Summary
The total body clearance and fractional extraction of isoprenaline (ISO) have been determined, and the relation between these parameters and cardiac output established. Whether desipramine, an inhibitor of neuronal uptake, altered the plasma catecholamine response to ISO was also investigated.
Seven healthy subjects were given i.v., infusions of ISO in two, consecutive 25-min periods, at constant dose rates of 31–43 and 80–124 pmol·kg−1·min−1, respectively. The total-body (ER), pulmonary (ERp) and forearm (ERf) fractional extractions and the total body clearance (CL) of ISO were obtained from measurements of cardiac output and the steady-state ISO concentration in mixed central venous, arterial and forearm venous plasma.
ISO-induced increases in cardiac output resulted in increases in CL, decreases in ER and no consistent change in ERf. ERp did not differ from zero. ISO also produced a dose-dependent increase in the mixed venous plasma concentrations of noradrenaline and 3,4-dihydroxyphenylglycol (DOPEG), and a decrease in that of adrenaline. Pretreatment with desipramine did not alter any of the pharmacokinetic parameters of ISO. Desipramine, however, reduced the mixed venous baseline plasma levels of noradrenaline (47%) and DOPEG (40%), and tended to reduce that of adrenaline (34%). It enhanced the plasma noradrenaline response 2.4-fold, abolished the plasma DOPEG response and did not alter the plasma adrenaline response to ISO.
Hence, owing to its haemodynamic effects, ISO modifies its own pharmacokinetics which involve non-neuronal removal processes only. The increased DOPEG in plasma resulting from the ISO-induced increase in noradrenaline release was presynaptic in origin. Desipramine appears to reduce sympathetic activity. The enhancement by desipramine of the ISO-induced increase in plasma noradrenaline points towards recapture by neuronal uptake of at least 58% of the noradrenaline released in response to ISO.
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References
Bakhle YS, Vane JR (1974) Pharmacokinetic function of the pulmonary circulation. Physiol Rev 54: 1007–1045
Best JD, Halter JB (1982) Release and clearance rates of epinephrine in man: Importance of arterial measurements. J Clin Endocrinol Metab 55: 263–268
Brown MJ, Jenner DA, Allison DJ, Dollery CT (1981) Variations in individual organ release of noradrenaline measured by an improved radioenzymatic technique; limitations of peripheral venous measurements in the assessment of sympathetic nervous activity. Clin Sci 61: 585–590
Brown MJ, Lhoste FJM, Zamboulis C, Ind PW, Jenner DA, Dollery CT (1982) Estimation of sympathetic activity in essential hypertension. Clin Pharmacol Ther 31: 16–22
Callingham BA, Burgen ASV (1966) The uptake of isoprenaline and noradrenaline by the perfused rat heart. Mol Pharmacol 2: 37–42
Chang PC, van der Krogt JA, van Brummelen P (1987) Demonstration of neuronal and extraneuronal uptake of circulating norepinephrine in the forearm. Hypertension 9: 647–653
Clutter WE, Bier DM, Shah SD, Cryer PE (1980) Epinephrine plasma clearance rates and physiologic thresholds for metabolic and hemodynamic actions in man. J Clin Invest 66: 94–101
Esler M (1982) Assessment of sympathetic nervous function in humans from noradrenaline plasma kinetics. Clin Sci 62: 247–254
Gillis CN, Roth JA (1976) Pulmonary disposition of circulating vasoactive hormones. Biochem Pharmacol 25: 2547–2553
Goldstein DS, Horwitz D, Keiser HR, Polinsky RJ, Kopin IJ (1983) Plasma 1-[3H]norepinephrine, d-[14C]norepinephrine, and d,1-[3H]isoproterenol kinetics in essential hypertension. J Clin Invest 72: 1748–1758
Goldstein DS, Zimlichman R, Stull R, Folio CJ, Levinson PD, Keiser HR, Kopin IJ (1985) Measurement of regional neuronal removal of norepinephrine in man. J Clin Invest 76: 15–21
Goldstein DS, Zimlichman R, Stull R, Keiser HR (1986) Plasma catecholamine and hemodynamic responses during isoproterenol infusions in humans. Clin Pharmacol Ther 40: 233–238
Goldstein DS, Eisenhofer G, Stull R, Folio CJ, Keiser HR, Kopin IJ (1988) Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J Clin Invest 81: 213–220
Halbrügge T, Ungell A-L, Wölfel R, Graefe K-H (1988a) Total body, systemic and pulmonary clearance and fractional extraction of unlabelled and differently3H-labelled noradrenaline in the anaesthetized rabbid. Naunyn-Schmiedebergs Arch Pharmacol 338: 361–367
Halbrügge T, Gerhardt T, Ludwig J, Heidbreder E, Graefe K-H (1988b) Assay of catecholamines and dihydroxyphenylethyleneglycol in human plasma and its application in orthostasis and mental stress. Life Sci 43: 19–26
Hasking GJ, Esler MD, Jennings GL, Burton D, Johns JA, Korner PI (1986) Norepinephrine spillover to plasma in patients with congestive heart failure: Evidence of increased overall and cardiorenal sympathetic nervous activity. Circulation 73: 615–621
Hertting G (1964) The fate of3H-isoproterenol in the rat. Biochem Pharmacol 13: 1119–1128
Hertting G (1965) Effects of drugs and sympathetic denervation on noradrenaline uptake and binding in animal tissues. In: Koelle GB, Douglas WW, Carlsson A (eds) Pharmacology of cholinergic and adrenergic transmission. Pergamon Press, Oxford, pp 277–288
Iversen LL (1967) The uptake and storage of noradrenaline in sympathetic nerves. Cambridge Univ. Press, Cambridge
Kjeldsen SE, Westheim A, Aakesson I, Eide I, Leren P (1986) Plasma adrenaline and noradrenaline during orthostasis in man: The importance of arterial sampling. Scand J Clin Lab Invest 46: 397–401
Langer SZ (1980) Presynaptic regulation of the release of catecholamines. Pharmacol Rev 32: 337–362
Ludwig J, Gerhardt T, Halbrügge T, Walter J, Graefe K-H (1988) Plasma concentrations of noradrenaline and 3,4-dihydroxyphenylethyleneglycol under conditions of enhanced sympathetic activity. Eur J Clin Pharmacol 35: 261–267
Majewski H (1983) Modulation of noradrenaline release through activation of presynaptic β-adrenoceptors. J Auton Pharmacol 3: 47–60
Trendelenburg U (1988) The extraneuronal uptake and metabolism of catecholamines. In: Trendelenburg U, Weiner N (eds) Handbook of experimental pharmacology, catecholamines I, vol 90/I. Springer, Berlin Heidelberg New York, pp 280–319
Vincent HH, Man in't Veld AJ, Boomsma F, Wenting GJ, Schalekamp MADH (1982) Elevated plasma noradrenaline in response to β-adrenoceptor stimulation in man. Br J Clin Pharmacol 13: 717–721
Ziegler MG, Chernow B, Woodson LC, Coyle J, Cruess D, Lake CR (1986) The effect of propranolol on catecholamine clearance. Clin Pharmacol Ther 40: 116–119
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Ludwig, J., Halbrügge, T., Vey, G. et al. Haemodynamics as a determinant of the pharmacokinetics of and the plasma catecholamine responses to isoprenaline. Eur J Clin Pharmacol 37, 493–500 (1989). https://doi.org/10.1007/BF00558130
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DOI: https://doi.org/10.1007/BF00558130