Metabolite Of Epinephrine Research Articles

SAT284 Is Stress Vulnerability In CAH Related To Epinephrine Deficiency And CYP21A2 Genotype?

Abstract Disclosure: A. Nordenstrom: None. K. Ekbom: None. R. Said: None. A. Strandqvist: None. H. Lönnberg: None. M. Lindberg: None. N. Bertman: None. A.L. Hirschberg: None. H. Falhammar: None. A. Rickenlund: None. Introduction: Primary adrenal insufficiency due to CYP21A2 deficiency results in epinephrine deficiency.The lack of a sufficient increase in epinephrine during high intensity exercise has been described, and increased hydrocortisone doses cannot compensate and normalize glucose response. Clinically patients with CAH seem vulnerable to stress. A possible role of epinephrine deficiency for stress vulnerability has not been studied previously. Research question: Do patients with CAH show increased stress sensitivity, depression and anxiety compared to healthy controls? Is stress sensitivity related to the severity of CAH, e.g. CYP21A2 genotype? Can vulnerability to different types of stress be correlated to the individual’s capacity to produce epinephrine? Methodology: 26 patients, aged 18-52 years, (13 F, 13 M) and 14 sex-matched controls. Plasma metanephrines (metabolites of catecholamines) were measured at start and at the peak of physical exertion on a maximum work test using ergometer cycle. All participants answered validated questionnaires regarding perceived stress (PSS), depression and anxiety (HADS), signs of fatigue syndrome (KEDS).Plasma metanephrine (metabolite of epinephrine) was correlated to CYP21A2 genotype. The results of the psychological questionnaires were correlated to the metanephrine levels and to the CYP21A2 genotype. Results: Patients with CAH had lower metanephrine levels than controls and it was related to CYP21A2 genotype. The few included patients with null genotype had virtually no metanephrin and lower levels than individuals with I2G genotype which has not been shown before.The patients scored higher on anxiety and stress and for risk of fatigue syndromed than controls. However, the men with null genotype did not report increased anxiety and depression compared to controls. Men with I2G genotype had lower scores than I172N genotype.There was a clear sex difference in that women had higher scores than men and women with severe genotypes, null and I2G, had more signs of depression and anxiety. There were no differences for perceived stress. Interpretation/Conclusions: Over all the results for the patients on the questionnaires showed a similar pattern with increasing signs of stress vulnerability with milder genotype and increasing, but deficient, metanephrine levels. An interesting finding was that a total epinephrine deficiency, as in null genotype, with less somatic effects of stress (increased heart rate etc), may be beneficial for some aspects of perceived stress tolerance. However, it may put these patients at increased risk of fatigue or burn out syndrome. The psychological effects of the virilization due to CAH per se may partly overshadow the effects of the epinephrine deficiency in women with CAH. Larger studies are needed to be able to study what role the capacity to produce epinephrine, has for the psychological stress vulnerability in CAH. Presentation: Saturday, June 17, 2023

Central GABAA receptor mediates taurine-induced hypothermia and possibly reduces food intake in thermo-neutral chicks and regulates plasma metabolites in heat-exposed chicks.

The aim of this study was to examine the central action of taurine on body temperature and food intake in neonatal chicks under control thermoneutral temperature (CT) and high ambient temperature (HT). Intracerebroventricular injection of taurine caused dose-dependent hypothermia and reduced food intake under CT. The mRNA expression of the GABAA receptors, GABAAR-α1 and GABAAR-γ, but not that of GABABR, significantly decreased in the diencephalon after central injection of taurine. Subsequently, we found that picrotoxin, a GABAAR antagonist, attenuated taurine-induced hypothermia. Central taurine significantly decreased the brain concentrations of 3-methoxy-4-hydroxyphenylglycol, a major metabolite of norepinephrine; however, the concentrations of serotonin, dopamine, and the epinephrine metabolites, 3,4-hydroxyindoleacetic acid and homovanillic acid, were unchanged. Although hypothermia was not observed under HT after central injection of taurine, plasma glucose and uric acid levels were higher, and plasma sodium and calcium levels were lower, than those in chicks under CT. In conclusion, brain taurine may play a role in regulating body temperature and food intake in chicks through GABAAR. The changes in plasma metabolites under heat stress suggest that brain taurine may play an important role in maintaining homeostasis in chicks.

