European Journal of Clinical Pharmacology
Europ. J. din. Pharmacol. 11, 125-128 (1977)
© by Springer-Verlag 1977
Monoamine Metabolites in Cerebrospinal Fluid during Treatment with Clonidine or Alprenolol L. Bertilsson, K. Haglund, J. Ostman, M. D. Rawlins*, V.-A. Ringberger and F. Sj6qvist Departments of Medicine and Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden
Summary. Lumbar cerebrospinal fluid (CSF) concentrations of the major metabolites of noradrenaline (4-hydroxy-3-methoxyphenyl glycol, HMPG), serotonin (5-hydroxyindoleacetic acid) and dopamine (homovanillic acid) were measured before and during the administration of clonidine or alprenolol to hypertensive patients. The noradrenaline receptor stimulant clonidine significantly decreased the CSF level of HMPG, but there was no consistent change in the concentration of serotonin or dopamine metabolites. Patients on alprenolol showed no change in the levels of these metabolites in CSF.
(Offerhaus and van Zwieten, 1974) lowers the bloodpressure more when administered directly to the brain than after its systemic injection. We have investigated whether clonidine and alprenolol, in doses which lower arterial blood pressure, alter the concentration of the major metabolites of noradrenaline, dopamine and serotonin in the cerebrospinal fluid (CSF) of hypertensive patients.
Key words: Clonidine, alprenolol, amine metabolites, cerebrospinal fluid, hypertension, noradrenaline.
Eleven patients (9 males) with moderate hypertension were selected. Seven were treated with clonidine (Table 1) and four with alprenolol (Table 2). Their ages ranged from 28 to 55 years, and secondary causes of hypertension had been excluded from all but one patient by physical examination and laboratory investigations (serum electrolytes, 24-hour urinary catecholamine excretion, endogenous creatinine clearance and isotope renography). Patient 1 had mild proteinuria, an endogenous creatinine clearance of 63 ml/min, but normal plasma renin activity and a normal intravenous pyelogram. This patient also received allopurinol (100 mg tds) for the treatment of asymptomatic hyperuricaemia. No patient had any history of depression or psychosis, or had been given antidepressants or neuroleptic drugs for other reasons. Patient 7 (Table 1) received diazepam 5-10 mg per day throughout the study for the treatment of tension headaches. All patients freely consented to participate in the study after a full discussion of its aims, and of the procedure involved. All patients were free to withdraw from the study at any time, but none took advantage of this opportunity. Approval of the project was obtained from the Ethical Committee of the Karolinska Institute.
Clonidine is an effective hypotensive agent in man and animals, and is widely used for long-term treatment of patient s with arterial hypertension. Evidence obtained from animal studies suggests that its action may be mediated via an effect on catecholaminergic neurons within the central nervous system (Kobinger, 1967; Sattler and van Zwieten, 1967), resulting in reduced sympathetic outflow (Schmitt et al., 1971). In hypertensive patients treatment with clonidine is associated with a reduction in urinary catecholamines (H6kfelt et al., 1970). Whilst the central effects of r-receptor blocking drugs are now well documented (Jefferson, 1974), their possible contribution to the antihypertensive action of this class of compounds is equivocal. Observations in experimental animals show that alprenolol * Present address: Department of Pharmacological Sciences (Clinical Pharmacology), Newcastle upon Tyne, England
Patients, Materials and Methods
M 'M M M M M F
43
52 30 55 37 45 41 44
Age (years)
84
82 121 91 76 72 88 57
Weight (kg)
514
450 450 900 450 675 450 225
Dose of clonidine (~tg/day)
165/106
170/116 159/97 176/111 157/98 167/107 153/111 176/102
