Trimethylamine-<i>N</i>-oxide acutely increases cardiac muscle contractility

Oakley, Carlee I.; Vallejo, Julian; Wang, Derek; Gray, Mark; Tiede-Lewis, LeAnn M.; Shawgo, Tilitha; Daon, Emmanuel; Zorn, George L.; Stubbs, Jason R.; Wacker, Michael

doi:10.1152/ajpheart.00507.2019

Cited by 18 publications

(13 citation statements)

References 70 publications

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“…However, other work indicates that 0•3-3 μM TMAO disrupts T-tubule organisation and Ca 2þ handling in isolated murine cardiomyocytes (49) , suggesting a curious scenario in which concentrations more than 10-fold lower than circulating levels in healthy mice (10) are significantly damaging. Distinct from these studies, recent work supports modest positive inotropic effects of TMAO when applied at extremely high (0•3-3 mM) levels (50) . Further work is needed to clarify the cardiac functional influences of relevant concentrations of TMAO.…”

Section: Myocardial Dysfunctionmentioning

confidence: 87%

TrimethylamineN-oxide: heart of the microbiota–CVD nexus?

et al. 2020

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We critically review potential involvement of trimethylamine-N-oxide (TMAO) as a link between diet, the gut microbiota and cardiovascular disease (CVD). Generated primarily from dietary choline and carnitine by gut bacteria and hepatic flavin monooxygenase (FMO) activity, TMAO could promote cardiometabolic disease when chronically elevated. However, control of circulating TMAO is poorly understood, and diet, age, body mass, sex hormones, renal clearance, FMO3 expression and genetic background may explain as little as 25% of TMAO variance. The basis of elevations with obesity, diabetes, atherosclerosis or coronary heart disease (CHD) is similarly ill-defined, although gut microbiota profiles/remodelling appear critical. Elevated TMAO could promote CVD via inflammation, oxidative stress, scavenger receptor (SR) up-regulation, reverse cholesterol transport (RCT) inhibition, and cardiovascular dysfunction. However, concentrations influencing inflammation, SRs and RCT (≥100 µM) are only achieved in advanced heart failure (HF) or chronic kidney disease (CKD), and greatly exceed pathogenicity of <1-5 µM levels implied in some TMAO-CVD associations. There is also evidence CVD risk is insensitive to TMAO variance beyond these levels in omnivores and vegetarians, and that major TMAO sources are cardioprotective. Assessing available evidence suggests modest elevations in TMAO (≤10 µM) are a non-pathogenic consequence of diverse risk factors (aging, obesity, dyslipidaemia, insulin-resistance/diabetes, renal dysfunction), indirectly reflecting CVD risk without participating mechanistically. Nonetheless, TMAO may surpass a pathogenic threshold as a consequence of CVD/CKD, secondarily promoting disease progression. TMAO might thus reflect early CVD risk while providing a prognostic biomarker or secondary target in established disease, although mechanistic contributions to CVD await confirmation.

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Section: Myocardial Dysfunctionmentioning

confidence: 87%

TrimethylamineN-oxide: heart of the microbiota–CVD nexus?

et al. 2020

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“…39) TMA, the precursor of TMAO, is also known to be a full agonist at human G-protein coupled trace amin-associated receptor 5 (TAAR5) that does not recognize TMAO. 40) Recently, in rat isolated aortic rings TMAO has been shown to have a receptor-independent direct contractile effect that could be modulated by perivascular adipose tissue and endothelium, the mechanism of which remains to be solved. 16) Similarly, TMAO increases cardiac contractility by modulating intracellular calcium levels in human and mice cardiac tissues ex vivo.…”

Section: Discussionmentioning

confidence: 99%

Trimethylamine-<i>N</i>-oxide (TMAO) Selectively Disrupts Endothelium-Dependent Hyperpolarization-Type Relaxations in a Time-Dependent Manner in Rat Superior Mesenteric Artery

