Loop diuretics decrease the renal elimination rate and increase the plasma levels of trimethylamine-N-oxide.

AIMS: Trimethylamine-N-oxide (TMAO) is a novel cardiovascular risk marker. We explored the association of commonly used cardiovascular medications with TMAO levels in patients and validated the identified associations in mice. METHODS: Detailed history of drug treatment was recorded in 300 patients with cardiovascular disease without diabetes in an observational, cross-sectional study. Animal study was performed in CD1 mice. RESULTS: Median plasma TMAO (interquartile range) level was 2.144 (1.570-3.104) µmol l-1 . Among nine cardiovascular drug groups, the use of loop diuretics (0.510 ± 0.296 in users vs. 0.336 ± 0.272 in nonusers, P = 0.008) and mineralocorticoid receptor antagonists (0.482 ± 0.293 in users vs. 0.334 ± 0.272 in nonusers, P = 0.007) was associated with increased log-TMAO. Acute concomitant administration of furosemide or torasemide with TMAO in mice significantly influenced TMAO pharmacokinetic profile and almost doubled the plasma TMAO area under the curve. Furosemide decreased the TMAO excretion rate by 1.9-fold during the first 30 min after administration and increased TMAO concentrations in kidney, heart and liver, suggesting the interaction of furosemide and TMAO with efflux transporters. The concentrations of TMAO in blood plasma after the administration of the organic anion transporter inhibitor probenecid were not different from those of the control group, suggesting an effect not mediated by organic anion transporters. CONCLUSIONS: Loop diuretics increased plasma TMAO concentration by decreasing its urinary excretion rate. Loop diuretic use should be considered a potential confounder in TMAO studies.

Inhibition of L-carnitine biosynthesis and transport by methyl-γ-butyrobetaine decreases fatty acid oxidation and protects against myocardial infarction.

BACKGROUND AND PURPOSE: The important pathological consequences of ischaemic heart disease arise from the detrimental effects of the accumulation of long-chain acylcarnitines in the case of acute ischaemia-reperfusion. The aim of this study is to test whether decreasing the L-carnitine content represents an effective strategy to decrease accumulation of long-chain acylcarnitines and to reduce fatty acid oxidation in order to protect the heart against acute ischaemia-reperfusion injury. KEY RESULTS: In this study, we used a novel compound, 4-[ethyl(dimethyl)ammonio]butanoate (Methyl-GBB), which inhibits γ-butyrobetaine dioxygenase (IC50 3 µM) and organic cation transporter 2 (OCTN2, IC50 3 µM), and, in turn, decreases levels of L-carnitine and acylcarnitines in heart tissue. Methyl-GBB reduced both mitochondrial and peroxisomal palmitate oxidation rates by 44 and 53% respectively. In isolated hearts treated with Methyl-GBB, uptake and oxidation rates of labelled palmitate were decreased by 40%, while glucose oxidation was increased twofold. Methyl-GBB (5 or 20 mg·kg(-1)) decreased the infarct size by 45-48%. In vivo pretreatment with Methyl-GBB (20 mg·kg(-1)) attenuated the infarct size by 45% and improved 24 h survival of rats by 20-30%. CONCLUSIONS AND IMPLICATIONS: Reduction of L-carnitine and long-chain acylcarnitine content by the inhibition of OCTN2 represents an effective strategy to protect the heart against ischaemia-reperfusion-induced damage. Methyl-GBB treatment exerted cardioprotective effects and increased survival by limiting long-chain fatty acid oxidation and facilitating glucose metabolism.

Cardioprotective effects of N-hydroxyguanidine PR5 in myocardial ischaemia and reperfusion in rats.

1. The potential for the N-hydroxyguanidine compound PR5 (N-(3, 4-dimethoxy-2-chlorobenzylideneamino)-N'-hydroxyguanidine) as a cardioprotective agent in heart ischaemia and reperfusion injury was investigated using rat models. 2. Administration of 1-10 mg kg-1 of PR5 5 min before 10 min of left coronary artery occlusion, followed by 20 min reperfusion, strongly inhibited reperfusion burst of arrhythmias and markedly improved the survival of the animals (e.g. ventricular fibrillation incidence 93 vs 43% (P<0.05); mortality 47 vs 0% (P<0.05), for controls and for 3 mg kg-1 of PR5, respectively). 3. Administration of 3 mg kg-1 of PR5 1 min before reperfusion to rats subjected to 10 min occlusion, 20 min reperfusion was most effective in reducing arrhythmias and decreasing mortality (43 vs 0%, P<0.05), but effects were also seen when PR5 was administered 0, 1 and 5 min after start of reperfusion. 4. Coronary occlusion/reperfusion (10 - 20 min) increased malondialdehyde (MDA) of rat hearts (0.88+/-0.13 for sham vs 1.45+/-0.12 nmol mg-1 protein for ischaemic; P<0.05). In rats where 3 mg kg-1 PR5 were administered 1 min before reperfusion the increase was attenuated (MDA being 1.04+/-0.12; P<0.05 vs ischaemic). 5. PR5 caused a substantial reduction of the infarction size in rats subjected to 180 min left coronary artery occlusion, followed by 120 min of reperfusion; the necrotic zone being 326+/-32 mg for controls vs 137+/-21 mg for animals treated with 3x3 mg kg-1 of PR5 (P<0.01). 6. PR5 reduced the elevation of the ST-segment of the ECGs, as well as caused pronounced attenuation of the rapid blood pressure drop seen at the start of reperfusion following coronary artery occlusion. 7 We conclude that the N-hydroxyguanidine PR5 provides remarkable protection against ischaemia and reperfusion induced myocardial necrosis and life-threatening arrhythmias. These effects of PR5 are discussed in relation to a recently discovered ability of N-hydroxyguanidines to function as electron acceptors at the xanthine oxidase enzyme.