Roles of uptake1 and catechol-O-methyltransferase in removal of circulating catecholamines in the rabbit.

Anesthetized rabbits were simultaneously infused with [3H]norepinephrine (NE), [3H]epinephrine (Epi), [3H]dopamine (DA), and [3H]isoproterenol (Iso), and their plasma clearances and fractional extractions across the systemic (ERS), as well as pulmonary (ERP), circulation were determined before and after blockade of uptake1 by desipramine (2 mg/kg). Desipramine reduced the clearance of NE, Epi, and DA by 39, 13, and 14%, respectively, but did not affect Iso clearance. Similar results were obtained with respect to the effects of desipramine on ERS. By contrast, desipramine reduced ERP of NE and DA (which for both amines was markedly lower than ERS) by > 70%; its effect on the very low ERP of Epi was not determinable. Comparison of the desipramine-sensitive components of ERS and ERP indicated that for uptake1 NE was the preferred substrate in the systemic circulation and DA was preferred in the pulmonary circulation. In the absence and presence of desipramine, catechol-O-methyltransferase inhibition had no effect on the clearance of NE, Epi, and DA and decreased Iso clearance by 25%. Hence the contribution by uptake1 to the removal of circulating catecholamines depends on the type of amine and on whether the systemic or pulmonary circulation is considered. Moreover catechol-O-methyltransferase does not appear to contribute to the clearance of NE, Epi, and DA but plays a definite role in the removal of circulating Iso.

The part played by catechol-O-methyltransferase in the plasma kinetics of 3,4-dihydroxyphenylglycol and 3,4-dihydroxyphenylalanine in the anaesthetized rabbit.

The present study, carried out in anaesthetized rabbits, aimed at determining the effects of catechol-O-methytransferase (COMT) inhibition on the plasma kinetics of infused 3,4-dihydroxyphenylglycol (DOPEG) and 3,4-dihydroxyphenylalanine (DOPA) as well as on endogenous plasma noradrenaline, DOPEG, DOPA and 3-methoxy-4-hydroxyphenylglycol (MOPEG). The plasma kinetics of infused MOPEG were also evaluated. To block the function of COMT, 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592) was given intravenously. Dose-finding experiments, in which the drug-induced fall in endogenous plasma MOPEG was used to quantify COMT inhibition, indicated that a Ro 40-7592 dose of 3 mg/kg followed by 1.5 mg/kg every 30 min was sufficient to obtain a virtually complete inhibition of COMT. More than 150 min of COMT inhibition were required for endogenous MOPEG to disappear from plasma, since the plasma half-life of MOPEG was 54 min. COMT inhibition produced marked increases in the plasma levels of endogenous DOPA (1.7-fold) and DOPEG (3.9-fold) and did not alter endogenous plasma noradrenaline. The results concerning the effect of COMT inhibition on the plasma kinetics of infused DOPA and DOPEG were as follows: the plasma clearance of DOPA was not altered, whereas that of DOPEG fell by 41%; the plasma half-life of DOPA increased from 4.9 to 13.0 min and that of DOPEG from 4.8 to 31.0 min; there was an increase in the volume of distribution of DOPA (2 to 3-fold) and DOPEG (4 to 5-fold).(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of catechol-O-methyltransferase inhibition on the plasma clearance of noradrenaline and the formation of 3,4-dihydroxyphenylglycol in the rabbit.

