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Pulse-radiolytic investigations of catechols and catecholamines. I. Adrenaline and adrenochrome.

Adrenaline (epinephrine), adrenochrome and C4-substituted catechol model compounds were pulse-irradiated in aqueous neutral and alkaline solutions. Transient spectra are reported after oxidizing adrenaline and reducing adrenochrome. All species appearing during 20 msec interval after the pulse have been identified: the OH adduct with an absorption maximum at 300-310 nm, the semiquinone (at 245 nm), and adrenaline quinone (at 340 nm). The reaction of superoxide anions (O2-) with adrenaline was less efficient, compared with OH radicals. A novel oxidation product, derived from the semiquinone and O2-, has been identified as the 4-hydroxy-3,6-dioxo derivate. The pulse-radiolytic reduction of adrenochrome by hydrated electrons (eaq-) yielded the semiquinone of adrenochrome (absorbing at 470 nm), which subsequently decays by a second-order process. The dismutation products leuco-adrenochrome (absorbing at 300 nm, pH 9-8) and the adrenochrome tautomer (absorbing at 375 nm) are unstable, forming 5,6-dihydro-N-methyl indole and regenerating adrenochrome.

Adrenochrome↗

Direct and respiratory chain-mediated redox cycling of adrenochrome.

Adrenochrome is reduced by ascorbate in a reaction accompanied by a large and rapid oxygen uptake. The rates of adrenochrome reduction and the concomitant oxygen uptake are decreased in the presence of superoxide dismutase or catalase. The species formed on the one-electron reduction of adrenochrome (i.e., the semiquinone) was shown by pulse radiolysis to rapidly react with oxygen (9.10(8) M-1.s-1), indicating the occurrence of a redox cycling in a system formed by adrenochrome, a reducing agent, and oxygen. Adrenochrome is also reduced to the corresponding semiquinone by complex I of beef heart submitochondrial particles supplemented with NADH, while succinate is unable to support this reduction. The o-semiquinone is the intermediate species in the superoxide-generating cycle resulting from both non-enzymatic and enzymatic reduction. The toxic effects of adrenochrome and its pathophysiological role can be explained, at least in part, on the basis of the demonstrated cycle.

Adrenochrome↗

Catecholamine-induced myocardial cell damage: catecholamines or adrenochrome.

Recent evidence suggests that catecholamine-induced myocardial damage may be due to the cardiotoxic property of its non-physiological metabolite, adrenochrome. We investigated whether catecholamine-mediated myocardial damage is the result of catecholamine stimulation per se or the consequence of physiological or non-physiological metabolites. In the Langendorff perfused rat heart, fresh epinephrine (10(-6) M) solution increased cumulative lactate dehydrogenase (LDH) release when the perfusion pressure was 100 cm but not 65 cm, 3640 +/- 665 v. control 545 +/- 45 mIU/g/35 min respectively (P less than 0.01). In the left atrial perfused rat heart working against a hydrostatic pressure of 100 cm, fresh epinephrine (10(-6) M) solution produced the greatest increase in cumulative LDH release, 9346 +/- 1806 v. control 472 +/- 47 mIU/g/45 min respectively (P less than 0.01). Beta 1 but not alpha 1 adrenergic stimulation provoked enzyme leakage. Beta-adrenoceptor antagonism with atenolol 10(-5) M prevented catecholamine-induced leakage. Physiological metabolites of epinephrine viz metanephrine 10(-6) M, dihydroxymandelic acid 10(-6) M, vanillylmandelic acid 10(-6) M, and the non-physiological metabolite adrenochrome 10(-6) M to 10(-4) M did not increase the cumulative LDH release over 45 min. When adrenochrome 10(-4) M was perfused for 120 min enzyme release occurred, albeit only a third of that induced by epinephrine 10(-6) M over 45 min. We demonstrate that epinephrine-induced myocardial cellular damage is due to the direct effect of catecholamine stimulation acting on the beta-adrenergic receptor. The amount of left ventricular work appears to determine the extent of cellular damage. Physiological metabolites and the non-physiological metabolite, adrenochrome are not responsible for catecholamine-induced myocardial cellular damage. Epinephrine 10(-6) M caused a positive inotropic effect, whereas adrenochrome 10(-4) M induced contractile failure. Contractile failure was due to a negative inotropic effect and coronary artery vasoconstriction. Adrenochrome induces myocardial cellular damage and contractile failure but only in a concentration of 10(-4) M, this concentration does not appear to have pathophysiological relevance.