before clonidine
144/93
136/94 140/94 155/96 134/83 137/97 125/90 180/99
during clonidine
Blood pressure
13.6
9.5 14.8 12.0 15.1 13.9 19.8 9.9
before clonidine
H V A (ng/ml)
11.1
8.2 9.4 8.7 11.6 9.5 18.6 11.5 50.6
19.0 64.9 53.8 50.6 74.6 40.9
during before clonidine clonidine
H M P G (ng/ml)
62.3
17.8 83.3 58.1 58.2 38.2 93.2 87.4
140/89 138/92 123/87 157/111 139/95
8.2 6.1 9.5 13.4 9.3
8.4 5.8 9.9 12.2 9.1
H M P G (ng/ml) placebo alprenolol
a One patient could not repeat the exercise test because of a sprained ankle
154/90 165/119 134/99 183/125 159/108
32 28 35 44 35
8 M 9 F 10 M 11 M Means
74 55 90 78 74
Age Weight Blood pressure (years) (kg) placebo alprenolol
No. Sex
22.3 12.4 36.8 24.4 24.0
23.9 14.5 36.0 21.9 24.1
H V A (ng/ml) placebo alprenolol
9.3 8.4 15.0 9.9 10.7
12.3 10.2 15.7 8.5 11.7
5 - H I A A (ng/ml) placebo alprenolol
4 40 38 19 25
Alprenolol plasma concentration •. (mean steady state) ng/ml
Table 2. Blood pressure and cerebrospinal fluid monoamine metabolites before and during treatment with alprenolol (600 mg daily for 6 weeks)
Patient
21.5
4.2 22.5 19.0 29.6 13.9 30.5 31.0
3.6 6.8 2.7 2.5 3.9
placebo
2.6 1.9 1.4 1.1 1.8
alprenolol
Plasma renin activity ng/ml/h
r = 0.82, p < 0.05, respectively)
19.7
11.0 19.1 21.4 24.8 15.1 29.0 17.4
during clonidine
5 - H I A A (ng/ml) during before clonidine clonidine
The pretreatment concentrations of 5-HIAA and H V A and of 5 - H I A A and H M P G were significantly correlated (r = 0.88, p < 0.05;
Means
1 2 3 4 5 6 7
Patient No. Sex
Table 1. Blood pressure and CSF monoamine metabolite concentrations before and during clonidine therapy
-35
a
-34 -50
Change of heart rate at maximal exercise (beats/ miffute)
r,.
t~
0
2.
O
O
O
L. Bertilsson et al.: Monoamine Metabolites in Cerebrospinal Fluid
The lumbar punctures were performed at 8.00 h, after an overnight fast, with the patient lying until the puncture had been performed. Cerebrospinal fluid 13 ml was withdrawn, without syringe aspiration, into a silanized glass tube (plastic tubes were used in patients 5-7 due to an administrative mistake) and immediately centrifuged. The fluid was stored at -20 ° C, in 3.5 ml aliquots in silanized tubes prior to analysis for 5-hydroxyindoleacetic acid (5-HIAA; Bertilsson et al., 1972), homovanillic acid (HVA; Sj6quist and )i_ngggLrd, 1972) and total 4-hydroxy-3-methoxyphenyl glycol (HMPG; Bertilsson, 1973) by mass fragmentography. The clonidine-treated patients commenced therapy after the first lumbar puncture with a starting dose of 150 micrograms (Catapresan ®) twice daily, except one patient who received 75 micrograms twice daily. The dose was generally increased every third or fourth day until an adequate hypotensive response had been achieved. Blood pressure was measured twice daily with a mercury sphygmomanometer by one trained nurse. The pretreatment blood pressure was calculated from the mean of the pressures recorded from the fourth to the sixth day of hospitalisation. Posttreatment pressures were calculated as the mean of all measurements recorded during the period when the final dose of clonidine was taken. The alprenolol-treated patients had been treated initially with placebo for six weeks and then given alprenolol 600 mg (Aptin ®, Hfissle, M61ndal, Sweden) daily for another six weeks. The blood pressure was measured at the same time as on the day of admission by the same observer, who used a sphygmomanometer with a concealed scale, and who was unaware of previous blood pressure recordings. The "/3-blockade" was measured both as a decrease in heart rate at nearly maximal exercise on a bicycle ergometer, and as the decrease in plasma renin activity. The mean steady state plasma concentration of alprenolol was calculated from the area under the curve measured the day before the lumbar puncture (for further details of this design and methods see Collste et al., 1976).
