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  • 1
    Electronic Resource
    Electronic Resource
    The effect of cocaine on uptake of and sensitivity to noradrenaline in isolated nictitating membranes before and after storage in the cold (1970)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 267 (1970), S. 383-398 
    Details
    ISSN: 1432-1912
    Keywords: Cocaine ; Cold-Stored Tissues ; Neuronal Uptake of Nor-adrenaline ; Nictitating Membrane of Cat ; Supersensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary Experiments were carried out on fresh isolated cat nictitating membranes as well as on muscles stored in the cold for 7 days. Storage reduced the cocaine-induced supersensitivity to (−)-noradrenaline but did not abolish it it also reduced responses to tyramine, and about halved the noradrenaline content of the tissue. Cocaine failed to potentiate responses of fresh or of stored muscles to the methoxamine (which is not taken up by adrenergic nerves). The incubation with 2.5 ml of 100 ng/ml of (−)-noradrenaline (in the presence of the inhibitor of catechol-O-methyl transferase), fresh muscles removed noradrenaline from the incubation medium at a rate of about 70 ng per gram of tissue per min; 10 Μg/ml of cocaine reduced rate of removal by 81%. Muscles stored in the cold removed less noradrenaline from the medium (about 45 ng/g×min−1) than fresh ones, and cocaine reduced the rate of removal by 56%. The neuronal uptake mechanism of the nictitating membrane does not seem to be stereoselective, since the rate of removal of (+)-noradrenaline from the incubation medium was similar to that of the (−)-isomer. It is concluded that cold storage of the muscle abolishes neither the neuronal uptake of noradrenaline nor the ability of cocaine to impair this uptake; however, both parameters were reduced. Since the sensitizing action of cocaine is similarly reduced, there is no reason to doubt the causal relation between impairment by cocaine of neuronal uptake and ensuing supersensitivity to (−)-noradrenaline.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00997276
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  • 2
    Electronic Resource
    Electronic Resource
    The prejunctional effect of cocaine on the isolated nictitating membrane of the cat (1972)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 275 (1972), S. 69-82 
    Details
    ISSN: 1432-1912
    Keywords: Cocaine ; Nictitating Membrane ; Uptake Theory ; Inhibition of Uptake ; Supersensitivity
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Pairs of smooth muscles isolated from the nictitating membrane of reserpine-pretreated cats were incubated four times with 1.2 ml of Krebs' solution containing 10 ng/ml of 3H-(±)-noradrenaline for 7.5 min each (in the presence of ascorbic acid and EDTA to prevent autoxidation and of U-0521 to block COMT). The appearance of deaminated 3H-catechols in the bath was measured and regarded as a measure of neuronal uptake. 2. Cocaine caused a concentration-dependent inhibition of the rate of deamination; the ID50 was 5.62 μM. 3. Cocaine caused a concentration-dependent increase in responses of the isolated muscles to 0.059 μM (−)-noradrenaline with a maximum increase of about 115 times normal. 4. The results were applied to the model proposed by Maxwell et al. (1966). The agreement between the expected and observed relationship between rate of uptake and degree of supersensitivity was satisfactory. Apparently, the effect of cocaine on the nictitating membrane is predominatly or entirely prejunctional. 5. The results indicate that the true K m for noradrenaline and the true K i for cocaine are considerably smaller than the apparent Km and Ki values obtained with conventional methods.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00505068
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  • 3
    Electronic Resource
    Electronic Resource
    On the stereoselectivity of the neuronal uptake in the cat's nictitating membrane (1972)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 275 (1972), S. 45-68 
    Details
    ISSN: 1432-1912