The purpose of this study was to elucidate the finding of Friedgen et al. (1993 b) that catechol-O-methyltransferase (COMT) inhibition is much more effective in increasing the plasma concentration of endogenous dihydroxyphenylglycol (DOPEG) than in increasing the plasma concentration of infused DOPEG. To this end, reserpine-pretreated rabbits were anaesthetized and infused with noradrenaline and/or DOPEG, and the plasma clearances of infused noradrenaline (ClNA) and DOPEG (ClDOPEG) as well as the plasma DOPEG response to noradrenaline infusion [as reflected by the ratio of the steady-state increase in plasma DOPEG (delta DOPEG) to that in plasma noradrenaline (delta NA)] were determined before and after blockade of neuronal uptake by desipramine. Experiments were carried out either under control conditions or after COMT inhibition by i.v. administration of 3,4-dihydroxy-4'-methyl-5-nitrobenzophenone (Ro 40-7592). On the assumption that rates of neuronal noradrenaline uptake equal steady-state rates of neuronal DOPEG formation, the desipramine-sensitive components of ClNA and delta DOPEG/delta NA were used to estimate the apparent plasma clearance of DOPEG formed intraneuronally (Clf-DOPEG) in response to noradrenaline infusion. ClNA was 83.6 ml kg-1 min-1 in the absence and 48.1 ml kg-1 min-1 in the presence of desipramine. Neither the former nor the latter value was altered after COMT inhibition.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma clearances and extractions of four catecholamines in the anesthetized rabbit: the role of amine removal by blood cells.

The purpose of the present study was to compare the plasma kinetics of norepinephrine (NA), epinephrine (A), isoprenaline (ISO), and dopamine (DA) in the anesthetized rabbit. To this end, a mixture of trace amounts of 3H-labeled NA, A, ISO, and DA was infused either into a femoral vein or into the ascending aorta, and the plasma amine clearances (Cl), the fractional amine extractions across the pulmonary (ERp) as well as systemic (ERs) circulation, and the cardiac output of plasma (COp) were determined at steady state of the amine infusion. The values of ERp, ERs, and COp were also used to calculate total-body fractional extractions [ERtot = ERp + ERs(1 - ERp)] and theoretical clearances (Clcalc = ERtot * COp). The four catecholamines differed as to their values of Cl and ERs and even more so with respect to ERp. The Cl was lowest for NA, intermediate for A and ISO, and highest for DA. Statistically significant pulmonary extractions were observed for NA (8.8%) and DA (24.0%), but not for A and ISO. The systemic extraction was lowest for ISO (63%) and highest for DA (75%). Cl values were higher than values of Clcalc and the ratio of Cl/Clcalc increased in the order of NA < A < ISO < DA. In vitro experiments, in which whole rabbit blood was incubated in the presence of added NA, A, ISO, and DA, showed a pronounced ability of blood cells to remove catecholamines from plasma. The four amines rapidly disappeared from plasma at rates increasing in the order of NA < A < ISO < DA.(ABSTRACT TRUNCATED AT 250 WORDS)

Estimation of noradrenaline concentrations in the axoplasm of noradrenergic neurones in man.

The plasma concentrations of noradrenaline (NA) and its primary neuronal metabolite, dihydroxyphenylglycol (DOPEG), were examined during graded orthostasis and NA infusion in 13 healthy subjects to estimate the NA concentration difference between the site of neuronal DOPEG formation and that in plasma. Stimulation of NA release by graded orthostasis resulted in similar absolute increments in plasma NA and DOPEG with both plasma concentrations being dependent on the degree of orthostasis. The mean value of the delta DOPEG/delta NA ratio amounted to 0.999 (0.745; 1.341). NA was infused i.v. during two consecutive 30-min periods at constant rates of 0.43 and 0.86 nmol kg-1 min-1, respectively. This infusion resulted in a delta DOPEG/delta NA ratio of 0.048 (0.036; 0.064) for the first and 0.078 (0.067; 0.090) for the second infusion period (p less than 0.01). For each individual subject, the factor quantifying the NA concentration difference between the site of neuronal DOPEG formation and plasma was calculated from the square root of the ratio of 'delta DOPEG/delta NA during orthostasis to delta DOPEG/delta NA during the low rate of NA infusion'. The average NA concentration at the site of neuronal DOPEG formation (i.e. the axoplasm of noradrenergic neurones) was found to be 4.6-fold higher than that in plasma.

Carrier-mediated outward transport of dopamine from adrenergic varicosities of the vas deferens of reserpine-pretreated rats.