Action Potentials↗

Effects of adrenochrome on calcium accumulating and adenosine triphosphatase activities of the rat heart microsomes.

The influence of adrenochrome (1-100 microgram/ml or 5.6 x 10(-6)-5.4 x 10(-4) M) on microsomal calcium binding, calcium uptake and Ca++-stimulated Mg++-dependent adenosine triphosphatase (ATPase) activities was studied in vitro. Adrenochrome decreased microsomal calcium binding, calcium uptake and Ca++-stimulated Mg++-dependent ATPase activities. The inhibitory effect of adrenochrome on microsomal calcium uptake activity of the isolated membrane was independent of pH (6.0-8.0), calcium concentrations (10-200 muM), protein concentration (0.02-0.10 mg/ml), temperature (25-37 degrees C) and incubation time (2-30 min). Kinetic study of calcium uptake activity in different concentrations of ATP showed that the inhibition was of a mixed type. Perfusion of hearts with adrenochrome resulted in marked depression in contractile force and the microsomal fraction obtained from these hearts showed depressed calcium binding, calcium uptake and Ca++-stimulated Mg++-dependent ATPase activities. The depression in microsomal The influence of adrenochrome (1-100 microgram/ml or 5.6 x 10(-6)-an irreversible nature. It is proposed that cardiodepressant action of adrenochrome may partly be explained on the basis of its inhibitory effect on the calcium transporting ability of the sarcoplasmic reticulum.

Adrenochrome↗

Adrenochrome-induced coronary artery constriction in the rat heart.

Adrenochrome, an oxidation product of epinephrine, has been demonstrated to produce cardiotoxic effects. In this study, we have investigated whether this agent can alter coronary resistance in isolated rat hearts. Concentrations of adrenochrome from 1 to 1000 ng/ml increased coronary pressure in a dose- and time-dependent manner. The highest concentration produced a 3-fold elevation in pressure after a 1-hr perfusion. Myocardial contractile force decreased only with either 100 or 1000 ng/ml of adrenochrome and this effect was evident after substantial elevations in coronary pressure. The elevation in coronary pressure was significantly reduced by two calcium antagonists, verapamil and D-600. Furthermore, the degree of constriction by adrenochrome was dependent on the CaCl2 concentration in the perfusion medium. High concentrations of indomethacin or propranolol attenuated the degree of coronary pressure elevation, whereas acetylsalicylic acid and phenoxybenzamine were without effect. Sulfinpyrazone, which has been shown to reduce the arrhythmogenic action of adrenochrome in vivo, significantly reduced the coronary pressure increases. These results suggest that adrenochrome is a potent coronary constricting agent in the rat heart and its action is seemingly dependent on external Ca++ availability.

Adrenochrome↗

Modification of adrenochrome-induced cardiac contractile failure and cell damage by changes in cation concentrations.

Adrenochrome has been shown to produce cardiac necrosis as well as failure in the isolated rat hearts. These effects of adrenochrome were influenced by alterations in the Ca2+, Na+, K+, and Mg2+ concentrations of the perfusion medium. Increasing the Ca2+ or K+ concentration or decreasing the Na+ concentration of the adrenochrome-containing perfusion medium partially maintained contractile force but increased the severity of ultrastructural damage. Reducing the K+ concentration of the medium did not alter the failure of contractile force development but increased the severity of ultrastructural damage due to adrenochrome. Reducing the Ca2+ or increasing the Mg2+ concentration of the perfusion medium completely prevented myocardial necrosis due to adrenochrome. Omission of Mg2+ from the perfusion medium neither altered the time course of contractile failure nor effected the severity of necrosis due to adrenochrome. These results for the most part parallel the influence of similar ionic interventions on the severity of necrosis produced by excessive amount of catecholamines.

Adrenochrome↗

Involvement of carbonyl reductase in superoxide formation through redox cycling of adrenochrome and 9,10-phenanthrenequinone in pig heart.

The effects of adrenochrome, a metabolite of epinephrine (adrenaline), and 9,10-phenanthrenequinone (PQ), a component of diesel exhaust particles, on the stereoselective reduction of 4-benzoylpyridine (4-BP) were examined in pig heart cytosol. PQ was a potent inhibitor for the 4-BP reduction, while adrenochrome was a poor inhibitor. A similar result was observed in the effects of adrenochrome and PQ on the reduction of all-trans retinal. Furthermore, although PQ mediated efficiently the formation of superoxide anion radical through its redox cycling in pig heart cytosol, adrenochrome had no ability to mediate the superoxide formation. These may be because the reactivity for adrenochrome, catalyzed by pig heart carbonyl reductase (PHCR), is much lower than that for PQ. The optimal pH for the reduction of PQ in pig heart cytosol was around 5.5. Dicumarol, a potent inhibitor of DT-diaphorase, had little effect on the time course of NADPH oxidation during the reduction of PQ. Therefore, it is concluded that PHCR plays a critical role in superoxide formation through redox cycling of PQ.