    Keywords: Stereoselectivity of Uptake ; Noradrenaline ; Neuronal Uptake ; Neuronal Deamination ; Nictitating Membrane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary 1. Pairs of smooth muscles isolated from the nictitating membrane of the cat were incubated with 1.2 ml of Krebs' solution containing 10 ng/ml of 3H-(±)-noradrenaline for 7.5 min (in the presence of U-0521 to inhibit COMT). Removal of the amine from the bath as well as the appearance of deaminated 3H-catechols in the bath were measured. 2. Pretreatment with reserpine did not affect the rate of removal, while increasing the rate of deamination. The ability of the muscles to retain exogenous amine for one hour was reduced to 12% of normal. 3. A certain fraction of the total production of deaminated 3H-catechols escaped into the medium. For any given duration of incubation this fraction was independent of the concentration of noradrenaline in the medium. On repeated incubation the fraction remained constant. Therefore, reliable estimates of the rate of deamination were obtained with repeated incubations of the same muscle. 4. Sympathetic denervation and/or cocaine revealed that 60% of removal (of which 10% are due to dilution) and 25% of deamination are extraneuronal. 5. For incubations of 7.5 min measured rates of deamination represent initial rates, measured rates of removal do not. 6. Unlabelled (−)- and (+)-noradrenaline were equipotent (ID50=about 1 μM) in inhibiting the deamination of 10 ng/ml of 3H-(±)-noradrenaline. This inhibitory effect must be exerted on neuronal deamination, since extraneuronal deamination (in denervated muscles) was not affected by the addition of unlabelled isomers. 7. It is proposed that, under these experimental conditions, neuronal unptake is the rate limiting step for neuronal deamination, and that neuronal uptake in the cat's nictitating membrane lacks stereoselectivity.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00505067
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  • 4
    Electronic Resource
    Electronic Resource
    The influence of block of catechol-O-methyl transferase on the sensitivity of isolated organs to catecholamines (1971)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 271 (1971), S. 59-92 
    Details
    ISSN: 1432-1912
    Keywords: Supersensitivity to Catecholamines ; Block of COMT-U-0521 ; V-0521 ; Isolated Nictitating Membrane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary The sensitivity of various isolated organs to catecholamines was tested before and after block of catechol-O-methyl transferase (COMT) by U-0521 (3′,4′-dihydroxy-2-methyl propiophenone; 18 μg/ml for 20 min). Isolated Nictitating Membrane of the Cat. The sensitivity to catecholamines was increased by inhibition of COMT whenever the experimental conditions resulted in a high potency of the amine, i.e., when the ED50 of the amine (in the absence of U-0521) was below about 10−6 M. Thus, block of COMT potentiated the effects of (−)-noradrenaline and (−)-adrenaline after denervation (or in the presence of cocaine) but not on muscles with an intact adrenergic innervation; it also increased the sensitivity to theβ-effects but not to theα-effects of isoprenaline. No potentiation was observed for dopamine which has a low potency even after denervation. The relation between potency of the catecholamine and the degree of the sensitizing effect of U-0521 was not due to saturation of COMT or of access to the enzyme. Measurements in denervated muscles of the production of O-methylated metabolites from (±)-noradrenaline-H3 (added to the bath for 20 min in concentrations of about 10−7 to 10−4 M), and of the extraneuronal accumulation of noradrenaline-H3 did not reveal any saturation of either the enzyme or the extraneuronal accumulation of the amine. When block of COMT resulted in supersensitivity to a catecholamine, the time required to reach steady-state responses was usually increased. This is consistent with the view that block of the enzyme impaired a site of loss. Block of COMT failed to produce any substantial potentiation of the effects of the indirectly acting amines, tyramine and mephentermine. O-methylation of the released transmitter seems to occur after the amine has reached the receptors of the effector cells. Isolated Strips of Cat and Bat Spleen. Results were quantitatively similar, since block of COMT potentiated the effects of (−)-noradrenaline and (−)-adrenaline in the presence but not (or only very little) in the absence of cocaine. However, the degree of supersensitivity after block of COMT (in the presence of cocaine) was smaller than in the nictitating membrane. In the cat spleen, cocaine causes a small but significant degree of supersensitivity to isoprenaline but not to methoxamine. Isolated Sat Aorta, Block of COMT did not increase the effect of cocaine. It is suggested that differences in the morphology of the adrenergic innervation contribute to the observed organ differences.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF01002173