Effect suppresive therapy with levothyroxine on the state of the cardiovascular and sympathoadrenal systems

Thyroid hormones can affect the cardiovascular system directly by binding to nuclear thyroid receptors, as well as indirectly by changing the neuro – humoral status of the body as a whole. The aim of the work was to assess the effect of levothyroxine suppressive therapy on the regulation of the heart rate and activity of the sympathoadrenal system, as well as the level of cortisol in the blood of young patients with thyroid cancer. It is shown that the effect of suppressive therapy with levothyroxine on the state of the cardiovascular system is manifested in an increase in the risk of tachycardia and changes in heart rate variability associated with the body mass index. Patients with thyroid cancer had a sharp decrease in normetanephrine (norepinephrine metabolite) in the urine. The levels of metanephrine (metabolite of adrenaline) and dopamine in the urine was dependent on the tonus of the autonomic nervous system and blood pressure. The revealed shifts indicate that against the background of subclinical hyperthyroidism, the mechanisms aimed at stabilizing the heart rate and preventing the effects of hyperstimulation of thyroid and beta-adrenoreceptors of the myocardium are included.

Morphology, Biochemistry, and Pathophysiology of MENX-Related Pheochromocytoma Recapitulate the Clinical Features.

Pheochromocytomas (PCCs) are tumors arising from neural crest-derived chromaffin cells. There are currently few animal models of PCC that recapitulate the key features of human tumors. Because such models may be useful for investigations of molecular pathomechanisms and development of novel therapeutic interventions, we characterized a spontaneous animal model (multiple endocrine neoplasia [MENX] rats) that develops endogenous PCCs with complete penetrance. Urine was longitudinally collected from wild-type (wt) and MENX-affected (mutant) rats and outputs of catecholamines and their O-methylated metabolites determined by mass spectrometry. Adrenal catecholamine contents, cellular ultrastructure, and expression of phenylethanolamine N-methyltransferase, which converts norepinephrine to epinephrine, were also determined in wt and mutant rats. Blood pressure was longitudinally measured and end-organ pathology assessed. Compared with wt rats, mutant animals showed age-dependent increases in urinary outputs of norepinephrine (P = .0079) and normetanephrine (P = .0014) that correlated in time with development of tumor nodules, increases in blood pressure, and development of hypertension-related end-organ pathology. Development of tumor nodules, which lacked expression of N-methyltransferase, occurred on a background of adrenal medullary morphological and biochemical changes occurring as early as 1 month of age and involving increased adrenal medullary concentrations of dense cored vesicles, tissue contents of both norepinephrine and epinephrine, and urinary outputs of metanephrine, the metabolite of epinephrine. Taken together, MENX-affected rats share several biochemical and pathophysiological features with PCC patients. This model thus provides a suitable platform to study the pathogenesis of PCC for preclinical translational studies aimed at the development of novel therapies for aggressive forms of human tumors.

Social instability and immunity in rhesus monkeys: the role of the sympathetic nervous system

Social instability can adversely affect endocrine, immune and health outcomes, and recent evidence suggests that the sympathetic nervous system (SNS) might mediate these effects. We conducted two studies with adult male rhesus monkeys (Macaca mulatta) to understand how social conditions affect measures of SNS activity and immune function. In Experiment 1, animals were socialized in stable social conditions, then were switched to unstable (stressful) social conditions, then were returned to stable conditions. Analysis revealed quadratic effects for measures of behaviour, urinary metabolites of epinephrine and norepinephrine, and expression of immune response genes: as expected, social instability adversely impacted most measures, and the effects remediated upon re-imposition of stable conditions. Cortisol levels were unaffected. In Experiment 2, we used the sympathomimetic drug methamphetamine to challenge the SNS; animals also underwent socialization in stable or unstable groups. Surprisingly, while methamphetamine elevated plasma catecholamines, responses in lymph nodes tracked the social, and not the drug, condition: social instability upregulated the density of SNS fibres in lymph nodes and downregulated Type I interferon gene expression. Together, these results indicate that the SNS is extremely sensitive to social conditions; full understanding of the adverse effects of social instability on health should therefore incorporate measures of this health-relevant system.

