Cardiovascular function depends on an adequate vascular tone facilitating appropriate blood flow to individual tissues according to their needs. The tone results from the interplay between vasodilatation and vasoconstriction. Its rapid and efficient regulation is secured by many interconnected physiological mechanisms, both at the level of the vascular smooth muscle and the endothelium. The purpose of this review is to provide an update of the current knowledge on the mechanisms of physiological vasodilatation. First, two principal intracellular signaling pathways linked to the activation of protein kinases PKA and PKG are introduced. Subsequently, the role of endothelium-derived relaxing factors together with the endothelium-dependent hyperpolarization is discussed. The roles of ion channels and gap junctions in the communication between endothelium and vascular smooth muscle cells are particularly discussed. Finally, principal vasodilatory stimuli (mechanical, thermal, chemical) and their mechanisms of action are briefly introduced.

• Keywords
• EDRF, NO, PKA, PKG, Vasodilatation,
• Publication type
• Journal Article MeSH
• Review MeSH

Elevated low-density lipoprotein (LDL) cholesterol levels lead to atherosclerosis and platelet hyperaggregability, both of which are known culprits of arterial thrombosis. Normalization of LDL cholesterol in familial hypercholesterolemia (FH) is not an easy task and frequently requires specific treatment, such as regularly performed lipid apheresis and/or novel drugs such as proprotein convertase subtilisin kexin 9 monoclonal antibodies (PCSK9Ab). Moreover, a high resistance rate to the first-line antiplatelet drug acetylsalicylic acid (ASA) stimulated research of novel antiplatelet drugs. 4-methylcatechol (4-MC), a known metabolite of several dietary flavonoids, may be a suitable candidate. The aim of this study was to analyse the antiplatelet effect of 4-MC in FH patients and to compare its impact on two FH treatment modalities via whole-blood impedance aggregometry. When compared to age-matched, generally healthy controls, the antiplatelet effect of 4-MC against collagen-induced aggregation was higher in FH patients. Apheresis itself improved the effect of 4-MC on platelet aggregation and blood from patients treated with this procedure and pretreated with 4-MC had lower platelet aggregability when compared to those solely treated with PCKS9Ab. Although this study had some inherent limitations, e.g., a low number of patients and possible impact of administered drugs, it confirmed the suitability of 4-MC as a promising antiplatelet agent and also demonstrated the effect of 4-MC in patients with a genetic metabolic disease for the first time.

• Keywords
• 4-methylcathechol, familial hypercholesterolemia, lipid apheresis, platelet,
• MeSH
• Hyperlipoproteinemia Type II * drug therapy   MeSH
• Cholesterol, LDL MeSH
• Humans MeSH
• Antibodies, Monoclonal pharmacology   therapeutic use   MeSH
• Proprotein Convertase 9 MeSH
• Proprotein Convertases therapeutic use   MeSH
• Blood Component Removal * methods   MeSH
• Subtilisin MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-methylcatechol MeSH Browser
• Cholesterol, LDL MeSH
• Antibodies, Monoclonal MeSH
• Proprotein Convertase 9 MeSH
• Proprotein Convertases MeSH
• Subtilisin MeSH

A polyphenol-rich diet has beneficial effects on cardiovascular health. However, dietary polyphenols generally have low bioavailability and reach low plasma concentrations. Small phenolic metabolites of these compounds formed by human microbiota are much more easily absorbable and could be responsible for this effect. One of these metabolites, 4-methylcatechol (4-MC), was suggested to be a potent anti-platelet compound. The effect of 4-MC was tested ex vivo in a group of 53 generally healthy donors using impedance blood aggregometry. The mechanism of action of this compound was also investigated by employing various aggregation inducers/inhibitors and a combination of aggregometry and enzyme linked immunosorbent assay (ELISA) methods. 4-MC was confirmed to be more potent than acetylsalicylic acid on both arachidonic acid and collagen-triggered platelet aggregation. Its clinically relevant effect was found even at a concentration of 10 μM. Mechanistic studies showed that 4-MC is able to block platelet aggregation caused by the stimulation of different pathways (receptors for the von Willebrand factor and platelet-activating factor, glycoprotein IIb/IIIa, protein kinase C, intracellular calcium elevation). The major mechanism was defined as interference with cyclooxygenase-thromboxane synthase coupling. This study confirmed the strong antiplatelet potential of 4-MC in a group of healthy donors and defined its mechanism of action.

• Keywords
• aggregation, blood, flavonoid, human, metabolite, platelet,
• MeSH
• Phenols MeSH
• Immunologic Tests * MeSH
• Catechols * pharmacology   MeSH
• Humans MeSH
• Polyphenols MeSH
• Platelet Function Tests MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-methylcatechol MeSH Browser
• Phenols MeSH
• Catechols * MeSH
• Polyphenols MeSH

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.

