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At least 19 recordsLinked to original sources
PubMed1978

Biochemical activities of the derivatives of dehydrodicaffeic acid dilactone.

Activities of derivatives of dehydrodicaffeic acid dilactone (DDCAD) to inhibit catechol-O-methyltransferase (COMT), cyclic AMP phosphodiesterase (PDE) and DOPA decarboxylase (DDC) were examined. Among those tested, 2,6-bis-(5',6'-dibromo-4'-hydroxy-3'-methoxyphenyl)-3,7-dioxabicyclo-[3,3,0]-octane 4,8-dione was found to be the strongest inhibitor of both COMT and PDE. There were no derivatives which showed a stronger inhibition against DDC than the original compound, DDCAD.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1975

Properties of catechol O-methyltransferases from brain and liver of rat and human.

Kinetic and electrophoretic properties of catechol O-methyltransferases (EC 2.1.1.6) from brain and liver were studied. The enzyme of either rat or human tissues exhibited a single molecular form when subjected to electrophoresis at pH7.9. At pH9 a second, apparently oxidized, form was detected. Isoelectric-focusing experiments also indicated only one enzyme form, which was identical from extracts of brain and liver of each species (pI = 5.2 for rat, 5.5 for human). Similarities between brain and liver catechol O-methyltransferase of a given species were also demonstrated by kinetic parameters, meta/para ratios of products, and inhibitor potencies. Human catechol O-methyltransferase exhibited lower Km values than did the rat enzyme for S-adenosyl-L-methionine, dopamine and dihydroxybenzoic acid. Adrenochrome inhibited both rat and human enzyme. It was concluded (1) that only a single enzyme form could be demonstrated in the physiological pH region; (2) that catechol O-methyltransferase of brain could not be distinguished from the liver enzyme of the same species; and (3) that species differences exist between the enzymes of rat and human tissues.

Adrenochrome↗
PubMed1975

Microassay of human erythrocyte catechol-O-methyltransferase: removal of inhibitory calcium ion with chelating resin.

A radiochemical micromethod for the determination of catechol-O-methyltransferase (COMT) activity in human red blood cells (RBC) is described. The method avoids artifacts that occur with other assay procedures. Erythrocyte lysates are exposed to a particulate chelating agent (Chelex-100) to remove endogenous divalent cations that inhibit COMT. 3,4-Dihydroxybenzoic acid rather than norepinephrine is used as a substrate to increase both the sensitivity and the reproducibility of the procedure. An internal standard of purified rat liver COMT is added to lysates to detect possible variations in endogenous activators or inhibitors of the enzyme. Blood samples from 373 unselected subjects age 16-18 were assayed for RBC COMT activity with this assay procedure. The COMT activity in these blood samples ranged from 3-25 units with a mean activity of 11.3 plus or minus 4.2 (mean plus or minus S.D.).

Adolescent↗
PubMed1979

Toxic interaction between narcotic analgesics and inhibitors of catechol-O-methyltransferase.

A lethal synergism between morphine and tropolone, an inhibitor of catechol-O-methyltransferase, was previously noted in adult male Holtzman rats. The present research demonstrates that this phenomenon generalizes across factors of sex, age, strain (Sprague--Dawley, Wistar) and species (Swiss albino mice). Acute toxicity was also significantly increased (1.5--1.9 times) in the case of codeine, methadone, meperidine and levorphanol, but to a lesser extent than for morphine (4.0 times) in the S-D strain. Another COMT inhibitor, 3,5-dihydroxy-4-methoxybenzoic acid, interacted with morphine in S-D rats to an equal degree as did tropolone. Post-treatment with 1 mg/kg of naloxone in rats or naltrexone in mice reduced the high lethality associated with morphine plus tropolone. There was a pronounced lowering of whole brain norepinephrine (NE) level after morphine plus tropolone in Wistar rats with doses of each component that alone caused no change in NE. Brain dopamine (DA) was elevated by tropolone and by its combination with morphine. Each drug alone caused slight lowering of brain serotonin. Enhancement by tropolone of the toxicity of (+)-amphetamine in mice and rats was of similar magnitude as for morphine. The possible role of brain NE and/or DA in the sensitivity to acute toxic effects of opioids in rodents is suggested by these data, as well as a parallel in this regard with amphetamine-type stimulants.

Aging↗
PubMed1975

Further study of the adrenoceptors of the saphenous vein of the dog: influence of factors which interfere with the concentrations of agonists at the receptor level.