In vasa deferentia of reserpine-pretreated rats a carrier-mediated (i.e., desipramine-sensitive) outward transport of endogenous dopamine was induced by either tyramine or ouabain. The dopamine taking part in the efflux induced by tyramine (and the concomitant efflux of DOPAC) was derived from ongoing synthesis of dopamine. Inhibition of MAO trebled the rate of spontaneous efflux of dopamine and reduced the spontaneous efflux of DOPAC by 90%. After inhibition of MAO, desipramine caused a further five-fold increase in the basal efflux of dopamine with no change in the basal efflux of DOPAC. Inhibition of COMT failed to affect the spontaneous efflux of dopamine but increased that of DOPAC. It is concluded that, after depletion of the noradrenaline stores by pretreatment with reserpine, an outward transport of axoplasmic dopamine is induced by the same mechanisms that (without any pretreatment with reserpine) are known to initiate an outward transport of noradrenaline.

Role of nitric oxide formation in the regulation of haemodynamics and the release of noradrenaline and adrenaline.

This study in the anaesthetized rabbit aimed at determining the role of nitric oxide (NO), the putative endothelium-derived relaxing factor, in the regulation of haemodynamics and the release into plasma of noradrenaline and adrenaline. Specific inhibition of NO formation was achieved by i.v. bolus injection of L-NG-monomethyl-arginine (L-NMMA; 3-100 mg kg-1). Phenylephrine was infused i.v. at constant rates (2.5-20 micrograms kg-1 min-1) in order to assess baroreflex-mediated changes in release due to direct peripheral vasoconstriction. Rates of noradrenaline and adrenaline release into plasma were determined by the radio-tracer technique. L-NMMA, but not D-NMMA, dose-dependently increased mean arterial pressure and total peripheral vascular resistance, whereas both heart rate and cardiac output decreased concomitantly. The corresponding ED50 values for L-NMMA ranged from 11.2 to 18.5 mg kg-1. Inhibition of NO formation by L-NMMA as well as phenylephrine infusion caused decreases in the plasma clearance of noradrenaline and adrenaline which were correlated with the drug-induced decreases in cardiac output. Both L-NMMA and phenylephrine reduced the rate of noradrenaline release into plasma as they increased total peripheral resistance. Moreover, the curvilinear relationship between these two parameters obtained for L-NMMA was virtually identical to that produced by phenylephrine, indicating that the reduction in noradrenaline release by L-NMMA is mediated solely by the baroreflex. From the L-NMMA-induced maximum inhibition of noradrenaline release, it is concluded that the counter-regulation against peripheral vasodilation by NO accounts for 69% of basal noradrenaline release.(ABSTRACT TRUNCATED AT 250 WORDS)

Plasma norepinephrine and dihydroxyphenylglycol in essential hypertension.

The aim of the present study was to examine whether essential hypertension is associated with altered plasma concentrations of dihydroxyphenylglycol, the principal presynaptic metabolite of norepinephrine. Forearm venous plasma dihydroxyphenylglycol and norepinephrine were determined at rest and during graded orthostasis in 47 normotensive control subjects and 58 outpatients with essential hypertension. There was no group difference in age. At supine rest as well as during sitting and standing, hypertensive subjects had plasma norepinephrine concentrations similar to those in normotensive control subjects, but plasma dihydroxyphenylglycol concentrations were higher than those in normotensive control subjects. Both groups showed a linear relation between plasma dihydroxyphenylglycol (ordinate) and plasma norepinephrine (abscissa). The resulting regression line was steeper (p less than 0.02) and its ordinate intercept higher (p less than 0.01) in hypertensive than in control subjects. Eleven normotensive and 14 hypertensive subjects were also tested 3 hours after desipramine (1.5 mg/kg orally) was administered to inhibit neuronal norepinephrine reuptake. The drug did not alter plasma norepinephrine, but did reduce plasma dihydroxyphenylglycol and did abolish plasma dihydroxyphenylglycol responses to upright posture in both groups of subjects. The mean plasma dihydroxyphenylglycol concentration observed in the presence of desipramine again was higher in the hypertensive than in the control group (p less than 0.01) and closely agreed, in both groups, with the dihydroxyphenylglycol concentration given by the ordinate intercept of the dihydroxyphenylglycol versus norepinephrine regression line in the absence of desipramine.(ABSTRACT TRUNCATED AT 250 WORDS)

Vasodilatation by endothelium-derived nitric oxide as a major determinant of noradrenaline release.