24-h Urinary Vanillylmandelic Acid (VMA) is not a Sensitive Pa-rameter to Identify Acute or Chronic Stress Generated by High Intensity Exercise in Animal Model

Vanillylmandelic acid (VMA) is the main urinary end-stage metabolite of epinephrine and norepinephrine. Its con- centration can be elevated in some cases of cancer, but also after other stress stimuli. The aim of the study was to investigate the effect of high intensity physical training (HIPT) and acute exercise on urinary VMA concentration and metabolic aspects related to glucose metabolism in animal model. Wistar rats underwent four sets of 10 jumps/day supporting a load equivalent to 50% of body weight, in a water tank for six weeks. A control group was kept in sedentary condition during the same period of time. After six weeks, sedentary and trained animals underwent an exercise session with the same characteristics of HIPT. Acute high intensity effort did not change 24-hour urinary VMA concentration in both trained and untrained rats. Both groups increased glycaemia and lactacidaemia while serum insulin reduced. Acute exercise elevated free fatty acid concentration and decreased gastrocnemius muscle glycogen content in sedentary animals. It was concluded that high intensity physical training and acute exercise interfere on glucose metabolism profile without change 24-h VMA.

Genetic Screening for von Hippel-Lindau Gene Mutations in Non-syndromic Pheochromocytoma: Low Prevalence and False-positives or Misdiagnosis Indicate a Need for Caution

Genetic testing of tumor susceptibility genes is now recommended in most patients with pheochromocytoma or paraganglioma (PPGL), even in the absence of a syndromic presentation. Once a mutation is diagnosed there is rarely follow-up validation to assess the possibility of misdiagnosis. This study prospectively examined the prevalence of von Hippel-Lindau (VHL) gene mutations among 182 patients with non-syndromic PPGLs. Follow-up in positive cases included comparisons of biochemical and tumor gene expression data in 64 established VHL patients, with confirmatory genetic testing in cases with an atypical presentation. VHL mutations were detected by certified laboratory testing in 3 of the 182 patients with non-syndromic PPGLs. Two of the 3 had an unusual presentation of diffuse peritoneal metastases and substantial increases in plasma metanephrine, the metabolite of epinephrine. Tumor gene expression profiles in these 2 patients also differed markedly from those associated with established VHL syndrome. One patient was diagnosed with a partial deletion by Southern blot analysis and the other with a splice site mutation. Quantitative polymerase chain reaction, multiplex ligation-dependent probe amplification, and comparative genomic hybridization failed to confirm the partial deletion indicated by certified laboratory testing. Analysis of tumor DNA in the other patient with a splice site alteration indicated no loss of heterozygosity or second hit point mutation. In conclusion, VHL germline mutations represent a minor cause of non-syndromic PPGLs and misdiagnoses can occur. Caution should therefore be exercised in interpreting positive genetic test results as the cause of disease in patients with non-syndromic PPGLs.

Age at Diagnosis of Pheochromocytoma Differs According to Catecholamine Phenotype and Tumor Location

Pheochromocytomas and paragangliomas (PPGLs) are diagnosed earlier in patients with hereditary than sporadic disease. Whether other factors influence age at diagnosis is unclear. We examined ages at which PPGLs were diagnosed according to different catecholamine phenotypes and locations of tumors. Retrospective multicenter study. Patients with PPGLs included 172 with and 183 without identified germline mutations or hereditary syndromes. BIOCHEMICAL MEASUREMENTS: Differences in plasma concentrations of metanephrine, a metabolite of epinephrine, were used to distinguish epinephrine-producing tumors from those lacking epinephrine production. Patients with epinephrine-producing tumors were diagnosed 11 yr later (P < 0.001) than those with tumors lacking appreciable epinephrine production. Among patients without evidence of a hereditary condition, those with and without epinephrine-producing tumors had respective mean ± se ages of 50 ± 2 and 42 ± 2 yr (P < 0.001) at diagnosis. Patients with multiple endocrine neoplasia type 2 and neurofibromatosis type 1, all with epinephrine-producing tumors, were similarly diagnosed with disease at a later age than patients with tumors that lacked appreciable epinephrine production secondary to mutations of von Hippel-Lindau and succinate dehydrogenase genes (40 ± 2 vs. 31 ± 1 yr, P < 0.001). Among the latter patients, those with multifocal tumors were diagnosed earlier than those with solitary tumors (19 ± 3 vs. 34 ± 2 yr, P < 0.001). The variations in ages at diagnosis associated with different tumor catecholamine phenotypes and locations suggest origins of PPGLs from different chromaffin progenitor cells with variable susceptibility to disease causing mutations. Different optimal age cut-offs for mutation testing are indicated for patients with and without epinephrine-producing tumors (44-49 vs. 30-35 yr, respectively).