Results In the group of patients treated with clonidine (Table 1) there was a positive correlation between the pretreatment levels of 5-HIAA and HVA. This has previously been reported in other series (e. g. Gottfries et al., 1971; Asberg et al., 1976). The levels both of 5-HIAA and HVA before drug treatment were lower (p < 0.05) in the patients treated with alprenolol (Table 2) than in those treated with clonidine (Table
127
1). This finding cannot be explained at present. In patients 1-6 the administration of clonidine was associated with a fall in both systolic and diastolic pressure (p < 0.05). All these six patients had lower CSF concentration of HMPG during clonidine treatment (p < 0.05), but there were no consistent or significant changes in the cerebrospinal fluid concentration of HVA or 5-HIAA. In the seventh patient there was no siginificant hypotensive effect after treatment with clonidine in the low dose of 75 micrograms tds, nor was there any decrease in the cerebrospinal fluid concentration of HMPG. Treatment with alprenolol caused no change in the concentration of the three amine metabolites (Table 2), although in all four patients both the systolic and diastolic blood pressure decreased. Three patients had a significant plasma concentration of unchanged alprenolol and all had evidence of effective/3-adrenergic blockade, with a decrease in standing plasma renin activity, and a decrease in heart rate at maximal exercise.
Discussion These findings indicate that clonidine, in doses that reduce blood pressure, lowers the cerebrospinal fluid concentration of HMPG in man, as has been shown in CSF from the monkey (Reid, 1976), and in the rat brain (Braestrup, 1974). Changes in CSF amine metabolites have been shown to be a valuable tool for pharmacodynamic studies of psychotropic drugs in man. Thus, the noradrenaline and serotonin reuptake inhibitors nortriptyline and chlorimipramine decrease the CSF levels of HMPG and 5-HIAA, respectively (Bertilsson et al., 1974). Similarly, the dopamine receptor blocker chlorpromazine increases HVA in CSF (Sedvall et al., 1975). The decrease of HMPG in CSF induced by clonidine during treatment of hypertension, shown in this report, is consistent with its presumed central adrenoceptor stimulating activity (see, for example, Svensson et al., 1975). When given in very high doses to rats propranolol has been found to increase HVA and HMPG in brain (Wiesel, 1976). The usual antihypertensive doses of alprenolol do not appear to affect the cerebrospinal fluid concentration of HMPG, HVA or 5-HIAA in man (Table 2).
Acknowledgements.The study was supported by the Swedish Medical Research Council (3902-05A), the Bank of Sweden Tercenternary Fund 75/110) and funds from the Karolinska Institute.