In the anaesthetized rabbit, L-NG-monomethyl-arginine (L-NMMA), a specific inhibitor of nitric oxide (NO) formation, was used to assess the role of endothelium-derived NO in the regulation of haemodynamics and noradrenaline release (RNA). L-NMMA dose-dependently increased mean arterial pressure and total peripheral resistance (TPR), but decreased heart rate, cardiac output and RNA. The curvilinear relationship between RNA and TPR obtained for L-NMMA was virtually identical with that produced by phenylephrine, indicating that L-NMMA-induced decreases in RNA are mediated by the baroreflex. Since the maximum RNA inhibition by L-NMMA was 69%, the counterregulation against peripheral vasodilatation by endothelium-derived NO accounts for 69% of basal RNA.

Clinical aspects on presynaptic noradrenaline metabolism.

In healthy subjects, similar absolute increments in plasma noradrenaline (NA) and dihydroxyphenylglycol (DOPEG) were observed in response to upright posture or isoprenaline infusion. Blockade of neuronal uptake by desipramine abolished these plasma DOPEG responses and reduced plasma DOPEG per se. In essential hypertensives we found higher than normal plasma DOPEG levels at any given plasma NA. Evidence is provided that both the desipramine-sensitive and -resistant pool of plasma DOPEG contribute to this hypertensive-normotensive difference.

Effects of nisoldipine on stress-induced changes in haemodynamics and plasma catecholamines in normotensives and hypertensives.

In a double-blind, placebo-controlled crossover study 10 mg nisoldipine was given orally twice daily for 3.5 days to 12 normotensives and 12 essential hypertensives. In each study period, subjects were exposed to 6 min of physical exercise and 3 min of mental stress following the morning dose on day 3 and 4, respectively. Blood pressure, heart rate, systolic time intervals (day 3 only) and plasma levels of noradrenaline, adrenaline, dopamine as well as dihydroxyphenylglycol (DOPEG; the main presynaptic metabolite of noradrenaline) were determined at rest and at the end of both tests. Nisoldipine increased resting heart rate in normotensives and hypertensives, but reduced resting BP and BP during mental stress in hypertensives only. It also increased plasma concentrations of noradrenaline and DOPEG at rest and plasma noradrenaline concentrations during mental stress in both groups. However, nisoldipine affected neither exercise- nor stress-induced changes in any of the parameters monitored here. There was a correlation between the drug-induced percentage fall in resting BP and the height of BP during placebo treatment. While the resting values of plasma DOPEG were higher in hypertensives than in normotensives, those of plasma noradrenaline were not. Consequently, the linear relationship that existed between the resting plasma concentrations of DOPEG and noradrenaline in both groups was shifted to higher DOPEG levels in hypertensives when compared with normotensives. In conclusion, the effectiveness of nisoldipine in lowering BP was the more pronounced the higher the BP to begin with. Nisoldipine did not attenuate exercise- or stress-induced increases in plasma catecholamines. Essential hypertension may be associated with an enhanced presynaptic formation of DOPEG.

The heterogeneity of the neuronal distribution of exogenous noradrenaline in the rat vas deferens.

After loading of the incubated rat vas deferens with 0.2 mumol/l 3H-noradrenaline (followed by 100 min of wash-out with amine-free solution), the efflux of endogenous and exogenous compounds was determined by HPLC with electrochemical detection and by column chromatography with scintillation counting. Two different types of heterogeneity of labelling were found. The first one is due to the preferential labelling of varicosities close to the surface of the tissue, the second one to the preferential labelling of vesicles close to the surface of loaded varicosities. As diffusion distances within the tissue and within varicosities are then longer for endogenous than for exogenous amine and metabolites, the composition of spontaneous efflux of exogenous compounds differed from that for endogenous compounds. Because of preferential neuronal and vesicular re-uptake of endogenous noradrenaline, the percentage contribution by noradrenaline to overall efflux was: endogenous less than exogenous. While 3H-DOPEG was the predominant exogenous metabolite, DOPEG and MOPEG equally contributed to the "endogenous" efflux. Desipramine abolished the consequences of the first heterogeneity of labelling, i.e., it increased the efflux more for endogenous than for exogenous noradrenaline; moreover it decreased the efflux of 3H-DOPEG, but increased that of 3H-MOPEG. The reserpine-like compound Ro 4-1284, on the other hand, abolished the consequences of the second type of heterogeneity; it reduced the specific activity of "total efflux" (i.e., of the sum of noradrenaline + DOPEG + MOPEG) to the specific activity of the tissue noradrenaline. The degree of heterogeneity of labelling was reduced after inhibition of monoamine oxidase and also when the tissues were loaded with 2 or 20 mumol/l 3H-noradrenaline. It is proposed that the various "compartments" and "pools" of noradrenaline described in the literature reflect the two heterogeneities described here.