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  • 5
    Electronic Resource
    Electronic Resource
    1,1′-Diisopropyl-2,4′-cyanine (disprocynium24), a potent uptake2 blocker, inhibits the renal excretion of catecholamines (1997)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 356 (1997), S. 115-125 
    Details
    ISSN: 1432-1912
    Keywords: Key words Disprocynium24 ; Noradrenaline ; Adrenaline ; Dopamine ; Renal excretion ; Organic cation transport ; Inulin clearance ; Uptake2
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 1,1′-Diisopropyl-2,4′-cyanine (disprocynium24), a potent inhibitor of the extraneuronal monoamine transport system (uptake2), was previously shown to reduce the clearance of catecholamines from plasma not only by blocking uptake2 but presumably also by blocking organic cation transport. To provide more direct evidence for the latter conclusion, the present study was carried out in anaesthetized rabbits. It aimed at determining the effect of disprocynium24 on the renal excretion of catecholamines which is known to be, at least in part, a consequence of organic cation transport in the kidney. To this end, the plasma clearance due to renal excretion (Clu) of endogenous as well as infused 3H-labelled adrenaline, noradrenaline and dopamine was determined for 60-min periods of urine collection in rabbits treated either with disprocynium24 (270 nmol kg-1 i.v followed by i.v. infusion of 80 nmol kg-1 min-1) or vehicle. Two groups of animals were studied: group I (monoamine oxidase and catechol-O-methyltransferase intact) and group II (monoamine oxidase and catechol-O-methyltransferase inhibited). A third group of animals with intact monoamine oxidase and catechol-O-methyltransferase was used to study the effect of disprocynium24 on the glomerular filtration rate (as determined by measuring the plasma clearance of inulin). In vehicle controls, Clu of endogenous adrenaline, noradrenaline and dopamine was 7.2, 5.2 and 153.6 ml kg-1 min-1, respectively, in group I and 10.4, 7.0 and 134.3 ml kg-1 min-1, respectively, in group II. Similar control values of Clu were obtained for infused 3H-adrenaline and 3H-noradrenaline, but not for infused 3H-dopamine; Clu of 3H-dopamine (4.9 ml kg-1 min-1 in group I and 15.4 ml kg-1 min-1 in group II) was considerably smaller than Clu of endogenous dopamine, indicating that most of the dopamine in urine (i.e., 98% in group I and 92% in group II) was derived from the kidneys rather than from the circulation. By contrast, only about one quarter of the noradrenaline in urine (32% in group I and 24% in group II) and none of the urinary adrenaline were of renal origin. In both groups, disprocynium24 markedly reduced the Clu of endogenous catecholamines (by 72-90%) and of infused 3H-catecholamines (by 49-69%). Moreover, it preferentially inhibited the renal excretion of those components of urinary dopamine and noradrenaline which were derived from the kidney. Therefore, disprocynium24 inhibits the tubular secretion of catecholamines and, hence, organic cation transport in the kidney. This conclusion was substantiated by the observation that disprocynium24 did not alter the glomerular filtration rate.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/PL00005018
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  • 6
    Electronic Resource
    Electronic Resource
    The effect of hydrocortisone on the sensitivity of the isolated nictitating membrane to catecholamines (1974)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 286 (1974), S. 1-48 
    Details
    ISSN: 1432-1912
    Keywords: Hydrocortisone ; Catecholamines ; Postjunctional Supersensitivity ; Extraneuronal COMT ; Nictitating Membrane