128
References Asberg, M., Ringberger, V.-A., Sj6qvist, F., Thor6n, P., Tr~iskman, L., Tuck, J. R.: Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with clorimipramine. Clin. Pharmacol. Ther. In press Bertilsson, L.: Quantitative determination of 4-hydroxy-3 methoxyphenyl glycol and its conjugates in cerebrospinal fluid by mass fragmentography. J. Chromatogr. 87, 147-153 (1973) Bertilsson, L., Asberg, M., Thor6n, P.: Differential effect of chlorimipramine and nortriptyline on cerebrospinal fluid metabolites of serotonin and noradrenaline in depression. Europ. J. clin. Pharmacol. 7, 365-368 (1974) Bertilsson, L., Atkinson, A. J., Jr., Althaus, J. R., H~irfast, A., Lindgren, J.-E., Holmstedt, B.: Quantitative determination of 5-hydroxyindole-3-acetic acid in cerebrospinal fluid by gas chromatography-mass spectrometry. Anal. Chem. 44, 1434-1438 (1972) Braestrup, C.: Effects of phenoxybenzamine, aceperone and clonidine on the level of 3-methoxy-4-hydroxyphenylglycol (MOPEG) in rat brain. J. Pharm. Pharmacol. 26, 139-141 (1974) Collste, P., Haglund, K., Frisk-Holmberg, M., Orme, M., Rawlins, M., (3stman, J.: Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension. II. Relationship to its effect on blood pressure and plasma renin activity. Europ. J. clin. Pharmacol. 10, 89-95 (1976) Gottfries, C. G., Gottfries, I., Johansson. B., Olsson, R., Persson, T., Roos, B.-E., Sj6str6m, R.: Acid monoamine metabolites in human cerebrospinal fluid and their relations to age and sex. Neuropharmacol. 10, 665-672 (1971) H61delt, B., Hedeland, H., Dymling, J. F.: Studies on catecholamines, renin and aldosterone following Catepresan (2-(2,6-dichlor-phenylamine)-2-imidazolinehydrochloride) in hypertensive patients. Europ. J. Pharmacol. 10, 389-397 (1970) Jefferson, J. W.: Beta-adrenergic receptor blocking drugs in psychiatry. Arch. Gen. Psychiat. 31, 681-691 (1974) Kobinger, W.: Ober den Wirkungsmechanismus einer neuen antihypertensiven Substanz mit Imidazolinstruktur. NaunynSchmiedeberg's Arch. Pharmacol. 258, 48-58 (1967)
L. Bertilsson et al.: Monoamine Metabolites in Cerebrospinal Fluid Offerhaus, L., von Zwieten, P. A.: Comparative studies on central factors contributing to the hypotensive action of propranolol, alprenolol, and their enantiomers. Cardiovasc. Res. 4, 488-495 (1974) Reid, J.: Clonidine and central noradrenaline turnover. In: The central actions of drugs in the regulation of blood pressure, (ed. D. S. Davies, J. L. Reid). In press Sattler, R. W., van Zwieten, P. A.: Acute hypotensive action of 2-(2,6-dichlorophenylamino)-2-imidazolinehydrochloride (St 155) after infusion into the cat's vertebral artery. Europ. J. Pbarmacol. 2, 9-13 (1967) Schmitt, H., Schmitt, Mme H., Fenard, S.: Evidence for an c~-sympathomimetic component in the effects of Catapresan on vasomotor centres: antagonism by piperoxane. Europ. J. Pharmacol. 14, 98-100 (1971) Sedvall, G., Alfredsson, G., Bjerkenstedt, L., Eneroth, P., Fyr6, B., H~irnryd, C., Swahn, C.-G., Wiesel, F.-A., Wode-Helgodt, B.: Selective effects of psychoactive drugs on levels of monoamine metabolites and prolactin in cerebrospinal fluid of psychiatric patients. Proceedings of the Sixth International Congress of Pharmacol (eds. J. Tuomisto, M. K. Paasonen) 3, 255-267 (1975) Sj6quist, B., )~ngg~rd, E.: Gas chromatographic determination of homovanillic acid in human cerebrospinal fluid by electron capture detection and by mass fragmentography with a deuterated internal standard. Anal. Chem. 44, 2297-2301 (1972) Svensson, T. H., Bunney, B. S., Aghajanian, G. K.: Inhibition of both noradrenergic and serotonergic neurons in brain by the a-adrenergic agonist clonidine. Brain Res. 92, 291-306 (1975) Wiesel, F.-A.: Effects of high dose propranolol treatment on dopamine and norepinephrine metabolism in regions of rat brain. Neuroscience Lett. 2, 35-38 (1976)
Received: February 2, 1976, and in revised form: July 3, 1976, accepted: August 26, 1976 Dr. L. Bertilsson Dept. of Clinical Pharmacology Huddinge University Hospital S-1 41 86 Huddinge Sweden
Europ. J. din. Pharmacol. 11, 125-128 (1977)
© by Springer-Verlag 1977
Monoamine Metabolites in Cerebrospinal Fluid during Treatment with Clonidine or Alprenolol L. Bertilsson, K. Haglund, J. Ostman, M. D. Rawlins*, V.-A. Ringberger and F. Sj6qvist Departments of Medicine and Clinical Pharmacology, Karolinska Institute, Huddinge University Hospital, Huddinge, Sweden
Summary. Lumbar cerebrospinal fluid (CSF) concentrations of the major metabolites of noradrenaline (4-hydroxy-3-methoxyphenyl glycol, HMPG), serotonin (5-hydroxyindoleacetic acid) and dopamine (homovanillic acid) were measured before and during the administration of clonidine or alprenolol to hypertensive patients. The noradrenaline receptor stimulant clonidine significantly decreased the CSF level of HMPG, but there was no consistent change in the concentration of serotonin or dopamine metabolites. Patients on alprenolol showed no change in the levels of these metabolites in CSF.