The importance of plasma 3,4-dihydroxyphenylglycol (DOPEG) in analyses of the sympathetic nervous system in vivo.

In the anaesthetized rabbit, plasma DOPEG was used as a tool to estimate both, the total-body rate of neuronal re-uptake of noradrenaline (NA) and the factor F by which the NA concentration in the synaptic cleft exceeds that in plasma. The NA re-uptake rate was 3.5 times higher than the rate of NA net release into plasma and amounted to 863 pmol kg-1 min-1. F was 3.4. In a study in humans it was found that essential hypertension appears to be associated with an enhanced formation of that part of DOPEG which originates from NA leaking out of the transmitter storage vesicles.

The involvement of desipramine-sensitive processes in the extraction of various catecholamines from plasma in the anaesthetized rabbit.

The effects of desipramine on the total body plasma clearance (Cl) as well as the systemic fractional extraction (ERs) of noradrenaline, dopamine, adrenaline, and isoprenaline, and on the pulmonary fractional extraction (ERp) of dopamine and adrenaline were determined in the anaesthetized rabbit. Under control conditions, noradrenaline, dopamine, adrenaline, and isoprenaline had Cl values of 59.5, 116.2, 68.0, 78.4 (ml kg-1 min-1) and ERs values of 0.709, 0.789, 0.694, 0.669, respectively. The ERp of dopamine was 0.235, while that of adrenaline did not differ from zero. Desipramine reduced the Cl of noradrenaline (by 20%), but did not affect that of the other amines. It also reduced the ERs of noradrenaline (by 31%), dopamine (by 10%) and adrenaline (by 10%); the ERp of dopamine was diminished by 84%.

The synaptic noradrenaline concentration in humans as estimated from simultaneous measurements of plasma noradrenaline and dihydroxyphenylglycol (DOPEG).

A linear relationship between plasma DOPEG (ordinate) and plasma noradrenaline (NA; abscissa) was found during orthostasis as well as during NA infusion. The slope of the former (slopeR) was 13 times steeper than that of the latter (slopeI). This difference in slopes suggests that the NA concentration in the synaptic cleft is markedly higher than in plasma. The factor (F) characterizing this concentration difference was obtained from F2 = slopeR/slopeI. It amounted to 3.6.

Plasma 3,4-dihydroxyphenylglycol as a tool to assess the role of neuronal uptake in the anaesthetized rabbit.

(1.) The purpose of this study was to investigate the role of neuronal uptake in the appearance in plasma of the primary noradrenaline metabolite 3,4-dihydroxyphenylglycol (DOPEG). To this end, steady-state changes in mixed central-venous plasma concentrations of noradrenaline and DOPEG produced by noradrenaline infusions or by changes in sympathetic tone were determined in anaesthetized rabbits either under control conditions or after treatment with desipramine (2 mg kg-1). The steady-state kinetics of infused DOPEG were also evaluated. (2.) Infused DOPEG (2.9 nmol kg-1 min-1 i.v. for 75 min) reached steady-state concentrations in plasma within less than 30 min, disappeared from plasma with a half-life of 2.3 min and showed a total-body plasma clearance of 84.0 ml kg-1 min-1. (3.) Constant-rate infusions of noradrenaline (1.2-5.9 nmol kg-1 min-1 i.v. for 75 min) produced increases in plasma noradrenaline and DOPEG concentrations which were linearly related to the rate of noradrenaline infusion. Thus, the plasma clearance of infused noradrenaline (75.8 ml kg-1 min-1) as well as the increase in plasma DOPEG expressed in % of that in plasma noradrenaline (9.4%) was virtually independent of the noradrenaline infusion rate. (4.) Desipramine reduced the plasma clearance of infused noradrenaline by 35.4% and the increment in plasma DOPEG relative to that in plasma noradrenaline by 75.3%.(ABSTRACT TRUNCATED AT 250 WORDS)

Effects of N-ethylmaleimide on 5-hydroxytryptamine transport and sodium content in rabbit platelets.

