Sensitivity of [11C]phenylephrine kinetics to monoamine oxidase activity in normal human heart.
Phenylephrine labeled with 11C was developed as a radiotracer for imaging studies of cardiac sympathetic nerves with PET. A structural analog of norepinephrine, (-)-[11C]phenylephrine (PHEN) is transported into cardiac sympathetic nerve varicosities by the neuronal norepinephrine transporter and stored in vesicles. PHEN is also a substrate for monoamine oxidase (MAO). The goal of this study was to assess the importance of neuronal MAO activity on the kinetics of PHEN in the normal human heart. MAO metabolism of PHEN was inhibited at the tracer level by substituting deuterium atoms for the two hydrogen atoms at the alpha-carbon side chain position to yield the MAO-resistant analog D2-PHEN. METHODS: Paired PET studies of PHEN and D2-PHEN were performed in six normal volunteers. Hemodynamic and electrocardiographic responses were monitored. Blood levels of intact radiotracer and radiolabeled metabolites were measured in venous samples taken during the 60 min dynamic PET study. Myocardial retention of the tracers was regionally quantified as a retention index. Tracer efflux between 6 and 50 min after tracer injection was fit to a single exponential process to obtain a washout half-time for all left ventricular regions. RESULTS: Although initial heart uptake of the two tracers was similar, D2-PHEN cleared from the heart 2.6 times more slowly than PHEN (mean half-time 155+/-52 versus 55+/-10 min, respectively; P < 0.01). Correspondingly, heart retention of D2-PHEN at 40-60 min after tracer injection was higher than PHEN (mean retention indices 0.086+/-0.018 versus 0.066+/-0.011 mL blood/ min/mL tissue, respectively; P < 0.003). CONCLUSION: Efflux of radioactivity from normal human heart after uptake of PHEN is primarily due to metabolism of the tracer by neuronal MAO. Related mechanistic studies in the isolated rat heart indicate that vesicular storage of PHEN protects the tracer from rapid metabolism by neuronal MAO, suggesting that MAO metabolism of PHEN leaking from storage vesicles leads to the gradual loss of PHEN from the neurons. Thus, although MAO metabolism influences the rate of clearance of PHEN from the neurons, MAO metabolism is not the rate-determining step in the observed efflux rate under normal conditions. Rather, the rate at which PHEN leaks from storage vesicles is likely to be the rate-limiting step in the observed efflux rate. (+info)
Influence of vesicular storage and monoamine oxidase activity on [11C]phenylephrine kinetics: studies in isolated rat heart.
[11C]Phenylephrine (PHEN) is a radiolabeled analogue of norepinephrine that is transported into cardiac sympathetic nerve varicosities by the neuronal norepinephrine transporter and taken up into storage vesicles localized within the nerve varicosities by the vesicular monoamine transporter. PHEN is structurally related to two previously developed sympathetic nerve markers: [11C]-meta-hydroxyephedrine and [11C]epinephrine. To better characterize the neuronal handling of PHEN, particularly its sensitivity to neuronal monoamine oxidase (MAO) activity, kinetic studies in an isolated working rat heart system were performed. METHODS: Radiotracer was administered to the isolated working heart as a 10-min constant infusion followed by a 110-min washout period. Two distinctly different approaches were used to assess the sensitivity of the kinetics of PHEN to MAO activity. In the first approach, oxidation of PHEN by MAO was inhibited at the enzymatic level with the MAO inhibitor pargyline. In the second approach, the two hydrogen atoms on the a-carbon of the side chain of PHEN were replaced with deuterium atoms ([11C](-)-alpha-alpha-dideutero-phenylephrine [D2-PHEN]) to inhibit MAO activity at the tracer level. The importance of vesicular uptake on the kinetics of PHEN and D2-PHEN was assessed by inhibiting vesicular monoamine transporter-mediated storage into vesicles with reserpine. RESULTS: Under control conditions, PHEN initially accumulated into the heart at a rate of 0.72+/-0.15 mL/min/g wet. Inhibition of MAO activity with either pargyline or di-deuterium substitution did not significantly alter this rate. However, MAO inhibition did significantly slow the clearance of radioactivity from the heart during the washout phase of the study. Blocking vesicular uptake with reserpine reduced the initial uptake rates of PHEN and D2-PHEN, as well as greatly accelerated the clearance of radioactivity from the heart during washout. CONCLUSION: These studies indicate that PHEN kinetics are sensitive to neuronal MAO activity. Under normal conditions, efficient vesicular storage of PHEN serves to protect the tracer from rapid metabolism by neuronal MAO. However, it is likely that leakage of PHEN from the storage vesicles and subsequent metabolism by MAO lead to an appreciable clearance of radioactivity from the heart. (+info)
Inhibition of monoamine oxidase type A, but not type B, is an effective means of inducing anticonvulsant activity in the kindling model of epilepsy.