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Summary On the isolated nictitating membrane of the cat the supersensitivity to catecholamines induced by hydrocortisone was compared with the ability of hydrocortisone to block the extraneuronal uptake and metabolism of catecholamines. 1. Supersensitivity to catecholamines was induced by hydrocortisone whenever the ED50 for the catecholamine (in the absence of hydrocortisone) was 10 μM or less. 2. The degree of hydrocortisone-induced supersensitivity was (-)-noradrenaline 〉 (-)-adrenaline 〉 (±)-isoprenaline; while 28 μM hydrocortisone sufficed to induce supersensitivity to noradrenaline and adrenaline, 280 μM were required for inducement of supersensitivity to isoprenaline. 3. Hydrocortisone had no potentiating effects after block of COMT (by 0.1 mM U-0521). 4. Hydrocortisone failed to affect the sensitivity to amines which are not substrates of COMT and also to indirectly acting sympathomimetic amines (tyramine, mephentermine). 5. The sensitivity experiments are consistent with the existence of a quickly equilibrating, extraneuronal O-methylating compartment with high affinity for catecholamines; it has a saturable, hydrocortisone-sensitive uptake mechanism and little or no capacity for storage of unchanged catecholamine. This postulated compartment influences the concentration of catecholamines in the biophase whenever the concentration of the catecholamine is below the K m of the compartment. 6. When COMT was blocked, hydrocortisone inhibited the distribution of 3H-(-)-noradrenaline into a quickly equilibrating extraneuronal compartment of small size. 7. In intact smooth muscles the extraneuronal O-methylation of 3H-(-)-noradrenaline and 3H-(±)-isoprenaline was carried out by two metabolizing compartments. One of these compartments had a high, the other a low affinity for catecholamines (apparent K m 7.5–12.8 and 131–201 μM, respectively). 8. Hydrocortisone inhibited the O-methylation of catecholamines by the high affinity compartment; an apparent non-competitive type of inhibition was obtained against (-)-normadrenaline and (±)-isoprenaline as substrates. 9. The biochemical experiments demonstrate the existence of an extraneuronal, saturable, hydrocortisone-sensitive O-methylating compartment with high affinity for catecholamines; this compartment equilibrates quickly with the concentration of the catecholamine in the medium and has little or no ability to accumulate unchanged catecholamines. 10. The biochemical results are in full agreement with the results from sensitivity studies.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00499103
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  • 7
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and α1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 268-274 
    Details
    ISSN: 1432-1912
    Keywords: Key wordsα1-Adrenoceptor ; Decynium22 ; Disprocynium24 ; Extraneuronal monoamine transporter ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 1,1′-Diethyl-2,2′-cyanine (decynium22) and 1,1′-diisopropyl-2,4′-cyanine (disprocynium24) are highly potent inhibitors of the extraneuronal monoamine transporter. When given as i.v. bolus injections (4 μmol kg–1) to anaesthetized rabbits, both drugs elicited a transient fall in blood pressure without altering heart rate. The observed maximum fall in diastolic blood pressure was 59% after decynium22 and 43% after disprocynium24 administration. The pharmacokinetics of decynium22 and disprocynium24 were similar; they were characterized by short half-lives for elimination (8.2 and 4.5 min, respectively) and very high plasma clearances (173 and 180 ml kg–1 min–1, respectively). The mechanism underlying the blood pressure-lowering effect of decynium22 was explored in the isolated incubated rabbit aorta. Decynium22 antagonized the noradrenaline-induced contraction; the pA2 for this interaction was 7.6, and the slope of the corresponding Schild plot was unity. In a membrane preparation from rat myocardium, decynium22 as well as disprocynium24 inhibited the specific binding of [125I]-2-[β-(4-hydroxy-3-iodophenyl)-ethylaminomethyl]-tetralone (125I-HEAT), a selective ligand to α1-adrenoceptors. The Ki‘s were 5.3 and 240 nmol l–1 for decynium22 and disprocynium24, respectively. The type of binding inhibition by decynium22 was competitive. It is concluded that the two inhibitors of extraneuronal monoamine transport decynium22 and disprocynium24 lower blood pressure by blocking α1-adrenoceptors. A comparison of their potencies in blocking extraneuronal monoamine transport and α1-adrenoceptors clearly indicates that disprocynium24 is more suitable for studies designed to determine the role of extraneuronal monoamine transport in vivo. Considering its very fast elimination kinetics, disprocynium24 must be administered by constant rate-infusions in order to avoid large fluctuations of plasma levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171057
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  • 8
    Electronic Resource
    Electronic Resource
