pharmakologische Wirkungen des 2-(2,6-Dichlorphcnylamino)-2-imidazolinhydrochlorids, einer neuen antihypertensiven Substanz. Arznei mittel-Forsch. 16: 1038 1050(1966). Kobinger, W.: Pharmacological basis of the cardiovascular actions of clonidine; in Hyper tension: mechanisms and management, pp. 369-380 (1973). Reneman, R.S.: Weliens, D.; Jageneau, A.H.M., and Stynen, I..: Vertebral and carotid blood of the dog and the cat. Cardiovasc. Res. 8: 65 72 (1974). Sattler, R. W. and Zwieten, P.A. van: Acute hypotensive action of 2-(2.6-dichlorophenylamino)-2-imidazoline hydrochloride (St 155) after infusion into the cat’s vertebral artery. Eur. J. Pharmacol. 2: 9-13 (1967). Schmitt, H.: Schmitt, H.; Boissier, J.R., and Giudiceili, J.F.: (1967): Centrally mediated decrease in sympathetic tone induced by 2-(2,6-dichlorophenylamino)-2-imidazoline (St 155, Catapresan®). Eur. J. Pharmacol. 2: 147 148 (1967). Schmitt. //., Schmitt, H.. and Fenard, S.: Evidence for an a-sympathomimctic component in the effects of catapresan on vasomotor centres: antagonism by piperoxan. Eur. J. Pharmacol. 14: 98-100(1971). Schmitt, H.: Schmitt, //., and Fenard, S.: Action of a-adrencrgic blocking drugs on the sympathetic centres and their interactions with the central sympatho-inhibitory effect of clonidine. Arzneimittel-Eorsch. 23: 40 44 (1973). Spanning, H. W. van and Zwieten, P.A. van: The interaction between a-methyl-dopa and tricyclic antidepressants. Int. J. clin. Pharmacol. 11: 65-67 (1975). Spanning, H. W. van and Zwieten, P.A. van: The interference of tricyclic antidepressants with the central hypotensive effect of clonidine. Eur. J. Pharmacol. 24: 402 404 (1973). Zwieten, P.A. van: The interaction between centrally acting hypotensive drugs and tricyclic antidepressants. Archs int. Pharmacodyn. Thcr. 214: 12-30 (1975a). Zwieten, P.A. van: Antihypertensive drugs with a central action. Prog. Pharmacol., vol. I, pp. 1-63 (Fischer, Stuttgart 1975 b).
