Heart rate dynamics in monoamine  oxidase-A- and -B-deficient mice

Holschneider, Daniel P.; Scremin, Oscar U.; Chialvo, Dante R.; Chen, Kevin; Shih, Jean C.

doi:10.1152/ajpheart.00600.2001

Cited by 16 publications

(14 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This phenomenon has been examined in detail in MAO A-and MAO B-deficient mice, which have a phenotype characterized by elevated tissue levels of norepinephrine, serotonin, and dopamine, as well as PEA (33), and show a greater baroreceptor-mediated reduction in heart rate in response to drug-induced hypertension. This result suggests that prevention of hypertension in chronic states of catecholaminergic͞indoleaminergic excess induced by MAO deficiency may be mediated by increased gain of the baroref lex.…”

Section: Discussionmentioning

confidence: 99%

Low monoamine oxidase B in peripheral organs in smokers

Fowler

Logan

Wang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

One of the major mechanisms for terminating the actions of catecholamines and vasoactive dietary amines is oxidation by monoamine oxidase (MAO). Smokers have been shown to have reduced levels of brain MAO, leading to speculation that MAO inhibition by tobacco smoke may underlie some of the behavioral and epidemiological features of smoking. Because smoking exposes peripheral organs as well as the brain to MAO-inhibitory compounds, we questioned whether smokers would also have reduced MAO levels in peripheral organs. Here we compared MAO B in peripheral organs in nonsmokers and smokers by using positron emission tomography and serial scans with the MAO B-specific radiotracers,L-[ 11 C]deprenyl and deuterium-substituted L-[ 11 C]deprenyl (L-[ 11 C]deprenyl-D2). Binding specificity was assessed by using the deuterium isotope effect. We found that smokers have significantly reduced MAO B in peripheral organs, particularly in the heart, lungs, and kidneys, when compared with nonsmokers. Reductions ranged from 33% to 46%. Because MAO B breaks down catecholamines and other physiologically active amines, including those released by nicotine, its inhibition may alter sympathetic tone as well as central neurotransmitter activity, which could contribute to the medical consequences of smoking. In addition, although most of the emphases on the carcinogenic properties of smoke have been placed on the lungs and the upper airways, this finding highlights the fact that multiple organs in the body are also exposed to pharmacologically significant quantities of chemical compounds in tobacco smoke. S moking is a major public health problem affecting multiple organ systems and resulting in Ϸ440,000 deaths per year in the United States alone (1). Yet, we still know very little about the molecular mechanisms underlying smoking behavior and toxicity. In addition, even though tobacco smoke contains Ϸ4,000 chemical compounds, pharmacological studies have focused mainly on nicotine (2). We have shown that smokers have reduced levels of brain monoamine oxidase (MAO; EC 1.4.3.4) and that this is not an effect of nicotine (3-5). MAO oxidizes amines and produces hydrogen peroxide as a byproduct. It is present in virtually every organ in the body and occurs in two different subtypes, MAO A and MAO B, which are different gene products. MAO A and B have different substrate and inhibitor specificities (6). MAO A preferentially oxidizes norepinephrine and serotonin and is selectively inhibited by clorgyline (7), whereas MAO B preferentially breaks down benzylamine and phenylethylamine (PEA), and is selectively inhibited by L-deprenyl (8). Both forms oxidize dopamine and tyramine (9). The relative ratios of MAO A and B in different organs are both organ-and species-dependent, making it difficult to use animals as a model for humans (10).Because MAO is one of the phase I oxidative enzymes (11), and its substrates include many physiologically active amines, including some of those released by nicotine, the documentation of reduced brain MAO B levels ...

show abstract

Section: Discussionmentioning

confidence: 99%

Low monoamine oxidase B in peripheral organs in smokers

Fowler

Logan

Wang

et al. 2003

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

show abstract

“…Home Cage Locomotor Activity-MAO A/B KO mice (n ϭ 8, age ϭ 16.8 Ϯ 0.4 weeks) and WT mice (n ϭ 11, age ϭ 16.5 Ϯ 0.3 weeks) received an intraperitoneal radiotransmitter implant (model TA10ETA-F20, Datasciences International) using methods reported previously (34). Beginning 2 weeks postsurgery, locomotor activity was recorded in the home cage of the animal in 10 s segments every 3 min over 7 days.…”

Section: Methodsmentioning

confidence: 99%

A Spontaneous Point Mutation Produces Monoamine Oxidase A/B Knock-out Mice with Greatly Elevated Monoamines and Anxiety-like Behavior