• Keywords
• 3-hydroxyphenylacetic acid, artery, blood pressure, coronary, flavonoids, gut microbiota, metabolite, pig, rat, vasorelaxation,
• MeSH
• Phenylacetates pharmacology   MeSH
• Flavonoids metabolism   pharmacology   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• Disease Models, Animal MeSH
• Rats, Inbred SHR MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 3-hydroxybenzeneacetic acid MeSH Browser
• Phenylacetates MeSH
• Flavonoids MeSH

Flavonoids are associated with positive cardiovascular effects. However, due to their low bioavailability, metabolites are likely responsible for these properties. Recently, one of these metabolites, 4-methylcatechol, was described to be a very potent antiplatelet compound. This study aimed to compare its activity with its 22 close derivatives both of natural or synthetic origin in order to elucidate a potential structure-antiplatelet activity relationship. Blood from human volunteers was induced to aggregate by arachidonic acid (AA), collagen or thrombin, and plasma coagulation was also studied. Potential toxicity was tested on human erythrocytes as well as on a cancer cell line. Our results indicated that 17 out of the 22 compounds were very active at a concentration of 40 μM and, importantly, seven of them had an IC50 on AA-triggered aggregation below 3 μM. The effects of the most active compounds were confirmed on collagen-triggered aggregation too. None of the tested compounds was toxic toward erythrocytes at 50 μM and four compounds partly inhibited proliferation of breast cancer cell line at 100 μM but not at 10 μM. Additionally, none of the compounds had a significant effect on blood coagulation or thrombin-triggered aggregation. This study hence reports four phenol derivatives (4-ethylcatechol, 4-fluorocatechol, 2-methoxy-4-ethylphenol and 3-methylcatechol) suitable for future in vivo testing.

• Keywords
• 4-methylcatechol, aggregation, catechol, flavonoid, platelet, whole blood,
• MeSH
• Platelet Aggregation * MeSH
• Phenol * MeSH
• Phenols pharmacology   MeSH
• Platelet Aggregation Inhibitors pharmacology   MeSH
• Humans MeSH
• Thrombin pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Phenol * MeSH
• Phenols MeSH
• Platelet Aggregation Inhibitors MeSH
• Thrombin MeSH

Flavonoids are abundant polyphenols in nature. They are extensively biotransformed in enterocytes and hepatocytes, where conjugated (methyl, sulfate, and glucuronide) metabolites are formed. However, bacterial microflora in the human intestines also metabolize flavonoids, resulting in the production of smaller phenolic fragments (e.g., hydroxybenzoic, hydroxyacetic and hydroxycinnamic acids, and hydroxybenzenes). Despite the fact that several colonic metabolites appear in the circulation at high concentrations, we have only limited information regarding their pharmacodynamic effects and pharmacokinetic interactions. Therefore, in this in vitro study, we investigated the interactions of 24 microbial flavonoid metabolites with human serum albumin and cytochrome P450 (CYP2C9, 2C19, and 3A4) enzymes. Our results demonstrated that some metabolites (e.g., 2,4-dihydroxyacetophenone, pyrogallol, O-desmethylangolensin, and 2-hydroxy-4-methoxybenzoic acid) form stable complexes with albumin. However, the compounds tested did not considerably displace Site I and II marker drugs from albumin. All CYP isoforms examined were significantly inhibited by O-desmethylangolensin; nevertheless, only its effect on CYP2C9 seems to be relevant. Furthermore, resorcinol and phloroglucinol showed strong inhibitory effects on CYP3A4. Our results demonstrate that, besides flavonoid aglycones and their conjugated derivatives, some colonic metabolites are also able to interact with proteins involved in the pharmacokinetics of drugs.

• Keywords
• CYP450 enzymes, O-desmethylangolensin, colonic flavonoid metabolites, pharmacokinetic interaction, phloroglucinol, polyphenols, resorcinol, serum albumin,
• MeSH
• Erythrocytes enzymology   MeSH
• Flavonoids * chemistry   metabolism   MeSH
• Hepatocytes enzymology   MeSH
• Humans MeSH
• Serum Albumin, Human * chemistry   metabolism   MeSH
• Cytochrome P-450 Enzyme System * chemistry   metabolism   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Names of Substances
• Flavonoids * MeSH
• Serum Albumin, Human * MeSH
• Cytochrome P-450 Enzyme System * MeSH

Quercetin is proven to decrease arterial blood pressure when given orally. Its bioavailability is, however, low and, therefore, its metabolites could rather be responsible for this effect. In particular, the colonic metabolites of quercetin, 3,4-dihydroxyphenylacetic acid (DHPA), 4-methylcatechol (4MC), and 3-(3-hydroxyphenyl)propionic acid (3HPPA), have been previously shown to decrease the blood pressure in spontaneously hypertensive rats (SHR). Interestingly, the mechanisms of action of these three metabolites are different. The aim of this study is hence to investigate if these metabolites can potentiate each other and thus decrease blood pressure in reduced doses. Three double-combinations of previously mentioned metabolites were administered to SHR as infusions to mimic a real biological situation. All combinations significantly decreased the blood pressure in SHR but there were important differences. The effect of DHPA and 4MC was mild and very short. A combination of DHPA with 3HPPA caused more pronounced effects, which were also rather short-lived. The last combination of 3HPPA and 4MC caused a long-lasting effect. In conclusion, certain combinations of quercetin metabolites have a more pronounced antihypertensive effect than single metabolites.