(Offerhaus and van Zwieten, 1974) lowers the bloodpressure more when administered directly to the brain than after its systemic injection. We have investigated whether clonidine and alprenolol, in doses which lower arterial blood pressure, alter the concentration of the major metabolites of noradrenaline, dopamine and serotonin in the cerebrospinal fluid (CSF) of hypertensive patients.
Key words: Clonidine, alprenolol, amine metabolites, cerebrospinal fluid, hypertension, noradrenaline.
Eleven patients (9 males) with moderate hypertension were selected. Seven were treated with clonidine (Table 1) and four with alprenolol (Table 2). Their ages ranged from 28 to 55 years, and secondary causes of hypertension had been excluded from all but one patient by physical examination and laboratory investigations (serum electrolytes, 24-hour urinary catecholamine excretion, endogenous creatinine clearance and isotope renography). Patient 1 had mild proteinuria, an endogenous creatinine clearance of 63 ml/min, but normal plasma renin activity and a normal intravenous pyelogram. This patient also received allopurinol (100 mg tds) for the treatment of asymptomatic hyperuricaemia. No patient had any history of depression or psychosis, or had been given antidepressants or neuroleptic drugs for other reasons. Patient 7 (Table 1) received diazepam 5-10 mg per day throughout the study for the treatment of tension headaches. All patients freely consented to participate in the study after a full discussion of its aims, and of the procedure involved. All patients were free to withdraw from the study at any time, but none took advantage of this opportunity. Approval of the project was obtained from the Ethical Committee of the Karolinska Institute.
Clonidine is an effective hypotensive agent in man and animals, and is widely used for long-term treatment of patient s with arterial hypertension. Evidence obtained from animal studies suggests that its action may be mediated via an effect on catecholaminergic neurons within the central nervous system (Kobinger, 1967; Sattler and van Zwieten, 1967), resulting in reduced sympathetic outflow (Schmitt et al., 1971). In hypertensive patients treatment with clonidine is associated with a reduction in urinary catecholamines (H6kfelt et al., 1970). Whilst the central effects of r-receptor blocking drugs are now well documented (Jefferson, 1974), their possible contribution to the antihypertensive action of this class of compounds is equivocal. Observations in experimental animals show that alprenolol * Present address: Department of Pharmacological Sciences (Clinical Pharmacology), Newcastle upon Tyne, England
Patients, Materials and Methods
M 'M M M M M F
43
52 30 55 37 45 41 44
Age (years)
84
82 121 91 76 72 88 57
Weight (kg)
514
450 450 900 450 675 450 225
Dose of clonidine (~tg/day)
165/106
170/116 159/97 176/111 157/98 167/107 153/111 176/102
before clonidine
144/93
136/94 140/94 155/96 134/83 137/97 125/90 180/99
during clonidine
Blood pressure
13.6
9.5 14.8 12.0 15.1 13.9 19.8 9.9
before clonidine
H V A (ng/ml)
11.1
8.2 9.4 8.7 11.6 9.5 18.6 11.5 50.6
19.0 64.9 53.8 50.6 74.6 40.9
during before clonidine clonidine
H M P G (ng/ml)
62.3
17.8 83.3 58.1 58.2 38.2 93.2 87.4
140/89 138/92 123/87 157/111 139/95
8.2 6.1 9.5 13.4 9.3
8.4 5.8 9.9 12.2 9.1
H M P G (ng/ml) placebo alprenolol
a One patient could not repeat the exercise test because of a sprained ankle
