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PubMed1977

Activation of myocardial beta-adrenoceptors by the nitrogen-free low affinity ligand 3',4'-dihydroxy-alpha-methylpropiophenone (U-0521).

The effect of 3',4'-dihydroxy-alpha-methylpropiophenone (U-0521) on the rate of spontaneously contracting cultured rat heart cells and right atria of rats and kittens was investigated. The action of U-0521 on the cellular content of cyclic AMP and on the adenylyl cyclase of heart membrane particels was also studied. 1. U-0521 caused positive chronotropic effects on single cultured heart cells and right atria of the rat. U-0521 was about 10(5) times less potent than (--)-isoprenaline. The maximum effect of U-0521 was smaller than the maximum effect of (--)-isoprenaline. A small positive chronotropic effect of U-0521 was also observed on kitten atria. 2. The beta-adrenoceptor blocker (--)-bupranolol antagonized the positive chronotropic effects of U-0521 to the same extent as the effects of (--)-isoprenaline on single cells and atria of the rat. The effects of both U-0521 and (--)-isoprenaline appear therefore mediated through the same beta-adrenoceptors. The positive chronotropic effects of U-0521 on kitten atria were also blocked by (--)-bupranolol. 3. Up to 0.1 mM U-0521 did not block the effects of (--)-isoprenaline on rat atria, not even in the presence of corticosterone or hydrocortisone. 4. 1 min incubations with equieffective (increase in cellular beating rate) concentrations of U-0521 (0.1 mM) and (--)-isoprenaline (1 nM) caused a significant increase in the cellular content of cAMP; this effect of both drugs was antagonized by 10 nM (--)-bupranolol. 5. 0.1--3.3 mM U-0521 did not stimulate the adenylyl cyclase of cell-free membrane particles of kitten ventricles. The cyclase was depressed by 10 mM U-0521. 3.3 mM U-0521 caused a 20% decrease of the maximum cyclase-stimulating effect of (--)-isoprenaline and a 1.6-fold increase of its apparent Km. 6. The results with U-0521 suggest that beta-adrenoceptors can be activated by agonists devoid of nitrogen. However, the affinity of U-0521 for the beta-adrenoceptor is very low (KU-0521 approximately 5.5 mM). The concentration of U-0521 (0.1 mM) causing maximal increases in beating rate of cultured cells probably occupies less than 7% of the available beta-adrenoceptors.

Adenylyl Cyclases↗
PubMed1982

Catechol-O-methyltransferase inhibition by U-0521 increases striatal utilization of levodopa.

The effects of U-0521, a catechol-O-methyltransferase (COMT) inhibitor, were studied on this enzyme activity and on Dopa metabolism in rat striatum. In vivo maximal inhibition (95%) of COMT activity was obtained at 5 min with enzyme recovery to 64% of basal activity at 120 min. When injected in increasing doses U-0521 (200 mg . kg-1) inhibited, at 10 min, COMT activity by 85% with an IC50 = 80 mg . kg-1. In rats pretreated with U-0521 and then with DOPA the accumulation of 3-O-methyldopa-(OMD) in the plasma was essentially blocked while Dopa, dopamine (DA) and 3,4-dihydroxyphenylacetic acid (DOPAC) accumulation in the striatum was significantly higher than in DOPA treated controls. U-0521, a potent COMT inhibitor, enhances the availability and utilization of levodopa in the brain and may thus be helpful in future treatment of parkinsonian patients.

Animals↗
PubMed1976

The effect of inhibitors of extraneuronal uptake on the distribution of 3H-(+/-)noradrenaline in nerve-free rabbit aortic strips.

1. Nerve-free rabbit aortic strips were exposed to 1.18muM 3H-(+/-)noradrenaline for 30 min. When either MAO or COMT was inhibited, far more O-methylated (MAO inhibited) than deaminated metabolites (COMT inhibited) were formed during the incubation. The accumulation of unchanged amine in the extraneuronal stores was inversely related to the rate of metabolism. 2. After inhibition of both metabolizing enzymes, nerve-free strips were first incubated with the amine and then washed out with amine free solution. Compartmental analysis of the efflux curves showed that two extraneuronal compartments were involved in accumulation (with half times of efflux of 3 and 11 min, respectively). 3. 86muM corticosterone or 30muM phenoxybenzamine greatly decreased the accumulation of noradrenaline in these two compartments. 4. When corticosterone or phenoxybenzamine was added to the wash out solution only, the half time of the efflux from both compartments was greatly increased. However, this effect was seen only after inhibition of COMT and not after inhibition of MAO only (the filling of the extraneuronal stores with unchanged noradrenaline being better after inhibition of COMT than when this enzyme was intact). The effect of corticosterone appeared to be reversible, that of phenoxybenzamine irreversible. 5. Analysis of the efflux of metabolites (in experiments in which only one enzyme was inhibited) indicated that corticosterone affected the efflux of noradrenaline but not that of the metabolites. 6. When either COMT or MAO was inhibited throughout the experiment, very little or no metabolism of noradrenaline occured during prolonged wash out. On the other hand, dis-inhibition of COMT during wash out (by the omission of U-0521 from the wash out solution after it had been present during the initial incubation) revealed that noradrenaline, stored extraneuronally during the initial incubation, is quickly O-methylated during wash out, especially when the efflux of the parent amine is inhibited by corticosterone. 7. The results show that COMT is the major extraneuronal noradrenaline-metabolizing enzyme of rabbit aorta, that inhibition of COMT is a pre-requisite for any corticosterone-sensitive accumulation of noradrenaline, that there are two important extraneuronal compartments (compartments III and IV; Henseling et al., 1976a), and that inhibitors of extraneuronal uptake inhibit both, influx and efflux of noradrenaline.