1. The present study analysed the mechanism underlying the inhibitory action of N-ethylmaleimide (NEM) on the 5-hydroxytryptamine (5-HT) uptake by blood platelets. 2. Rabbit platelets suspended in protein-free buffer were first preincubated for 45 min in the absence and presence of NEM (20 to 160 microM) or ouabain (0.5-2.0 microM) and then either analysed for their Na+ and K+ content or incubated (15s) with various concentrations of [3H]-5-HT (0.13-4.03 microM) to determine Km and Vmax for 5-HT uptake. 3. Both NEM and ouabain produced concentration-dependent decreases in Vmax with IC50 values of 52 and 0.58 microM, respectively. Neither drug changed Km significantly. 4. Both NEM and ouabain increased the Na+ and decreased the K+ content of platelets in a concentration-dependent manner. 5. There was a linear correlation between Vmax (expressed in % of control) and the reciprocal cellular Na+ content, with the results for both drugs falling onto one and the same regression line (r = 0.992; n = 8). This regression showed that an increase in Na+ content by 69% sufficed to reduce Vmax by 50%. 6. At concentrations that reduced 5-HT uptake by about 60%, neither NEM nor ouabain altered the potency of imipramine for inhibition of 5-HT uptake. 7. Hence, NEM inhibits 5-HT transport by inhibiting the Na+/K+-ATPase and not by a direct interaction with the 5-HT carrier. The consequential increase in the intracellular Na+ concentration reduces the transmembrane Na+ gradient and, therefore, hinders 5-HT inward transport. This action of the drug does not affect the ability of the carrier to bind 5-HT or imipramine.

Haemodynamics as a determinant of the pharmacokinetics of and the plasma catecholamine responses to isoprenaline.

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.(ABSTRACT TRUNCATED AT 250 WORDS)

Total body, systemic and pulmonary clearance and fractional extraction of unlabelled and differently 3H-labelled noradrenaline in the anaesthetized rabbit.

1. Rabbits were anaesthetized with urethane/chloralose and infused intravenously with trace amounts of 3H-2,5,6-, 3H-7,8- or 3H-7-(-)noradrenaline either without or with unlabelled (-)noradrenaline being simultaneously infused (0.2 micrograms kg-1 min-1). To obtain clearance values and extraction ratios for the pulmonary, systemic and total circulation, steady-state concentrations of infused noradrenaline were determined in mixed central venous (Cv) and arterial (Ca) plasma. Heart rate and blood pressure were recorded via the carotid artery, and the dye dilution method was used to determine the cardiac output of plasma. 2. The simultaneous infusion of unlabelled noradrenaline, which increased plasma levels of noradrenaline by a factor of 5, had no significant effect on either heart rate, blood pressure or cardiac output (when determined at steady state of the noradrenaline infusion). 3. The simultaneous infusion of unlabelled noradrenaline did not affect the clearance values of any of the three type of 3H-noradrenaline. Moreover, the clearances of the various types of 3H-noradrenaline were virtually identical and agreed with that of unlabelled noradrenaline. However, the clearance of labelled and unlabelled noradrenaline from arterial plasma was 1.15 times higher than that from central venous plasma. This factor corresponded to the ratio of Cv/Ca and pointed towards net removal of noradrenaline from the pulmonary circulation. 4. The fractional pulmonary extractions [1-(Ca/Cv)] of the three types of 3H-noradrenaline did not differ from each other and were not affected by the simultaneous infusion of unlabelled noradrenaline.(ABSTRACT TRUNCATED AT 250 WORDS)