154/90 165/119 134/99 183/125 159/108
32 28 35 44 35
8 M 9 F 10 M 11 M Means
74 55 90 78 74
Age Weight Blood pressure (years) (kg) placebo alprenolol
No. Sex
22.3 12.4 36.8 24.4 24.0
23.9 14.5 36.0 21.9 24.1
H V A (ng/ml) placebo alprenolol
9.3 8.4 15.0 9.9 10.7
12.3 10.2 15.7 8.5 11.7
5 - H I A A (ng/ml) placebo alprenolol
4 40 38 19 25
Alprenolol plasma concentration •. (mean steady state) ng/ml
Table 2. Blood pressure and cerebrospinal fluid monoamine metabolites before and during treatment with alprenolol (600 mg daily for 6 weeks)
Patient
21.5
4.2 22.5 19.0 29.6 13.9 30.5 31.0
3.6 6.8 2.7 2.5 3.9
placebo
2.6 1.9 1.4 1.1 1.8
alprenolol
Plasma renin activity ng/ml/h
r = 0.82, p < 0.05, respectively)
19.7
11.0 19.1 21.4 24.8 15.1 29.0 17.4
during clonidine
5 - H I A A (ng/ml) during before clonidine clonidine
The pretreatment concentrations of 5-HIAA and H V A and of 5 - H I A A and H M P G were significantly correlated (r = 0.88, p < 0.05;
Means
1 2 3 4 5 6 7
Patient No. Sex
Table 1. Blood pressure and CSF monoamine metabolite concentrations before and during clonidine therapy
-35
a
-34 -50
Change of heart rate at maximal exercise (beats/ miffute)
r,.
t~
0
2.
O
O
O
L. Bertilsson et al.: Monoamine Metabolites in Cerebrospinal Fluid
The lumbar punctures were performed at 8.00 h, after an overnight fast, with the patient lying until the puncture had been performed. Cerebrospinal fluid 13 ml was withdrawn, without syringe aspiration, into a silanized glass tube (plastic tubes were used in patients 5-7 due to an administrative mistake) and immediately centrifuged. The fluid was stored at -20 ° C, in 3.5 ml aliquots in silanized tubes prior to analysis for 5-hydroxyindoleacetic acid (5-HIAA; Bertilsson et al., 1972), homovanillic acid (HVA; Sj6quist and )i_ngggLrd, 1972) and total 4-hydroxy-3-methoxyphenyl glycol (HMPG; Bertilsson, 1973) by mass fragmentography. The clonidine-treated patients commenced therapy after the first lumbar puncture with a starting dose of 150 micrograms (Catapresan ®) twice daily, except one patient who received 75 micrograms twice daily. The dose was generally increased every third or fourth day until an adequate hypotensive response had been achieved. Blood pressure was measured twice daily with a mercury sphygmomanometer by one trained nurse. The pretreatment blood pressure was calculated from the mean of the pressures recorded from the fourth to the sixth day of hospitalisation. Posttreatment pressures were calculated as the mean of all measurements recorded during the period when the final dose of clonidine was taken. The alprenolol-treated patients had been treated initially with placebo for six weeks and then given alprenolol 600 mg (Aptin ®, Hfissle, M61ndal, Sweden) daily for another six weeks. The blood pressure was measured at the same time as on the day of admission by the same observer, who used a sphygmomanometer with a concealed scale, and who was unaware of previous blood pressure recordings. The "/3-blockade" was measured both as a decrease in heart rate at nearly maximal exercise on a bicycle ergometer, and as the decrease in plasma renin activity. The mean steady state plasma concentration of alprenolol was calculated from the area under the curve measured the day before the lumbar puncture (for further details of this design and methods see Collste et al., 1976).