In the present study the affinities of some sympathomimetic amines for alpha- and beta-adrenoceptors of the dog saphenous vein tissue were determined after all known factors interfering with the concentration of these agonists at the receptor level had been assessed and excluded. It was observed that in control experiments the relative potencies of sympathomimetic agonists for inducing contractions were: adrenaline (1.6) greater than noradrenaline (1.0) greater than phenylephrine (0.38) greater than isoprenaline (0.009). The elimination of neuronal uptake by cocaine, 4 X 10(-6) M, enhanced predominantly the effects of noradrenaline (by a factor of 7.5), whereas block of catechol-O-methyl transferase (COMT) by U-0521, 10(-4) M, only enhanced those of adrenaline (by a factor of 2.6) and block of beta-adrenoceptors by propranolol, 5 X 10(-7) M, enhanced those of isoprenaline (by a factor of 3) and adrenaline (by a factor of 1.8). Block of COMT enhanced the effects of adrenaline approximately as much as did the blockade of neuronal uptake; this seems to indicate that the affinity of adrenaline for extraneuronal and neuronal uptake processes is approximately the same. Regarding the relaxation-inducing capacity of sympathomimetic agents it was observed that isoprenaline, adrenaline and noradrenaline are full agonists, whereas phenylephrine was not able to produce relaxation amounting to more than 5% of the maximum. Denervation did not modify the relaxant effects of isoprenaline. After elimination of all known factors interfering with the concentration of the sympathomimetic agonists in the biophase, the ratios between the ED50's of each amine for alpha- and beta-adrenoceptors were: adrenaline = 34, noradrenaline = 109 and isoprenaline = 0.0041.

Animals↗
PubMed1975

The influence of environmental agents on prostaglandin biosynthesis and metabolism in the lung. Inhibition of lung 15-hydroxyprostaglandin dehydrogenase by exposure of guinea pigs to 100 per cent oxygen at atmospheric pressure.

Enzymes in the 100 000g supernatant fraction of guinea-pig lungs, in the presence of NAD-+, converted PGF-2 alpha (prostaglanding F-2 alpha) into a less-polar compound. The u.v. spectrum of this metabolite showed a strong absorption band at 230 nm, which is characteristic of a carbonyl group in conjugation with a double bond. Reduction of this metabolite with NaBH4 resulted in a compound that behaved like PGF2 ALPHA on t.l.c. and g.l.c. From this evidence we concluded that PGF2alpha is metabolized in vitro to 15-oxo-PGF2 alpha by the NAD-+-dependent prostaglandin dehydrogenase system of guinea-pig lung. The effect of exposure of the animal to SO-2 and O2 on the rate of prostaglanding biosynthesis and catabolism by lung fractions in vitro was studied. Exposure of guinea pigs to 500 p.m. of SO2 for 5h or to 50p.p.m for 9 days (6h/day) did not alter the production or degradation of prostaglandings by lung fractions in vitro. In contrast, exposure of guinea pigs to 100% O2 for 48 h inhibited the rate of prostaglanding metabolism in vitro by 60-70% without significantly altering the rate of biosynthesis by lung fractions. Inhibition of prostaglandin dehydrogenase activity in vitro by lung fractions after exposure of the animal to O2 was dependent on the duration of exposure. Gluthathione S-aryltransferase and catechol O-methyltransferase activites of guinea-pig lung 100 000g supernatant were unaltered by exposure of the animal to O2. Thus it appears that inhibition of pulmonary prostaglandin dehydrogenase by exposure of the animal to O2 is not the result of a general toxic response. It was postulated that the inhibition of prostaglanding dehydrogenase may occur after exposure of the animal to other oxidant gases.

Alcohol Oxidoreductases↗
PubMedDate not supplied

Role of catecholamine degradative enzymes and the adrenergic innervation in determining the cerebrovascular response to infused norepinephrine.

Cerebral blood flow responses to intra-arterial infusion of norepinephrine (NE) at 0.55 microgram/kg/min and 1.1 microgram/kg/min were studied in 3 groups of baboons. The flow was measured by the intracarotid 133xenon clearance technique using a computer program to calculate flow (height over area--H/A) flow (initial slope--is) and cerebral metabolic utilization of oxygen (CMRO2). The normal response to NE was to increase flow without significant changes in CMRO2. Blockade of catechol-o-methyl transferase (COMT) produced vasoconstrictor responses to these same NE doses. Monoamine oxidase blockade abolished the normal vasodilation. Denervation of the cerebral circulation with intracisternal 6-hydroxydopamine produced vasoconstrictor responses with flow (H/A) but not with flow (is). It is concluded that the extra-neuronal COMT enzyme is important in limiting the access of blood-borne NE to cerebrovascular constrictor receptors.

Adrenergic Fibers↗
PubMed1977

Response of the atrial pacemaker to dobutamine.