    Pharmacokinetic and α1-adrenoceptor antagonistic properties of two cyanine-type inhibitors of extraneuronal monoamine transport (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 268-274 
    Details
    ISSN: 1432-1912
    Keywords: α1-Adrenoceptor ; Decynium22 ; Disprocynium24 ; Extraneuronal monoamine transporter ; Pharmacokinetics
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract 1,1′-Diethyl-2,2′-cyanine (decynium22) and 1,1′-diisopropyl-2,4′-cyanine (disprocynium24) are highly potent inhibitors of the extraneuronal monoamine transporter. When given as i.v. bolus injections (4 μmol kg−1) to anaesthetized rabbits, both drugs elicited a transient fall in blood pressure without altering heart rate. The observed maximum fall in diastolic blood pressure was 59% after decynium22 and 43% after disprocynium24 administration. The pharmacokinetics of decynium22 and disprocynium24 were similar; they were characterized by short half-lives for elimination (8.2 and 4.5 min, respectively) and very high plasma clearances (173 and 180 ml kg−1 min−1, respectively). The mechanism underlying the blood pressure-lowering effect of decynium22 was explored in the isolated incubated rabbit aorta. Decynium22 antagonized the noradrenaline-induced contraction; the pA2 for this interaction was 7.6, and the slope of the corresponding Schild plot was unity. In a membrane preparation from rat myocardium, decynium22 as well as disprocynium24 inhibited the specific binding of [125I]-2-[β-(4-hydroxy-3-iodophenyl)-ethy-laminomethyl]-tetralone (125I-HEAT), a selective ligand to α1-adrenoceptors. The Ki's were 5.3 and 240 nmol l−1 for decynium22 and disprocynium24, respectively. The type of binding inhibition by decynium22 was competitive. It is concluded that the two inhibitors of extraneuronal monoamine transport decynium22 and disprocynium24 lower blood pressure by blocking α1-adrenoceptors. A comparison of their potencies in blocking extraneuronal monoamine transport and α1-adrenoceptors clearly indicates that disprocynium24 is more suitable for studies designed to determine the role of extraneuronal monoamine transport in vivo. Considering its very fast elimination kinetics, disprocynium24 must be administered by constant rate-infusions in order to avoid large fluctuations of plasma levels.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171057
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  • 9
    Electronic Resource
    Electronic Resource
    The role of extraneuronal amine transport systems for the removal of extracellular catecholamines in the rabbit (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 354 (1996), S. 275-286 
    Details
    ISSN: 1432-1912
    Keywords: Key words Plasma clearance of catecholamines ; MAO-inhibition ; COMT-inhibition ; Disprocynium24 ; Uptake2 ; Organic cation transporters
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract As selective inhibitors of the extraneuronal monoamine uptake system (uptake2) suitable for in-vivo studies were not available, the question of whether uptake2 plays a definite role in vivo is largely unresolved. We attempted to resolve the question by using 1,1′-diisopropyl-2,4′-cyanine iodide (disprocynium24), a novel agent that blocks uptake2 in vitro with high potency. Anaesthetized rabbits were infused with 3H-labelled noradrenaline, adrenaline and dopamine, and catecholamine plasma clearances as well as rates of spillover of endogenous catecholamines into plasma were measured before and during treatment with either disprocynium24 or vehicle. Four groups of animals were studied: group I, no further treatment; group II, monoamine oxidase (MAO) and catechol-O-methyltransferase (COMT) inhibited; group III, neuronal uptake (uptake1) inhibited; group IV, uptake1 as well as MAO and COMT inhibited. Disprocynium24 (270 nmol kg–1 i.v. followed by an i.v. infusion of 80 nmol kg–1 min–1) did not alter heart rate and mean arterial blood pressure, but increased cardiac output by 22% and decreased the total peripheral vascular resistance by 16% with no difference between groups. When compared with vehicle controls, catecholamine clearances (normalized for the cardiac output of plasma) were decreased and spillover rates increased in response to disprocynium24. Although there were statistically significant between-group differences in baseline clearances (which decreased in the order: group I 〉 group II 〉 group III 〉 group IV), the drug-induced clearance reductions relative to vehicle controls were similar in