Hamad

Ozkan

Shanmugasundaram

2021

Biological & Pharmaceutical Bulletin

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The vascular action of trimethylamine-N-oxide (TMAO)-the gut microbiota-derived metabolite-in contributing cardiovascular disease is a controversial topic. A recent study has shown that acute exposure of TMAO at moderate concentrations inhibits endothelium-dependent hyperpolarization (EDH)-type relaxations selectively in rat isolated femoral arteries, but not in mesenteric arteries. Here we determined the efficacy of higher TMAO concentrations with longer exposure times on vascular reactivity in rat isolated superior mesenteric arteries. Acetylcholine-induced EDH-type relaxations were examined before and after incubation with TMAO (0.1-10 mM) at increasing exposure times (1-24 h). One-and 4-h-incubations with TMAO at 0.1-3 mM did not cause any change in EDH-type relaxations. However, when the incubation time was increased to 24 h, responses to acetylcholine were reduced in arteries incubated with 1-3 mM TMAO. In addition, at higher TMAO concentration (10 mM) the decrease in EDH relaxations could be detected both in 4-h-and 24-h-incubations. The EDH-relaxations were preserved in rings incubated with 10 mM TMAO for 24 h in the presence of SKA-31 (10 µM), the small (SKCa)-and intermediate (IKCa)-conductance calciumactivated potassium channel activator. Contractile responses to phenylephrine increased in arteries exposed to 10 mM TMAO for 24 h. Interestingly, nitric oxide (NO)-mediated relaxations remained unchanged in arteries treated for 24 h at any TMAO concentration. Our study revealed that TMAO selectively disrupted EDH-type relaxations time-dependently without interfering with NO-induced vasodilation in rat isolated mesenteric arteries. Disruption of these relaxations may help explain the causal role of elevated TMAO levels in certain vascular diseases.

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“…As shown in Figure 1, since its first use for optical mapping in 2007, blebbistatin has all but replaced the other available EC uncouplers. In fact, in the last three years alone, blebbistatin was used twice as often (1,29,36,41,51,56,59,69,74,76,78,83,85,87) as any other uncoupler for imaging applications (25,27,33,46,54,55,80). The use of BDM/DAM and CytoD for optical mapping has essentially ceased, yet due to its lower cost, BDM/DAM may still be a reasonable choice for larger animal (i.e., non-rodent) studies (10,23,25,35,52,70,77), which require larger amounts of an EC uncoupler (72).…”

Section: Excitation-contraction Uncouplingmentioning

confidence: 99%

Stop the beat to see the rhythm: excitation-contraction uncoupling in cardiac research

Swift

Kay

Ripplinger

et al. 2021

American Journal of Physiology-Heart and Circulatory Physiology

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Optical mapping is an imaging technique that is extensively used in cardiovascular research, wherein parameter-sensitive fluorescent indicators are used to study the electrophysiology and excitation-contraction coupling of cardiac tissues. Despite the many benefits of optical mapping, eliminating motion artifacts within the optical signals is a major challenge, as myocardial contraction interferes with the faithful acquisition of action potentials and intracellular calcium transients. As such, excitation-contraction uncoupling agents are frequently used to reduce signal distortion by suppressing contraction. Compared to other uncoupling agents, blebbistatin is the most frequently used as it offers increased potency with minimal direct effects on cardiac electrophysiology. Nevertheless, blebbistatin may exert secondary effects on electrical activity, metabolism, and coronary flow, and the incorrect administration of blebbistatin to cardiac tissue can prove detrimental, resulting in erroneous interpretation of optical mapping results. In this "Getting It Right" perspective, we briefly review the literature regarding the use of blebbistatin in cardiac optical mapping experiments, highlight potential secondary effects of blebbistatin on cardiac electrical activity and metabolic demand, and conclude with the consensus of the authors on best practices for effectively using blebbistatin in optical mapping studies of cardiac tissue.

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Trimethylamine-N-oxide acutely increases cardiac muscle contractility

Cited by 18 publications

References 70 publications

TrimethylamineN-oxide: heart of the microbiota–CVD nexus?

TrimethylamineN-oxide: heart of the microbiota–CVD nexus?

Trimethylamine-<i>N</i>-oxide (TMAO) Selectively Disrupts Endothelium-Dependent Hyperpolarization-Type Relaxations in a Time-Dependent Manner in Rat Superior Mesenteric Artery

Stop the beat to see the rhythm: excitation-contraction uncoupling in cardiac research

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