Animals↗
PubMed1976

Uptake, distribution and metabolism of isoprenaline in the dog saphenous vein.

Dog saphenous vein strips were incubated with 2 muM 3H-isoprenaline. After 2 and 8 min of incubation small cross sections were cut and prepared for light and ultrastructural autoradiography. In addition, the accumulation of 3H-isoprenaline (3H-ISO) in the tissue as well as the formation of 3-O-methylisoprenaline (3H-OMI) were determined by liquid scintillation counting. The density of silver grains was 6.5 times higher on smooth muscle than on connective tissue. It decreased from the intima to adventitia when determined in the 2 min specimens, suggesting the existence of a selective transport of isoprenaline through the endothelium of the vein. The preferential distribution into the juxta-intimal part of the media which was observed after the 2 min incubation period was abolished by cortexone. Silver grain density, especially over the smooth muscle, was markedly increased by U-0521 and decreased by cortexone. Simultaneous treatment with cortexone and U-0521 led to a marked accumulation of silver grains over neuronal tissue; this accumulation was prevented by cocaine. Strips incubated at 0 degrees C and without oxygen showed almost no grains. In control conditions the saphenous vein strips removed 1968 +/- 19 pmoles-g-1 during 8 min of incubation. 86.3% of that value corresponded to 3H-OMI formation. O-methylation of 3H-ISO was strongly inhibited by U-0521 and, in a lesser degree, by cortexone. The influence of U-0521 on inhibition of O-methylation of 3H-ISO was not modified by cortexone. We found a linear correlation between silver grain densities per unit area of the vein strips and the 3H-isoprenaline accumulation determined by liquid scintillation counting, indicating a clear correspondence between silver grains and 3H-isoprenaline.

Animals↗
PubMed1984

The kinetic characteristics of the extraneuronal Q-methylating system of the dog saphenous vein and the supersensitivity to catecholamines caused by its inhibition.

The "half-saturating outside concentration" and the Vmax of the extraneuronal O-methylating system of the dog saphenous vein were determined in vitro for 3 catecholamines: isoprenaline, adrenaline and noradrenaline. Strips pretreated with 1 mmol/l pargyline were exposed to 30 mumol/l cocaine for 30 min before and during the 30 min incubation with the amines. Two methods were used to reach our aims: a) the classical one in which the 3H-O-methylated metabolites formed from a mixture of unlabelled and labelled amine were determined by using final concentrations of the substrate ranging from 0.2 and 12.8 mumol/l and b) an indirect one in which 0.2 mumol/l 3H-(+/-)-isoprenaline was used to assess the extraneuronal O-methylation of the tracer amine, and then those concentrations of unlabelled amines were determined which reduce the O-methylation of 3H-(+/-)-isoprenaline by 50% (IC50). The "half-saturating outside concentrations" and the Vmax obtained by the first method were: 1.3, 2.5 and 3.4 mumol/l and 241, 317 and 294 pmol/g/min for 3H-(+/-)-isoprenaline, 3H-(+/-)-adrenaline and 3H-(-)-noradrenaline, respectively. The IC50s obtained by the second method used were: 1.1, 0.6, 0.7 and 1.4 mumol/l for (+/-)-isoprenaline, (-)-isoprenaline, (-)-adrenaline and (-)-noradrenaline, respectively. It was observed that the contraction of the strips caused by adrenaline and noradrenaline distorted IC50 values. In the presence of 1 mumol/l phentolamine the IC50 for adrenaline and noradrenaline was about 2.5 times higher than in its absence.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

The influence of inhibition of catechol-O-methyl transferase or of monoamine oxidase on the extraneuronal metabolism of 3H-(-)-noradrenaline in the rat heart.

The extraneuronal metabolism of 3H-(-)-noradrenaline (1 nmol/l) was determined in rat hearts obtained from reserpine-pretreated animals (in the presence of 30 mumol/l cocaine). Inhibition of monoamine oxidase (MAO) (by pretreatment of the animals with pargyline) increased the formation of O-methylated metabolites by nearly that amount by which the formation of deaminated metabolites declined; hence, catechol-O-methyl transferase (COMT) seemed to be able to nearly fully compensate for the loss of MAO activity. However, when COMT was inhibited (by the presence of either 1 or 10 mumol/l U-O521), the increase in the formation of deaminated metabolites was smaller than the decrease in the formation of O-methylated metabolites; hence, MAO seemed to be unable to fully compensate for the loss of COMT activity. These results are discussed with regard to the hypothesis that the two extraneuronal enzymes co-exist in one compartment. As inhibition of COMT causes a much greater increase in the steady-state tissue/medium ratio for 3H-(-)-noradrenaline than does inhibition of MAO, it is suggested that it is this increase in the intracellular concentration of 3H-(-)-noradrenaline which - by promoting an efflux of the unchanged amine that is proportional to the tissue/medium ratio - actually decreases the net removal of 3H-(-)-noradrenaline from the perfusion fluid. The results are compatible with (but no evidence for) the hypothesis that the two enzymes co-exist in the same extraneuronal compartment.

Animals↗