groups I to IV and amounted to 29–38% for noradrenaline, 22–31% for adrenaline and 16–22% for dopamine. Hence, there was still a significant % reduction in catecholamine clearances even after the combined inhibition of MAO and COMT, and there was no increase in the % reduction of clearances after inhibition of uptake1. Noradrenaline spillover increased in response to disprocynium24 in all four groups by 1.6- to 1.9-fold, whereas a 1.5- to 2.0-fold increase in adrenaline and dopamine spillover was observed in groups II and IV only. The results indicate that disprocynium24 interferes with the removal of circulating catecholamines not only by inhibiting uptake2, but also by inhibiting related organic cation transporters. As disprocynium24 increased the spillover of endogenous catecholamines into plasma even after inhibition of MAO and COMT, organic cation transporters may also be involved in the removal of endogenous catecholamines before they enter the circulation.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00171058
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  • 10
    Electronic Resource
    Electronic Resource
    The contribution by monoamine oxidase and catechol-O-methyltransferase to the total-body and pulmonary plasma clearance of catecholamines (1996)
    Springer
    Naunyn-Schmiedeberg's archives of pharmacology 353 (1996), S. 193-199 
    Details
    ISSN: 1432-1912
    Keywords: Key words Noradrenaline ; Adrenaline ; Dopamine ; Total-body plasma clearance ; Pulmonary plasma clearance ; MAO inhibition ; COMT inhibition
    Source: Springer Online Journal Archives 1860-2000
    Topics: Medicine
    Notes: Abstract  To study the effects of inhibition of catechol-O-methyltransferase (COMT) and monoamine oxidase (MAO) on the removal of circulating catecholamines, anaesthetized rabbits were infused for 120 min with 3H-labelled noradrenaline, adrenaline and dopamine. Total-body plasma clearances (Cltot) and pulmonary fractional extractions (ERp) of the infused amines and the cardiac output of plasma (COp) were determined under steady-state conditions at the end of each of two consecutive 60-min treatment periods. MAO and COMT were inhibited by treatment with pargyline (40 mg/kg) and tolcapone (3 mg/kg followed by 1.5 mg/kg given every 30 min), respectively. Two groups of animals were studied. Group I involved animals treated with tolcapone throughout and given pargyline at the beginning of the second treatment period. In group II, pargyline was given at the beginning of the first, and the treatment with tolcapone was started at the beginning of the second treatment period. As previous experiments had shown that COMT inhibition alone is without any effect on Cltot of the three catecholamines considered here, the results obtained in the first treatment period of group I can be taken to reflect control results. At the end of the first treatment period, Cltot of noradrenaline, adrenaline and dopamine (expressed as a percentage of COp) was 88%, 85% and 142%, respectively, in group I (COMT inhibition) and 67%, 77% and 115%, respectively, in group II (MAO inhibition; P〈0.05 for the group difference regarding Cltot of noradrenaline and dopamine). MAO inhibition on top of COMT inhibition (group I) lowered Cltot of noradrenaline, adrenaline and dopamine by 23%, 12% and 26%, respectively, and COMT inhibition on top of MAO inhibition (group II) reduced Cltot of these catecholamines by 13%, 20% and 17%, respectively. At the end of the first treatment period, the pulmonary plasma clearance (Clp=ERp×COp) of noradrenaline and dopamine was 13 and 25 ml kg-1 min-1, respectively, in group I and 12 and 28 ml kg-1 min-1, respectively, in group II. Clp of adrenaline did not differ from zero in either group. Clp of noradrenaline and dopamine was reduced by 74% and 70%, respectively, when both enzymes were inhibited in group I and by 70% and 67%, respectively, when both enzymes were inhibited in group II. Hence, inhibition of either MAO or COMT alone had little, if any, effect on the removal of noradrenaline, adrenaline and dopamine on passage through the systemic and pulmonary circulation. Combined inhibition of both MAO and COMT was highly effective in reducing the pulmonary clearance of noradrenaline and dopamine, but produced only minor decreases in the total-body clearance of all three catecholamines.
    Type of Medium: Electronic Resource
    URL: http://dx.doi.org/10.1007/BF00168757
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