The anticonvulsant activity of inhibitors of monoamine oxidase (MAO) was reported early after the development of irreversible MAO inhibitors such as tranylcypromine, but was never clinically used because of the adverse effects of these compounds. The more recently developed reversible MAO inhibitors with selectivity for either the MAO-A or MAO-B isoenzyme forms have not been studied extensively in animal models of epilepsy, so it is not known which type of MAO inhibitor is particularly effective in this respect. We compared the following drugs in the kindling model of epilepsy: 1) L-deprenyl (selegiline), i.e., an irreversible inhibitor of MAO-B, which, however, also inhibits MAO-A at higher doses, 2) the novel reversible MAO-B inhibitor LU 53439 (3,4-dimethyl-7-(2-isopropyl-1,3, 4-thiadiazol-5-yl)-methoxy-coumarin), which is much more selective for MAO-B than L-deprenyl, 3) the novel reversible and highly selective MAO-A inhibitor LU 43839 (esuprone; 7-hydroxy-3, 4-dimethylcoumarin ethanesulfonate), and 4) the irreversible nonselective MAO inhibitor tranylcypromine. Esuprone proved to be an effective anticonvulsant in the kindling model with a similar potency as L-deprenyl. In contrast to esuprone and L-deprenyl, the selective MAO-B inhibitor LU 53439 was not effective in the kindling model; this substantiates the previous notion that the anticonvulsant activity of L-deprenyl is not related to MAO-B inhibition, but to other effects of this drug, such as inhibition of MAO-A. Drugs inhibiting both MAO-A and MAO-B to a similar extent (tranylcypromine) or combinations of selective MAO-A and MAO-B inhibitors (esuprone plus LU 53439) had no advantage over MAO-A inhibition alone, but were less well tolerated. The data thus suggest that selective MAO-A inhibitors such as esuprone may be an interesting new approach for the treatment of epilepsy. (+info)
Meta-analysis of the reversible inhibitors of monoamine oxidase type A moclobemide and brofaromine for the treatment of depression.
The reversible inhibitors of monoamine oxidase type A (RIMAs) are a newer group of antidepressants that have had much less impact on clinical psychopharmacology than another contemporary class of medications, the selective serotonin reuptake-inhibitors (SSRIs). The RIMAs agents are distinguished from the older monoamine oxidase inhibitors (MAOIs) by their selectivity and reversibility. As a result, dietary restrictions are not required during RIMA therapy, and hypertensive crises are quite rare. In this article, we describe a series of meta-analyses of studies of the two most widely researched RIMAs, moclobemide (MOC; Aurorex) and brofaromine (BRO). Our findings confirm that both BRO and MOC are as effective as the tricyclic antidepressants, and they are better tolerated. However, BRO is not being studied at present for reasons unrelated to efficacy or side effects. MOC, which is available throughout much of the world (but not the United States), is significantly more effective than placebo and, at the least, comparable to the SSRIs in both efficacy and tolerability. For MOC, higher dosages may enhance efficacy for more severe depressions. We also found evidence that supports clinical impressions that MOC is somewhat less effective, albeit better tolerated, than older MAOIs, such as phenelzine or tranylcypromine. Little evidence has yet emerged to suggest that the RIMAs share older MAOIs' utility for treatment of depressions characterized by prominent reverse neurovegetative features. Based on available evidence, the RIMAs appear to have a limited, but useful, role in the differential therapeutics of the depressive disorders. (+info)
Excess of high activity monoamine oxidase A gene promoter alleles in female patients with panic disorder.