Photoentrainment in blind and sighted rodent species: responses to photophase light with different wavelengths

Our study examined the impact of daylight (photophase) wavelength on the photoentrainment sensitivity of two species with vastly different visual systems. Social voles (Microtus socialis) and 'blind' mole rats (Spalax ehrenbergi) were exposed to short-wavelength (479 nm) or long-wavelength (697 nm) light at an intensity of 293 μW cm(-2). Rhythms of urine production, urinary 6-sulfatoxymelatonin (6-SMT), urinary metabolites of adrenaline and cortisol, and oxygen consumption (VO(2)) were used as markers for the sensitivity of the photoentrainment system. Significant 24-h rhythms were detected in all variables for both species under short-wavelength light, whereas ultradian rhythms of 12- or 8-h were detected under long-wavelength light. Wavelength inversely affected 6-SMT levels in M. socialis (negative correlation) and S. ehrenbergi (positive correlation). Increased levels of stress hormone metabolites were detected in M. socialis under the long-wavelength light whereas, in S. ehrenbergi elevated levels were secreted under short-wavelength light. Long-wavelength light increased VO(2) in M. socialis and decreased it in S. ehrenbergi; short-wavelength light elicited the opposite effects. Our results indicate that photophase wavelength is an integral light property for modulating photoperiodic responses in mammals, including visually challenged species. Finally, the spectral-induced differential responses between the two species potentially represent adaptive physiological flexibility in species with contrasting visual and habitat challenges.

A small molecule that mimics the metabolic activity of copper-containing amine oxidases (CuAOs) toward physiological mono- and polyamines

Primary aliphatic biogenic amines have been successfully oxidized using a quinonoid species that mimics the metabolic activity of copper-containing amine oxidase (CuAO) enzymes. Especially, high catalytic performances were observed with aminoacetone, a threonine catabolite, and methylamine, a metabolite of adrenaline, and with the primary amino groups of putrescine and spermidine which are both decarboxylation products of ornithine and S-adenosyl-methionine. Furthermore, contrary to flavine adenine dinucleotide (FAD)-dependent amine oxidase enzymes, no activity was found toward secondary and tertiary amines.

Comparison of influence of aerobic exercise, in water walking and yogic exercise, on 3-methoxy –4-hydroxy phenyl glycol-sulfate in depressed girls

Depression is a clinical disorder distinguished by physiological and psychological markers. Some studies have indicated that during depression some neural chemical transmitters including epinephrine are reduced. It seems that these chemical changes can cause depression symptoms. 3-metoxy-hydroxyphenyl glycol-sulphate (MHPG) is a metabolite of epinephrine that released from presynaptic nerve terminals of central nervous system and became sulphate in brain. It cross the blood-brain barrier and showed as a sulphate combination in urine. The propose of this proposal, was to determine the effect of 8 weeks of aerobic exercise, walking in water and yogic exercise on urine MHPG sulphate in the depressed girls.