Chen

Holschneider

et al. 2004

Journal of Biological Chemistry

133

126

View full text Add to dashboard Cite

A spontaneous monoamine oxidase A (MAO A) mutation (A863T) in exon 8 introduced a premature stop codon, which produced MAO A/B double knock-out (KO) mice in a MAO B KO mouse colony. This mutation caused a nonsense-mediated mRNA decay and resulted in the absence of MAO A transcript, protein, and catalytic activity and abrogates a DraI restriction site. The MAO A/B KO mice showed reduced body weight compared with wild type mice. Brain levels of serotonin, norepinephrine, dopamine, and phenylethylamine increased, and serotonin metabolite 5-hydroxyindoleacetic acid levels decreased, to a much greater degree than in either MAO A or B single KO mice. Observed chase/ escape and anxiety-like behavior in the MAO A/B KO mice, different from MAO A or B single KO mice, suggest that varying monoamine levels result in both a unique biochemical and behavioral phenotype. These mice will be useful models for studying the molecular basis of disorders associated with abnormal monoamine neurotransmitters. (21), indicating that the increase in 5-HT, a preferred substrate for MAO A, and concomitant decrease in 5-HIAA may form the basis for increased aggression, consistent with the association of low 5-HIAA levels in the cerebrospinal fluid of men who exhibit aggressive behavior (22,23). Although increased aggressive behavior has not been observed in MAO B KO mice (21), low platelet MAO B activity in humans is associated with, and considered a marker for, criminal or impulsive behavior (24), although whether this is accompanied in human subjects by a concomitant decrease in MAO A activity or other related genetic or biochemical aberration is not known.MAO A/B KO mice cannot be generated through the breeding of MAO A KO and MAO B KO mice, due to the close proximity of the isoenzyme genes on the X chromosomes, where the two genes are next to each other at their 3Ј tails, organized in opposite orientations with their last exons being less than 24 kb apart (determined by blat analysis of human and mouse MAO A and B

show abstract

“…One of the two telemetric leads, the cathode, was threaded subcutaneously to the right thoracic wall and sutured to the thoracic muscles. The other electrode, the anode, was stitched in place on the broadest back muscle near the left fl ank incision [11,26] .…”

Section: Telemetry and Implant Preparation Surgerymentioning

confidence: 99%

“…Using this approach, autonomic nervous dysfunctions have been successfully evaluated in genetically altered mouse models. These include mice overexpressing atrial ␤ 1 -adrenoreceptors [7] , transgenic mice with cardiac-specifi c Gs ␣ overexpression [9] , GIRK4 knockout mice [10] , mice lacking monoamine oxidase-A/B [11] , mice lacking ␤ 1 -and/or ␤ 2 -adrenergic receptor subtypes [8] , nNOS-defi cient mice [12] and others.…”

mentioning

confidence: 99%

Involvement of Voltage-Dependent Ca<sup>2+</sup> Channel β<sub>3</sub> Subunit in the Autonomic Control of Heart Rate Variability

Wu¹,

Ono²,

Murakami³

et al. 2006

Pharmacology

View full text Add to dashboard Cite

Noradrenaline release from sympathetic nerve terminals is dependent on Ca²⁺ entry through neuronal voltage-gated N-type Ca²⁺ channels. The accessory β₃ subunits of Ca²⁺ channels (Ca_Vβ₃) are preferentially associated with the α_1B subunit to form N-type Ca²⁺ channels, and are therefore expected to play a functional role in the stimulation-evoked release of noradrenaline. In this study, we employed Ca_Vβ₃-null, Ca_Vβ₃-overexpressing (Ca_Vβ₃-Tg), and wild-type (WT) mice to investigate the possible roles of Ca_Vβ₃ in the sympathetic regulation of heart rate in vivo. Telemetry was used to monitor the ECG and both time and frequency domain analyses were carried out to evaluate heart rate variability. In the frequency domain analysis, power spectral density of the RR interval series was computed using the fast Fourier transform algorithm. The resting heart rate was increased in Ca_Vβ₃-Tg mice compared with both Ca_Vβ₃-null and WT mice. Mice overexpressing Ca_Vβ₃ displayed decreased heart rate variability, which was measured by the time domain analysis of the standard deviation of RR intervals. In the frequency domain analysis, Ca_Vβ₃-Tg mice showed decreased spectral powers compared with WT and Ca_Vβ₃-null mice. Pharmacological blockade of β-adrenergic receptors with metoprolol decreased the heart rate in all genotypes, but the extent of the decrease was most obvious in Ca_Vβ₃-Tg mice. On the other hand, the spectral powers were decreased in response to parasympathetic blockade (atropine) in WT and Ca_Vβ₃-Tg mice. These results indicate the functional roles of Ca_Vβ₃ in regulating sympathetic nerve signaling.

show abstract

Heart rate dynamics in monoamine oxidase-A- and -B-deficient mice

Cited by 16 publications

References 34 publications

Low monoamine oxidase B in peripheral organs in smokers

Low monoamine oxidase B in peripheral organs in smokers

A Spontaneous Point Mutation Produces Monoamine Oxidase A/B Knock-out Mice with Greatly Elevated Monoamines and Anxiety-like Behavior

Involvement of Voltage-Dependent Ca<sup>2+</sup> Channel β<sub>3</sub> Subunit in the Autonomic Control of Heart Rate Variability

Contact Info

Product

Resources

About