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The lack of reliable measures of alcohol intake is a major obstacle to the diagnosis and treatment of alcohol-related diseases. Epigenetic modifications such as DNA methylation may provide novel biomarkers of alcohol use. To examine this possibility, we performed an epigenome-wide association study of methylation of cytosine-phosphate-guanine dinucleotide (CpG) sites in relation to alcohol intake in 13 population-based cohorts (ntotal=13 317; 54% women; mean age across cohorts 42–76 years) using whole blood (9643 European and 2423 African ancestries) or monocyte-derived DNA (588 European, 263 African and 400 Hispanic ancestry) samples. We performed meta-analysis and variable selection in whole-blood samples of people of European ancestry (n=6926) and identified 144 CpGs that provided substantial discrimination (area under the curve=0.90–0.99) for current heavy alcohol intake (⩾42 g per day in men and ⩾28 g per day in women) in four replication cohorts. The ancestry-stratified meta-analysis in whole blood identified 328 (9643 European ancestry samples) and 165 (2423 African ancestry samples) alcohol-related CpGs at Bonferroni-adjusted P<1 × 10−7. Analysis of the monocyte-derived DNA (n=1251) identified 62 alcohol-related CpGs at P<1 × 10-7. In whole-blood samples of people of European ancestry, we detected differential methylation in two neurotransmitter receptor genes, the γ-Aminobutyric acid-A receptor delta and γ-aminobutyric acid B receptor subunit 1; their differential methylation was associated with expression levels of a number of genes involved in immune function. In conclusion, we have identified a robust alcohol-related DNA methylation signature and shown the potential utility of DNA methylation as a clinically useful diagnostic test to detect current heavy alcohol consumption.

Callipeltin A, a cyclic depsipeptide from the New Caledonian Lithistida sponge Callipelta sp., is a macrocyclic lactone containing four amino acids in the L configuration, Ala, Leu, Thr (2 residues); one (Arg) in the D configuration; two N-methyl amino acids, N-MeAla and N-MeGln; a methoxy tyrosine, a 3,4-dimethyl-l-glutamine; and a 4-amino-7-guanidino-2,3 dihydroxypentanoic acid (AGDHE), formally derived from L-Arg. In cardiac sarcolemmal vesicles Callipeltin A induces a powerful (IC50 = 0.85 μM) and selective inhibition of the Na+/Ca2+ exchanger. In electrically driven guinea-pig atria, at concentrations ranging between 0.7 and 2.5 μM, Callipeltin A induces a positive inotropic effect, which at the highest concentrations is accompanied by a rise in resting tension. It is suggested that the positive inotropic effect is linked to the inhibition of the Na+/Ca2+ exchanger and that Callipeltin A may be an useful tool to study the role of the cardiac Na+/Ca2+ exchanger in physiological and pathological conditions.

The effect of amiloride on Na⁺/Ca²⁺ exchange activity and adenylate energy charge in isolated rat cardiac myocytes has been studied. Amiloride inhibits Na⁺/Ca²⁺ exchange activity in rat cardiac myocytes with an IC₅₀ of 1.76 mM when added to the external side of the cell membrane, whereas it is a weaker inhibitor when present at the cytoplasmic side. The adenylate energy charge in rat cardiac myocytes is unaffected by amiloride. Copyright 1993, 1999 Academic Press

The enrichment in phosphatidylinositol 4-phosphate and phosphatidylinositoI 4-5-bisphosphate of cardiac sarcolemmal vesicles stimulate Na+/Ca2+exchange activity. On the contrary the deacylation products of polyphosphoinositides are powerful inhibitors of Na+/Ca2+exchange: half maximal inhibition of 1.6 and 2.1 μM have been observed for glycerophosphoinositol 4-phosphate and glycerophosphoinositol 4-5-bisphosphate, respectively. The data indicate a bidirectional regulation of Na+/Ca2+exchanger and suggest that phosphorylated glycerophosphoinositoIs can be regarded as novel signal transducers of intracellular Ca2+regulation in heart cell.