Fast analysis of catecholamine metabolites MHPG and VMA in human plasma by HPLC with fluorescence detection and a novel SPE procedure

A fast and sensitive high-performance liquid chromatographic method has been developed for the determination in human plasma of MHPG (3-methoxy-4-hydroxyphenylethylenglycol) and VMA (vanillyl mandelic acid), the main metabolites of epinephrine and norepinephrine. Analyses were carried out at 325 nm while exciting at 285 nm on a reversed-phase column (Atlantis C18, 150 mm × 4.6 mm I.D., 5 μm) using a mobile phase composed of 2% methanol and 98% aqueous citrate buffer at pH 3.0. A careful solid-phase extraction procedure, based on mixed-mode reversed-phase – strong anion exchange Oasis cartridges (MAX, 30 mg, 1 mL), was developed for the pre-treatment of plasma samples. Extraction yields were satisfactory, always higher than 90%. Calibration curves were linear over the 0.2–40.0 ng mL −1 concentration range for MHPG and over the 0.5–40.0 ng mL −1 concentration range for VMA. The method was successfully applied to plasma samples of former drug users undergoing detoxification therapy and subjects “at risk” of developing drug addiction.

Sympathoadrenal function in patients with paroxysmal hypertension: pseudopheochromocytoma

The causes of paroxysmal hypertension in patients in whom pheochromocytoma has been excluded ('pseudopheochromocytoma') usually remain unclear. Blood pressure disturbances and symptoms of catecholamine excess in these patients may reflect activation of the sympathetic nervous and adrenal medullary systems. We therefore examined sympathoadrenal function in patients with pseudopheochromocytoma compared with age-matched control subjects in whom there was no suspicion of pheochromocytoma. Plasma catecholamines and hemodynamics were examined in response to intravenous glucagon, yohimbine, and trimethaphan in 11 patients with pseudopheochromocytoma and a comparison group of nine normotensive and five hypertensive volunteers. Adrenomedullary function was also assessed by abdominal F-fluorodopamine positron emission tomography and measurements of plasma metanephrine, the O-methylated metabolite of epinephrine. Compared with controls, patients with pseudopheochromocytoma had normal plasma concentrations of norepinephrine, but 120% higher (P < 0.05) baseline plasma concentrations of epinephrine, 80% higher (P < 0.01) baseline plasma concentrations of metanephrine, and sixfold larger (P < 0.05) increases in plasma epinephrine after glucagon. Adrenal 18F-fluorodopamine-derived radioactivity did not differ between groups. Compared with changes in plasma norepinephrine, falls in blood pressure after trimethaphan were 13-fold larger (P < 0.005) and increases in blood pressure after yohimbine were threefold larger (P < 0.01) in pseudopheochromocytoma patients than in controls. Patients with pseudopheochromocytoma exhibit a pattern of normal sympathetic noradrenergic outflow, adrenomedullary activation, and augmented blood pressure responses to changes in the sympathoneural release of norepinephrine.

Pseudopheochromocytoma

Pseudopheochromocytoma

Sympathoadrenal function in patients with paroxysmal hypertension

The cause of paroxysmal hypertension in patients in who pheochromocytoma has been excluded (“pseudopheochromocytoma”) usually remains a mystery. We hypothesized that sympathoadrenal activation would explain these blood pressure (BP) disturbances. Plasma catecholamines and hemodynamics were examined in response to i.v. glucagon, isoproterenol, yohimbine, and trimethaphan in 8 patients with pseudopheochromocytoma and a comparison group of 9 normotensives and hypertensives. Adrenal medullary function was further examined by 18F-fluorodopamine positron emission tomography and measurements of plasma metanephrine, a metabolite of epinephrine produced within the adrenals. Patients with pseudopheochromocytoma had greater increases in BP after yohimbine and greater falls in BP in response to trimethaphan than controls. Exaggerated BP responses were associated with smaller changes in plasma norepinephrine. Heart rate responses to isoproterenol were also exaggerated. Patients had larger glucagon-induced increases in plasma epinephrine and a tendency to elevated baseline plasma levels of epinephrine, metanephrine, and cortisol compared to controls. Prominent adrenal uptake of 18F-fluorodopamine in some patients was consistent with adrenal medullary enlargement. In conclusion, increased release of norepinephrine by sympathetic nerves does not appear to contribute to the BP disturbances in most patients with pseudopheochromocytoma. Increased functional activity of the adrenal medulla and exaggerated adrenoceptor-mediated cardiovascular responses appear more likely causes of the paroxysmal hypertension.