Adrenochrome↗

Functional effects of adrenochrome in isolated rabbit heart.

The cardiotoxic effects of catecholamines have been explained in part by the generation of oxygen free radicals and aminochromes. The role of aminochromes remains however controversial. It has previously been demonstrated that adrenochrome, an oxidation product of adrenaline, shows cardiotoxic properties only at very high concentrations, and it has been suggested that the deleterious effects observed may be caused by a worsening in myocardial perfusion. The functional properties of adrenochrome were examined in isolated spontaneously-beating rabbit hearts with depleted catecholamine stores (reserpin 7.0 mg/kg 16-24 hr before preparation, Langendorff, constant pressure: 70 cm H2O, Tyrode solution, [Ca++]sol. 1.8 mmol/l, 37 degrees). Cumulative concentration-response curves show an adrenochrome-concentration-dependent increase of contractility (left ventricular pressure, EC50 = 3.6 x 10(-6) M; +dp/dtmax, EC50 = 1.6 x 10(-5) M), whereas myocardial relaxation was impaired (-dp/dtmax, EC50 = 2.6 x 10(-5) M; -dp/dtmax/+dp/dtmax = 0.68 at 10(-4) M). Heart-rate was only slightly enhanced (+10% at 10(-4) M), and the coronary flow was markedly influenced only by adrenochrome 10(-4) M (-17%). The relative coronary flow (= global coronary flow/pressure-rate product) was concentration-dependently reduced (EC50 = 10(-5) M; -49% at 10(-4) M). We conclude that in isolated rabbit hearts, adrenochrome has a positive inotropic action but impairs myocardial relaxation, and coronary constrictor activity prevents an increase of myocardial oxygen supply, thus worsening myocardial oxygen-demand/supply balance.

Adrenochrome↗

Effects of adrenochrome and epinephrine on human arterial endothelial cells in vitro.

The effects of adrenochrome and epinephrine were investigated in cultured human umbilical arterial endothelial cells. The cells were exposed to either adrenochrome or epinephrine at levels of 50 and 200 microM, respectively, up to 24 hrs. At 3, 5, 7 and 24 hrs of the designed harvesting time, [3H]thymidine incorporation, protein content, [3H]cholesterol uptake, prostacyclin production and lipid peroxidation were measured. We found that adrenochrome at a level of 200 microM inhibited [3H]thymidine incorporation, decreased protein content, stimulated [3H]cholesterol uptake, and decreased prostacyclin production after 3, 5, 24 and 5 hrs of exposure, respectively, compared with control. It took 24 hrs however for epinephrine at a level of 200 microM to inhibit [3H]thymidine incorporation and prostacyclin production. When the concentration was reduced to 50 microM, only adrenochrome inhibited [3H]thymidine incorporation after 24 hrs of treatment. Both adrenochrome and epinephrine had no effect on lipid peroxidation. We suggest that atherogenic changes found in severe hypertension may be due to abnormal high concentration of epinephrine, especially oxidized epinephrine, on endothelial cell functions, such as DNA synthesis, cholesterol uptake and prostacyclin production.

Adrenochrome↗

Synthesis and analysis of aminochromes by HPLC-photodiode array. Adrenochrome evaluation in rat blood.

The catecholamine oxidation process induces cardiotoxicity and neurotoxicity. Catecholamines can oxidize to aminochromes through autoxidation or by enzymatic or non-enzymatic catalysis. Although some toxic effects seem to be related to the formation of aminochromes there is still scarce information concerning the identification and evaluation of these compounds in in vivo models. In this study five catecholamines were oxidized to their respective aminochromes: adrenaline/adrenochrome; noradrenaline/noradrenochrome; dopa/dopachrome; dopamine/dopaminochrome; and isoproterenol/isoprenochrome. The evaluation of the catecholamines oxidation profile was performed by HPLC with photodiode array detection and using either enzymatic (tyrosinase) or non-enzymatic [Ag(2)O, CuSO(4), NaIO(4) and K(3)Fe(CN)(6)] catalytic systems. The NaIO(4) was found to be the most efficient oxidant of catecholamines. An isocratic reverse-phase HPLC method was developed to analyse each pair of catecholamine-aminochrome. The analytical system was then applied to the detection of adrenochrome in rat blood at 490 nm. Thus, adrenochrome was administered i.p. to rats and its concentration in whole blood was monitored after 5, 15 and 25 min. Blood treatment for adrenochrome evaluation consists of an acidification for protein precipitation followed by a rapid neutralization. The results showed a rapid decrease of adrenochrome concentration in blood after its administration. The adrenochrome present in blood was characterized by UV and tandem mass spectrometry.