Results In the group of patients treated with clonidine (Table 1) there was a positive correlation between the pretreatment levels of 5-HIAA and HVA. This has previously been reported in other series (e. g. Gottfries et al., 1971; Asberg et al., 1976). The levels both of 5-HIAA and HVA before drug treatment were lower (p < 0.05) in the patients treated with alprenolol (Table 2) than in those treated with clonidine (Table
127
1). This finding cannot be explained at present. In patients 1-6 the administration of clonidine was associated with a fall in both systolic and diastolic pressure (p < 0.05). All these six patients had lower CSF concentration of HMPG during clonidine treatment (p < 0.05), but there were no consistent or significant changes in the cerebrospinal fluid concentration of HVA or 5-HIAA. In the seventh patient there was no siginificant hypotensive effect after treatment with clonidine in the low dose of 75 micrograms tds, nor was there any decrease in the cerebrospinal fluid concentration of HMPG. Treatment with alprenolol caused no change in the concentration of the three amine metabolites (Table 2), although in all four patients both the systolic and diastolic blood pressure decreased. Three patients had a significant plasma concentration of unchanged alprenolol and all had evidence of effective/3-adrenergic blockade, with a decrease in standing plasma renin activity, and a decrease in heart rate at maximal exercise.
Discussion These findings indicate that clonidine, in doses that reduce blood pressure, lowers the cerebrospinal fluid concentration of HMPG in man, as has been shown in CSF from the monkey (Reid, 1976), and in the rat brain (Braestrup, 1974). Changes in CSF amine metabolites have been shown to be a valuable tool for pharmacodynamic studies of psychotropic drugs in man. Thus, the noradrenaline and serotonin reuptake inhibitors nortriptyline and chlorimipramine decrease the CSF levels of HMPG and 5-HIAA, respectively (Bertilsson et al., 1974). Similarly, the dopamine receptor blocker chlorpromazine increases HVA in CSF (Sedvall et al., 1975). The decrease of HMPG in CSF induced by clonidine during treatment of hypertension, shown in this report, is consistent with its presumed central adrenoceptor stimulating activity (see, for example, Svensson et al., 1975). When given in very high doses to rats propranolol has been found to increase HVA and HMPG in brain (Wiesel, 1976). The usual antihypertensive doses of alprenolol do not appear to affect the cerebrospinal fluid concentration of HMPG, HVA or 5-HIAA in man (Table 2).
Acknowledgements.The study was supported by the Swedish Medical Research Council (3902-05A), the Bank of Sweden Tercenternary Fund 75/110) and funds from the Karolinska Institute.