The action of dobutamine, (+/-)-4- [2- [[3-(p-hydroxyphenyl)-1-methylpropyl]amino]ethyl] pyrocatechol hydrochloride was studied on the pacemaker of the isolated rat atria. The dose-chronotropic response curve showed a typical bell-dome shape of the sympathomimetic amines. Reserpinization of the animals did not change the curve of the agonist. Cocaine (6.7 microgram/ml) induced a decrease of the sensitivity of the rat atria pacemaker for dobutamine (p less than 0.001). Propranolol (3 X 10(-8) and 10(-7) M) provoked a shift to the right of the dose-response curve for dobutamine. Also, the last concentration of the antagonist depressed the maxima (p less than 0.01). Phentolamine failed to prove a possible alpha-adrenergic action of the drug on the pacemaker. The response to dobutamine was not affected when monoaminoxidase was inhibited by pretreatment with pargyline, or when catechol-O-methyltransferase was inhibited by exposure to U-0521 (3,4 dihydroxy-alpha-methylpropiophenone). These results indicate that dobutamine: a) is a beta-adrenergic agent, b) is not a good substrate of MAO, c) is a direct-acting sympathomimetic amine.

Adrenergic beta-Antagonists↗
PubMed1976

Studies on adrenal phenylethanolamine N- methyltransferase (PNMT) with S K & F 64139, a selective inhibitor.

SK&F 64139 is a potent, reversible inhibitor of phenylethanolamine N-methyltransferase; its IC50 concentration in our standard assay system was 1 X 10(-7) M. Kinetically, the compound is a competitive inhibitor with respect to norepinephrine but is uncompetitive when S-adenosylmethionine is the variable substrate. In contrast to a previously reported compound (SK&F 7698), the drug is only a weak alpha receptor antagonist (KB = 6 X 10(-6) M). In both the rat and squirrel monkey, SK&F 64139 produced dose-dependent decreases in the adrenal epinephrine content coupled with stoichiometrically equivalent increases in the norepinephrine pool(s). Further evidence for in vivo phenylethanolamine N-methyltransferase inhibitory activity was that the drug markedly inhibited the conversion of a tracer dose of 3H-norepinephrine to 3H-epinephrine in the rat adrenal gland after unit oral doses as low as 5 mg/kg.

Adrenal Glands↗
PubMed1977

Monoamine oxidase and catechol-O-methyl transferase activity in Tetrahymena.

Tetrahymena pyriformis strain HSM was found to have monomine oxidase (MAO) and a catechol-3-methyl transferase-like (COMT) activity. As in mammalian tissues, the MAO activity is predominantly localized in the mitochondrial pellet and COMT in the cytosol. The COMT-like activity was present in amounts comparable to several mouse tissues and was inhibited by tropolone. MAO activity was much lower than in any of the mouse tissues tested, and its activity varied greatly from preparation to preparation. The substrate preference of Tetrahymena MAO was tryptamine greater than serotonin greater than dopamine, and activity increased with increasing pH from pH 6.5 to pH 7.8, as does that of mouse liver MAO. Teh Km of Tetrahymena MAO for tryptamine was approximately 4 micrometer, an order of magnitude lower than that of mouse liver MAO. Sensitivity of inhibition by MAO inhibitors was variable. In some preparations, no inhibition was observed. In others clear inhibition was obtained, harmine and clorgyline being among the most potent inhibitors.

Animals↗
PubMed1975

Supersensitivity to catecholamines after impairment of extraneuronal uptake or catechol-O-methyl transferase.

In cat papillary muscle and nictitating membrane block of extraneuronal catechol-O-methyl transferase (COMT) by 3',4'-dihydroxy-alpha-methyl propiophenone (U-0521) or of extraneuronal uptake by hydrocortisone causes supersensitivity to catecholamines whenever the experimental conditions result in a high sensitivity of the organ to catecholamines. After block of monoamine oxidase the extraneuronal O-methylation of (-)-[3H]norepinephrine by the isolated nictiating membrane is due to two O-methylating systems (Km and Vmax: 7.5 muM and 0.73 nmoles - g-1 - min-1, and 131 muM and 8.5 nmoles - g-1 - min-1, respectively). Hydrocortisone (28 muM) blocked the activity of the high affinity system without affecting the low affinity system. Apparently, there exists an extraneuronal compartment of high affinity that has a hydrocortisone-sensitive uptake mechnism; this compartment influences the concentration of catecholamines below the Km of this compartment. Supersensitivity ensues when either uptake or enzyme is blocked. Since the sensitivity effects of U-0521 and hydrocortisone are not additive, the high affinity compartment must a) metabolize most of the catecholamine transported into the compartment, and b) have a limited storage capacity for catecholamines after block of COMT.

Animals↗