Animals↗

Reduction and azo coupling of quinones. A histochemical study of human cutaneous melanin and adrenochrome.

Cutaneous melanin in formol fixed skin and adrenochrome in dichromate fixed monkey adrenal after adequate bisulfite or dithonite reduction were found to give definite azo coupling reactions. Weaker reactions were obtained on unreduced material, and these disappeared on ferric chloride oxidation. Both cutaneous melanin and adrenochrome appear to exist in a quinhydrone status. Prolongation of dichromate treatment weakens or abolishes azo coupling capacity of adrenochrome. The findings support the concept of quinonization and reduction to prevent and restore azo coupling of enterochromaffin cells and noradrenaline islets of the adrenal. The most effective diazos for melanin were p-nitrodiazobenzene, fast black K and the diazosulfanilic acid, pH 1 pyronin B procedure, for adrenochrome. Diazosafranin and 2-chloro-4-nitrodiazobenzene were also useful. Blue and violet coupling products from toluidine blue and methylene violet RR fail to yield sufficient contrast to be convincing.

Adrenal Glands↗

Involvement of superoxide radicals on adrenochrome formation stimulated by arachidonic acid in bovine heart sarcolemmal vesicles.

Highly purified sarcolemmal membranes prepared from bovine heart muscle produced superoxide radicals, especially when incubated with NADPH or NADH, as revealed by the oxidation of adrenaline to adrenochrome. The reaction was inhibited by superoxide dismutase or by heat denaturation of the sarcolemmal vesicles. Less evident was the inhibitory effect shown by catalase, while mannitol, deferoxamine or dicumarol were uneffective. The formation of adrenochrome was an oxygen-dependent reaction with a Km for adrenaline of 8-10 microM. Moreover, the reaction was inhibited by preincubating the sarcolemmal membranes with propranolol, while the alpha-antagonist phentolamine was without effect. Adrenaline oxidation was unaffected by the presence of exogenous linolenic acid or methylarachidonic acid, while arachidonic acid, with a Km for this reaction of 175 microM, showed a marked stimulatory effect. This activation was suppressed by superoxide dismutase, catalase and NaCN, while mannitol was without effect. Moreover, the reaction was blocked by the cyclooxygenase inhibitor indomethacin, differently from the lipooxygenase inhibitor nordihydroguaiaretic acid. Also, the incubation of the sarcolemmal vesicles with phospholipase A2 and calcium produced a stimulation of adrenochrome formation which was partially suppressed by albumin. In the experiments using arachidonic acid or phospholipase A2, the addition of indomethacin blocked the adrenaline oxidation. These results indicate that arachidonic acid accentuated the heart sarcolemmal adrenochrome formation presumably by participating in the cyclooxygenase reaction.

Adrenochrome↗

Differential action on cancer and normal tissue by adrenochrome monoaminoguanidine methanesulfonate and cytochrome C combined with radiotherapy.

PURPOSE: The possibility that radioprotective effects on potent natural killer (NK) cells by adrenochrome monoaminoguanidine methanesulfonate+cytochrome C during radiotherapy (RT) for lung cancer might result in the radiosensitization of human lung cancer cells in vivo is examined. METHODS AND MATERIALS: Human lung cancer xenografts in the right hind legs of KSN mice (10 weeks old) were locally irradiated with 20 Gy of X ray. Adrenochrome monoaminogluanidine methanesulfonate (AMM) (10 mg/kg/day) and/or cytochrome C (CCC) (5 mg/kg/day) were given intraperitoneally immediately before or after RT, followed by daily administration for 4 days. Natural killer activities of host splenocytes were also tested with the standard 51Cr releasing assay with YAC-1 cells as target cells. In a clinical study, 65 patients with lung cancer were treated with more than 50 Gy of RT with or without combination with AMM+CCC, OK-432 or AMM+CCC+OK-432. Before and after RT, lymphocyte subsets in the peripheral blood were examined with dichromatic analysis using an Ortho Spectrum IIIFCM system and fluorescent MABs. In this study, the change in the absolute number of each subset was investigated. RESULTS: Adrenochrome monoaminoguanidine methanesulfonate+cytochrome C augumented NK activity in KSN nude mice, protected potent NK cells in patients with lung cancer against RT and sensitized the human lung cancer xenografts to RT. CONCLUSION: Adrenochrome monoaminoguanidine methanesulfonate+cytochrome C may have the potential as a differential modulator of radiosensitivity of normal tissues and of tumors.