A genetic contribution to the pathogenesis of panic disorder has been demonstrated by clinical genetic studies. Molecular genetic studies have focused on candidate genes suggested by the molecular mechanisms implied in the action of drugs utilized for therapy or in challenge tests. One class of drugs effective in the treatment of panic disorder is represented by monoamine oxidase A inhibitors. Therefore, the monoamine oxidase A gene on chromosome X is a prime candidate gene. In the present study we investigated a novel repeat polymorphism in the promoter of the monoamine oxidase A gene for association with panic disorder in two independent samples (German sample, n = 80; Italian sample, n = 129). Two alleles (3 and 4 repeats) were most common and constituted >97% of the observed alleles. Functional characterization in a luciferase assay demonstrated that the longer alleles (3a, 4 and 5) were more active than allele 3. Among females of both the German and the Italian samples of panic disorder patients (combined, n = 209) the longer alleles (3a, 4 and 5) were significantly more frequent than among females of the corresponding control samples (combined, n = 190, chi2 = 10.27, df = 1, P = 0.001). Together with the observation that inhibition of monoamine oxidase A is clinically effective in the treatment of panic disorder these findings suggest that increased monoamine oxidase A activity is a risk factor for panic disorder in female patients. (+info)
Schizophrenia, monoamine oxidase activity, and cigarette smoking.
Reduced monoamine oxidase activity has been proposed as a marker for vulnerability to schizophrenia. Reduced monamine oxidase activity has also been shown to occur in cigarette smokers. This study compared monamine oxidase activity level in a matched group of patients with schizophrenia who smoked with a group who did not. Lower levels of monoamine oxidase activity were found in the smokers and this is the likely explanation for the low levels hypothesized as a marker for schizophrenia. (+info)
Cerebral cortical blood flow maps are reorganized in MAOB-deficient mice.
Cerebral cortical blood flow (CBF) was measured autoradiographically in conscious mice without the monoamine oxidase B (MAOB) gene (KO, n=11) and the corresponding wild-type animals (WILD, n=11). Subgroups of animals of each genotype received a continuous intravenous infusion over 30 min of phenylethylamine (PEA), an endogenous substrate of MAOB, (8 nmol g-1 min-1 in normal saline at a volume rate of 0.11 microl g-1 min-1) or saline at the same volume rate. Maps of relative CBF distribution showed predominance of midline motor and sensory area CBF in KO mice over WILD mice that received saline. PEA enhanced CBF in lateral frontal and piriform cortex in both KO and WILD mice. These changes may reflect a differential activation due to chronic and acute PEA elevations on motor and olfactory function, as well as on the anxiogenic effects of this amine. In addition to its effects on regional CBF distribution, PEA decreased CBF globally in KO mice (range -31% to -41% decrease from control levels) with a lesser effect in WILD mice. It is concluded that MAOB may normally regulate CBF distribution and its response to blood PEA. (+info)
Monoamine oxidase: from genes to behavior.
Cloning of MAO (monoamine oxidase) A and B has demonstrated unequivocally that these enzymes are made up of different polypeptides, and our understanding of MAO structure, regulation, and function has been significantly advanced by studies using their cDNA. MAO A and B genes are located on the X-chromosome (Xp11.23) and comprise 15 exons with identical intron-exon organization, which suggests that they are derived from the same ancestral gene. MAO A and B knock-out mice exhibit distinct differences in neurotransmitter metabolism and behavior. MAO A knock-out mice have elevated brain levels of serotonin, norephinephrine, and dopamine and manifest aggressive behavior similar to human males with a deletion of MAO A. In contrast, MAO B knock-out mice do not exhibit aggression and only levels of phenylethylamine are increased. Mice lacking MAO B are resistant to the Parkinsongenic neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetra-hydropyridine. Both MAO A and B knock-out mice show increased reactivity to stress. These knock-out mice are valuable models for investigating the role of monoamines in psychoses and neurodegenerative and stress-related disorders. (+info)