128
References Asberg, M., Ringberger, V.-A., Sj6qvist, F., Thor6n, P., Tr~iskman, L., Tuck, J. R.: Monoamine metabolites in cerebrospinal fluid and serotonin uptake inhibition during treatment with clorimipramine. Clin. Pharmacol. Ther. In press Bertilsson, L.: Quantitative determination of 4-hydroxy-3 methoxyphenyl glycol and its conjugates in cerebrospinal fluid by mass fragmentography. J. Chromatogr. 87, 147-153 (1973) Bertilsson, L., Asberg, M., Thor6n, P.: Differential effect of chlorimipramine and nortriptyline on cerebrospinal fluid metabolites of serotonin and noradrenaline in depression. Europ. J. clin. Pharmacol. 7, 365-368 (1974) Bertilsson, L., Atkinson, A. J., Jr., Althaus, J. R., H~irfast, A., Lindgren, J.-E., Holmstedt, B.: Quantitative determination of 5-hydroxyindole-3-acetic acid in cerebrospinal fluid by gas chromatography-mass spectrometry. Anal. Chem. 44, 1434-1438 (1972) Braestrup, C.: Effects of phenoxybenzamine, aceperone and clonidine on the level of 3-methoxy-4-hydroxyphenylglycol (MOPEG) in rat brain. J. Pharm. Pharmacol. 26, 139-141 (1974) Collste, P., Haglund, K., Frisk-Holmberg, M., Orme, M., Rawlins, M., (3stman, J.: Pharmacokinetics and pharmacodynamics of alprenolol in the treatment of hypertension. II. Relationship to its effect on blood pressure and plasma renin activity. Europ. J. clin. Pharmacol. 10, 89-95 (1976) Gottfries, C. G., Gottfries, I., Johansson. B., Olsson, R., Persson, T., Roos, B.-E., Sj6str6m, R.: Acid monoamine metabolites in human cerebrospinal fluid and their relations to age and sex. Neuropharmacol. 10, 665-672 (1971) H61delt, B., Hedeland, H., Dymling, J. F.: Studies on catecholamines, renin and aldosterone following Catepresan (2-(2,6-dichlor-phenylamine)-2-imidazolinehydrochloride) in hypertensive patients. Europ. J. Pharmacol. 10, 389-397 (1970) Jefferson, J. W.: Beta-adrenergic receptor blocking drugs in psychiatry. Arch. Gen. Psychiat. 31, 681-691 (1974) Kobinger, W.: Ober den Wirkungsmechanismus einer neuen antihypertensiven Substanz mit Imidazolinstruktur. NaunynSchmiedeberg's Arch. Pharmacol. 258, 48-58 (1967)
L. Bertilsson et al.: Monoamine Metabolites in Cerebrospinal Fluid Offerhaus, L., von Zwieten, P. A.: Comparative studies on central factors contributing to the hypotensive action of propranolol, alprenolol, and their enantiomers. Cardiovasc. Res. 4, 488-495 (1974) Reid, J.: Clonidine and central noradrenaline turnover. In: The central actions of drugs in the regulation of blood pressure, (ed. D. S. Davies, J. L. Reid). In press Sattler, R. W., van Zwieten, P. A.: Acute hypotensive action of 2-(2,6-dichlorophenylamino)-2-imidazolinehydrochloride (St 155) after infusion into the cat's vertebral artery. Europ. J. Pbarmacol. 2, 9-13 (1967) Schmitt, H., Schmitt, Mme H., Fenard, S.: Evidence for an c~-sympathomimetic component in the effects of Catapresan on vasomotor centres: antagonism by piperoxane. Europ. J. Pharmacol. 14, 98-100 (1971) Sedvall, G., Alfredsson, G., Bjerkenstedt, L., Eneroth, P., Fyr6, B., H~irnryd, C., Swahn, C.-G., Wiesel, F.-A., Wode-Helgodt, B.: Selective effects of psychoactive drugs on levels of monoamine metabolites and prolactin in cerebrospinal fluid of psychiatric patients. Proceedings of the Sixth International Congress of Pharmacol (eds. J. Tuomisto, M. K. Paasonen) 3, 255-267 (1975) Sj6quist, B., )~ngg~rd, E.: Gas chromatographic determination of homovanillic acid in human cerebrospinal fluid by electron capture detection and by mass fragmentography with a deuterated internal standard. Anal. Chem. 44, 2297-2301 (1972) Svensson, T. H., Bunney, B. S., Aghajanian, G. K.: Inhibition of both noradrenergic and serotonergic neurons in brain by the a-adrenergic agonist clonidine. Brain Res. 92, 291-306 (1975) Wiesel, F.-A.: Effects of high dose propranolol treatment on dopamine and norepinephrine metabolism in regions of rat brain. Neuroscience Lett. 2, 35-38 (1976)
Received: February 2, 1976, and in revised form: July 3, 1976, accepted: August 26, 1976 Dr. L. Bertilsson Dept. of Clinical Pharmacology Huddinge University Hospital S-1 41 86 Huddinge Sweden