Adrenochrome↗

The adrenochrome pathway: the major route for adrenalin catabolism by polymorphonuclear leucocytes.

Oxygen radical production by polymorphonuclear leucocytes stimulated the oxidation of adrenalin through the adrenochrome pathway. This was detected either spectrophotometrically at 480 nm or separated by hplc and detected radiochemically. The oxidation was detectable within 5 min and continued for at least 4 h. Over the adrenalin concentration range 0.3 microM to 10 mM more than 80% of the oxidation that occurred was through the adrenochrome pathway, the remainder being through the amine oxidase, catechol methyl transferase pathway. Medium isolated after stimulation of the polymorphonuclear leucocytes was also able to oxidise adrenalin to adrenochrome. The results provide a cellular mechanism for the formation of adrenochrome and the other metabolites on this pathway of adrenalin metabolism, in inflammatory conditions where polymorphonuclear leucocyte infiltration occurs.

Adrenochrome↗

A new look at the rearrangement of adrenochrome under biomimetic conditions.

At physiological pH values, the rearrangement of adrenochrome leads, besides adrenolutin, to a major dimeric compound consisting of an adrenolutin moiety covalently linked to the angular 9-position of adrenochrome. When the reaction is carried out in air, the initially generated adrenolutin undergoes autoxidation to give 5,6-dihydroxy-1-methyl-isatin (DHMIs), which is smoothly oxidized to the 4,4'-dimer. Under an oxygen-depleted atmosphere, formation of these latter compounds is prevented, and the rearrangement of adrenochrome leads mainly to the adrenochrome dimer (about 50% yield) along with adrenolutin and 5,6-dihydroxy-1-methylindole (DHMI) in about 10% yield each. The product distribution is markedly dependent on the concentration of the aminochrome undergoing rearrangement, the nature of the buffer system used, and the pH of the medium. Heavy metal ions of common occurrence in biological systems, such as Cu2+, Zn2+, Co2+, significantly direct the reaction course towards the formation of adrenolutin, while Fe2+ and other cations with low redox potentials induce the almost exclusive formation of DHMI.

Adrenochrome↗

The adrenochrome hypothesis of schizophrenia revisited.

This paper reviews the current status of the adrenochrome theory of schizophrenia. An account is first given of all the experiments in which adrenochrome was reported to induce psychotomimetic effects in normal volunteers. Then the evidence is presented that adrenochrome may actually occur in the brain as a metabolite of adrenaline in the C2 group of adrenergic neurons in the medulla, together with an account of current ideas of the function of these neurons in higher limbic functions. Lastly the recent evidence is reviewed that the gene for the enzyme glutathione S-transferase is defective in schizophrenia. This enzyme detoxifies adrenochrome.

Journal Article↗

Protective effect of sulfinpyrazone against catecholamine metabolite adrenochrome-induced arrhythmias.

Single intravenous injection of adrenochrome (10 to 50 mg/kg body weight), an oxidation product of catecholamines, has been shown to induce arrhythmias and cause death in anesthetized rats in a dose-dependent manner. Sulfinpyrazone, which is an inhibitor of platelet aggregation, was found to protect animals from these adrenochrome effects. It is suggested that sudden death due to arrhythmias in patients following the first attack of myocardial infarction of during other stressful situations may be linked to the formation of adrenochrome from abnormally high catecholamine levels in blood. Furthermore, results presented here also suggest that the reduction in the mortality rate of patients on sulfinpyrazone therapy may involve an antiarrhythmic property of the drug.

Adrenochrome↗

Reduction of adrenochrome by rat liver and brain DT-diaphorase.

Liver and brain exhibit DT-diaphorase activity with adrenochrome as a substrate; the latter is an o-quinone derived from the autoxidation of adrenaline exhibiting neurotoxic and cardiotoxic properties. The reaction is strongly inhibited by dicoumarol, a classical inhibitor of DT-diaphorase. DT-diaphorase-reduced adrenochrome undergoes autoxidation as shown by the oxygen uptake occurring during the reaction. It is proposed that, physiologically, DT-diaphorase might exert a protective role by maintaining adrenochrome in its reduced, non-toxic form.

Adrenochrome↗