Summary
The 24 h urinary excretion of adrenaline, noradrenaline, metadrenaline, normetadrenaline and vanillylmandelic acid, plasma renin activity and plasma and urinary debrisoquine were measured before and during chronic treatment with oral debrisoquine in 14 in-patients with essential hypertension. There was a significant fall (mean ±SD) in the 24 h urinary excretion of vanillylmandelic acid (15.3±2.8 to 6.7±1.9 µmol) noradrenaline (199.0±105.8 to 125.2±43.3 nmol) and plasma renin activity (0.71±0.47 to 0.40±0.20 pmol Angio I ml−1 h−1) while the urinary normetadrenaline/noradrenaline ratio increased (10.4±6.1 to 17.1±5.1). No significant change was seen in the output of adrenaline or of O-methylated metabolites. Debrisoquine produces extensive noncompetitive inhibition of platelet monoamine oxidase in vivo at low therapeutic plasma concentrations. These changes support the view that treatment with debrisoquine produces intraneuronal inhibition of monoamine oxidase and post-ganglionic blockage. There was a significant correlation between the change in standing diastolic blood pressure and the daily dose (rs=−0.52), pre-dose plasma concentration (rs=−0.85) and mean daily urinary recovery (rs=−0.80), of debrisoquine. The full extent of the biochemical changes were seen at low dose and low plasma concentration and were not directly correlated with the fall in standing or supine blood pressure.
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Abrams, W. B., Pocelinko, R., Klausner, M., Hanauer, L., Whitman, E. N.: Clinical pharmacological studies with debrisoquine sulphate, a new antihypertensive agent. J. New Drugs4, 269–283 (1964)
Bing, R. F., Harlow, J., Smith, A. J., Townshend, M. M.: The urinary excretion of catecholamines and their derivates in primary hypertension in man. Clin. Sci.52, 319–323 (1977)
Cohen, E. L., Grim, C. E., Conn, J. W., Bough, W. M.: Accurate and rapid measurement of plasma renin activity by radioimmunoassay. J. Lab. and Clin. Med.77, 1025–1038 (1971)
Century, B., Rupp, L. R.: Comment on microfluorometric determination of monoamine oxidase. Biochem. Pharmacol.17, 2012–2013 (1968)
Connelian, T. P., Godrey, J. M.: The routine determination of urinary 4-hydroxy-3-methoxymandelic acid. Clin. Chem. Acta2, 410–412 (1964)
Esler, M., Julius, S., Zweifler, A., Randall, O., Harburg, E., Gardiner, H., DeQuattro, V.: Mild high-renin essential hypertension. Neurogenic human hypertension. N. Engl. J. Med.296, 405–411 (1977)
Kraml, M.: A rapid microfluorometric determination of monoamine oxidase. Biochem. Pharmacol.14, 1683–1685 (1965)
Lennard, M. S., Silas, J. H., Smith, A. J., Tucker, G. T.: Determination of debrisoquine and its 4-hydroxymetabolite in biological fluids by gas chromatography with flame-ionization and nitrogen-selective detection. J. Chromatogr.133, 161–166 (1977a)
Lennard, M. S., Silas, J. H., Smith, A. J., Tucker, G. T.: Concentration of debrisoquine by human platelets in vivo: relationship to hypotensive effect. Br. J. Clin. Pharmacol.4, 635p (1977b)
Louis, W. J., Doyle, A. E., Anavekar, S.: Plasma norepinephrine levels in essential hypertension. N. Engl. J. Med.28, 559–607 (1973)
Lowry, O. H., Rosebrough, N. H., Farr, A. L., Randall, R. J.: Protein measurement with the folin phenol reagent. J. Biol. Chem.193, 265–275 (1951)
Maas, J. W., Landis, G. H.: The metabolism of circulating norepinephrine by human subjects. J. Pharmacol. Exp. Ther.177, 600–612 (1971)
Malmfors, T., Abrams: The effects of debrisoquine and bretylium on adrenergic nerves as revealed by fluorescence histochemistry. J. Pharmacol. Exp. Ther.174, 99–110 (1970)
Malcolm, S. L., Marten, T. R.: Determination of debrisoquine and its 4-hydroxymetabolite in plasma by glc ms. Anal. Chem.48, 807–809 (1976)
Medina, M. A., Giachetti, A., Shore, P. A.: On the physiological disposition and possible mechanism of the antihypertensive action of debrisoquine. Biochem. Pharmacol.18, 891–901 (1969)
Neff, N. H., Yang, H. Y. T.: Another look at the monoamine oxidases and the monoamine oxidase inhibitor drugs. Life Sci.14, 2061–2074 (1974)
Pettinger, W. A., Korn, A., Spiegel, H., Solomon, H. J., Pocelinko, R., Abrams, W. B.: Debrisoquine, a selective inhibitor of intraneuronal monoamine oxidase in man. Clin. Pharmacol. Ther.10, 667–674 (1969)
Silas, J. H., Lennard, M. S., Tucker, G. T., Smith, A. J., Malcolm, S. L., Marten, T. R.: Why hypertensive patients vary in their response to oral debrisoquine. Br. Med. J.1, 422–425 (1977)
Solomon, H. M., Ashley, C., Spirt, N., Abrams, W. B.: The influence of debrisoquine on the accumulation and metabolism of biogenic amines by the human platelet in vivo and in vitro. Clin. Pharmacol. Ther.10, 229–238 (1969)
Townshend, M. M., Smith, A. J.: Factors influencing the urinary excretion of free catecholamines in man. Clin. Sci.44, 253–265 (1973)
Youdim, M. B., Woods, H. F., Mitchell, B., Grahame-Smith, D. G., Callender, S.: Human platelet monoamine oxidase in iron-deficiency anaemia. Clin. Sci.48, 289–295 (1975)
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Silas, J.H., Jones, J., Tucker, G.T. et al. Dissociation of biochemical and hypotensive effects of debrisoquine in hypertensive patients. Eur J Clin Pharmacol 16, 81–86 (1979). https://doi.org/10.1007/BF00563111
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DOI: https://doi.org/10.1007/BF00563111