Regular intake of polyphenol-rich food has been associated with a wide variety of beneficial health effects, including the prevention of cardiovascular diseases. However, the parent flavonoids have mostly low bioavailability and, hence, their metabolites have been hypothesized to be bioactive. One of these metabolites, 3-hydroxyphenylacetic acid (3-HPAA), formed by the gut microbiota, was previously reported to exert vasorelaxant effects ex vivo. The aim of this study was to shed more light on this effect in vivo, and to elucidate the mechanism of action. 3-HPAA gave rise to a dose-dependent decrease in arterial blood pressure when administered i.v. both as a bolus and infusion to spontaneously hypertensive rats. In contrast, no significant changes in heart rate were observed. In ex vivo experiments, where porcine hearts from a slaughterhouse were used to decrease the need for laboratory animals, 3-HPAA relaxed precontracted porcine coronary artery segments via a mechanism partially dependent on endothelium integrity. This relaxation was significantly impaired after endothelial nitric oxide synthase inhibition. In contrast, the blockade of SKCa or IKCa channels, or muscarinic receptors, did not affect 3-HPAA relaxation. Similarly, no effects of 3-HPAA on cyclooxygenase nor L-type calcium channels were observed. Thus, 3-HPAA decreases blood pressure in vivo via vessel relaxation, and this mechanism might be based on the release of nitric oxide by the endothelial layer.

Bisphenols, endocrine disrupting chemicals, have frequently been used for producing food packaging materials. The best-known member, bisphenol A (BPA), has been linked to impaired foetal development in animals. Possible negative effects of BPA on human health have resulted in the production of novel, so-called next-generation (NextGen) bisphenols whose effects on humans are much less explored or even missing. This review aimed to summarise and critically assess the main findings and shortages in current bisphenol research in relation to their potential impact on the cardiovascular system in real biological exposure. Because of the common presence of bisphenols in daily use products, humans are clearly exposed to these compounds. Most data are available on BPA, where total serum levels (i.e. included conjugated metabolite) can reach up to ∼430 nM, while free bisphenol levels have been reported up to ∼80 nM. Limited data are available for other bisphenols, but maximal serum levels of bisphenol S have been reported (680 nM). Such levels seem to be negligible, although in vitro studies have showed effects on ion channels, and thyroid, oestrogenic and androgenic receptors in low micromolar concentrations. Ex vivo studies suggest vasodilatory effects of bisphenols. This stays in clear contrast to the elevation of arterial blood pressure documented in vivo and in observatory cross-sectional human studies. Bisphenols are also claimed to have a negative effect on lipidic spectrum and coronary artery disease. Regardless, the reported data are generally inconsistent and unsatisfactory. Hence novel well-designed studies, testing in particular NextGen bisphenols, are needed.

Sudden unexpected death in epilepsy (SUDEP) is a fatal complication experienced by otherwise healthy epilepsy patients. Dravet syndrome (DS) is an inherited epileptic disorder resulting from loss of function of the voltage-gated sodium channel, Na_V 1.1, and is associated with particularly high SUDEP risk. Evidence is mounting that Na_Vs abundant in the brain also occur in the heart, suggesting that the very molecular mechanisms underlying epilepsy could also precipitate cardiac arrhythmias and sudden death. Despite marked reduction of Na_V 1.1 functional expression in DS, pathogenic late sodium current (I_Na,L) is paradoxically increased in DS hearts. However, the mechanisms by which DS directly impacts the heart to promote sudden death remain unclear. In this study, the authors sought to provide evidence implicating remodeling of Na⁺ - and Ca²⁺ -handling machinery, including Na_V 1.6 and Na⁺/Ca²⁺exchanger (NCX) within transverse (T)-tubules in DS-associated arrhythmias. The authors undertook scanning ion conductance microscopy (SICM)-guided patch clamp, super-resolution microscopy, confocal Ca²⁺ imaging, and in vivo electrocardiography studies in Scn1a haploinsufficient murine model of DS. DS promotes I_Na,L in T-tubular nanodomains, but not in other subcellular regions. Consistent with increased Na_V activity in these regions, super-resolution microscopy revealed increased Na_V 1.6 density near Ca²⁺release channels, the ryanodine receptors (RyR2) and NCX in DS relative to WT hearts. The resulting I_Na,L in these regions promoted aberrant Ca²⁺ release, leading to ventricular arrhythmias in vivo. Cardiac-specific deletion of Na_V 1.6 protects adult DS mice from increased T-tubular late Na_V activity and the resulting arrhythmias, as well as sudden death. These data demonstrate that Na_V 1.6 undergoes remodeling within T-tubules of adult DS hearts serving as a substrate for Ca²⁺ -mediated cardiac arrhythmias and may be a druggable target for the prevention of SUDEP in adult DS subjects.

Both pyridine and pyrano derivatives have been previously shown to possess biologically relevant activity. In this study, we report the incorporation of these two scaffolds into one molecule. The designed 3,3-dimethyl-6-oxopyrano[3,4-c]pyridines were synthesized by the acylation of enamine under Stork conditions followed by condensation of formed β-diketones with 2-cyanoacetamide. The structures of these compounds were confirmed by using a wide spectrum of physico-chemical methods. Their antiplatelet, anticoagulant and vasodilatory activity together with toxicity were evaluated. A series of 6-oxopyrano[3,4-c]pyridines 3a–j was obtained. Four of these compounds were reported for the first time. None of the tested compounds demonstrated anticoagulant effect but 8-methyl derivative (3a) was a potent antiplatelet compound with IC50 numerically twice as low as the clinically used acetylsalicylic acid. A series of further mechanistic tests showed that 3a interferes with calcium signaling. The compound is also not toxic and in addition possesses vasodilatory activity as well. Compound 3a is a promising inhibitor of platelet aggregation, whose mechanism of action should be studied in detail.