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.

The use of plasma metanephrine to normetanephrine ratio to determine epinephrine poisoning

Background Intravenous epinephrine (EPI) is used as a pharmacologic agent to acutely treat patients in cardiac arrest. Unfortunately, there have been several homicide cases where hospitalized patients died due to a purposeful overdose of epinephrine. We measured plasma epinephrine metabolites (metanephrine, MET, and normetanephrine, NMET) to determine if exogenous epinephrine can be distinguished from endogenous epinephrine concentrations in a controlled animal study. Methods Rabbits were subjected to three different protocols. In the physiologic stress group ( n=8), rabbits were immobilized for 30 min in a restraining tube. In the sub-lethal dose ( n=9), 0.01 mg/kg of epinephrine was injected into anesthetized rabbits. In the lethal dose group ( n=8), 1.0 mg/kg of epinephrine was administered into anesthetized rabbits. Blood was collected at regular intervals for up to 480 min. The plasma metanephrine and normetanephrine concentrations were measured by liquid chromatography/mass spectrometry and the serum cortisol concentrations by immunoassay. Results Serum cortisol and plasma metanephrine and normetanephrine concentrations increased in the stressed animals during immobilization demonstrating the endogenous stress model. Following a sub-therapeutic epinephrine dose, plasma metanephrine increased while plasma normetanephrine decreased. The peak plasma metanephrine concentrations were similar to the concentrations observed in the stressed animals; however, the ratio of plasma metanephrine to normetanephrine was significantly different. In the lethal epinephrine dose, both the plasma metanephrine concentrations and ratio of metabolites were significantly greater than those observed in the endogenously stressed animals. Conclusions The ratio of plasma metanephrine to normetanephrine is the best marker to determine the presence of exogenous therapeutic and lethal epinephrine administration. However, there were limitations to the study design that could alter these conclusions.

Dubin-Johnson-like black liver with normal bilirubin level

Black liver is a common finding in Dubin-Johnson syndrome (DJS), which is caused by the lack of multidrug resistance-associated protein 2 (MRP2). Impaired excretion of epinephrine metabolites is believed to be a cause of black liver in DJS. Recently, we experienced a patient with black liver whose serum bilirubin level was normal. Coarse brown granules were observed in the hepatocytes, and this finding closely resembled that observed in DJS. However, the granules were negative for Schmorl staining. The MRP2 gene did not show any mutation. Immunostaining study demonstrated MRP2 protein expression in the liver, and it was localized in the canalicular membranes of hepatocytes. This case illustrates for the first time that DJS is not the only cause of black liver.

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.

Ascorbic acid inhibits spinal meningeal catechol-o-methyl transferase in vitro, markedly increasing epinephrine bioavailability.

The spinal menings have previously been shown to contain catechol-o-methyl transferase (COMT), the enzyme that metabolizes epinephrine to the inactive metabolite metanephrine. The authors of this study aimed to quantitate the metabolism of epinephrine traversing the spinal meninges and to determine if that metabolism could be inhibited. In addition, they tried to determine the meningeal permeability of epinephrine. Macca nemestrina spinal meninges were mounted in a diffusion cell and epinephrine was added to the donor reservoir at time 0. Three hundred minutes later, all buffer in the recipient reservoir was collected and analyzed for epinephrine metabolites. The experiments were conducted with either ascorbic acid (1 mM) or sodium metabisulfite (5.3 mM) added as antioxidants. In the presence of sodium metabisulfite, 60 +/- 6% of the epinephrine traversing the meningeal specimens was metabolized by COMT. In contrast, in the presence of ascorbic acid, less than 3% of the epinephrine traversing the spinal meninges was metabolized by COMT (P = 0.0001). The meningeal permeability coefficient for epinephrine was 0.38 +/- 0.08 cm/min x 10(-3). Epinephrine permeability through the spinal meninges is low, and meningeal COMT markedly reduces the bioavailability of what little epinephrine can traverse the meninges. However, a clinically relevant concentration of ascorbic acid, a competitive inhibitor of COMT, almost completely blocks epinephrine metabolism and increases the bioavailability of epinephrine.