• Keywords
• blood pressure, in vivo, infusion, phenolic, quercetin, rat,
• MeSH
• Antihypertensive Agents pharmacokinetics   MeSH
• Biological Availability MeSH
• Phenols pharmacokinetics   MeSH
• Hypertension drug therapy   MeSH
• Catechols pharmacokinetics   MeSH
• Blood Pressure drug effects   MeSH
• Rats MeSH
• 3,4-Dihydroxyphenylacetic Acid pharmacokinetics   MeSH
• Coumaric Acids pharmacokinetics   MeSH
• Disease Models, Animal MeSH
• Rats, Inbred SHR MeSH
• Quercetin chemistry   MeSH
• Dose-Response Relationship, Drug MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• 4-methylcatechol MeSH Browser
• Antihypertensive Agents MeSH
• dihydro-3-coumaric acid MeSH Browser
• Phenols MeSH
• Catechols MeSH
• 3,4-Dihydroxyphenylacetic Acid MeSH
• Coumaric Acids MeSH
• Quercetin MeSH

Silymarin is a traditional drug and food supplement employed for numerous liver disorders. The available studies indicate that its activities may be broader, in particular due to claimed benefits in some cardiovascular diseases, but the contributions of individual silymarin components are unclear. Therefore, we tested silymarin flavonolignans as pure diastereomers as well as their sulfated metabolites for potential vasorelaxant and antiplatelet effects in isolated rat aorta and in human blood, respectively. Eleven compounds from a panel of 17 tested exhibited a vasorelaxant effect, with half maximal effective concentrations (EC50) ranging from 20 to 100 µM, and some substances retained certain activity even in the range of hundreds of nM. Stereomers A were generally more potent as vasorelaxants than stereomers B. Interestingly, the most active compound was a metabolite-silychristin-19-O-sulfate. Although initial experiments showed that silybin, 2,3-dehydrosilybin, and 2,3-dehydrosilychristin were able to substantially block platelet aggregation, their effects were rapidly abolished with decreasing concentration, and were negligible at concentrations ≤100 µM. In conclusion, metabolites of silymarin flavonolignans seem to have biologically relevant vasodilatory properties, but the effect of silymarin components on platelets is low or negligible.

• Keywords
• Silybum marianum, aorta, blood coagulation, metabolites, milk thistle, sulfates, thrombocytes, vasorelaxant,
• MeSH
• Platelet Aggregation drug effects   MeSH
• Aorta drug effects   MeSH
• Flavonolignans chemistry   pharmacology   MeSH
• Platelet Aggregation Inhibitors chemistry   pharmacology   MeSH
• Rats MeSH
• Humans MeSH
• Molecular Structure MeSH
• Vasodilator Agents MeSH
• Animals MeSH
• Check Tag
• Rats MeSH
• Humans MeSH
• Male MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Flavonolignans MeSH
• Platelet Aggregation Inhibitors MeSH
• Vasodilator Agents MeSH

Increased arterial stiffness is a degenerative vascular process, progressing with age that leads to a reduced capability of arteries to expand and contract in response to pressure changes. This progressive degeneration mainly affects the extracellular matrix of elastic arteries and causes loss of vascular elasticity. Recent studies point to significant interference of dietary polyphenols with mechanisms involved in the pathophysiology and progression of arterial stiffness. This review summarizes data from epidemiological and interventional studies on the effect of polyphenols on vascular stiffness as an illustration of current research and addresses possible etiological factors targeted by polyphenols, including pathways of vascular functionality, oxidative status, inflammation, glycation, and autophagy. Effects can either be inflicted directly by the dietary polyphenols or indirectly by metabolites originated from the host or microbial metabolic processes. The composition of the gut microbiome, therefore, determines the resulting metabolome and, as a consequence, the observed activity. On the other hand, polyphenols also influence the intestinal microbial composition, and therefore the metabolites available for interaction with relevant targets. As such, targeting the gut microbiome is another potential treatment option for arterial stiffness.

• Keywords
• aging, anti-inflammatory, antioxidant, arterial stiffness, autophagy, gut microbiome, polyphenol biotransformation, polyphenols,
• MeSH
• Food Analysis * MeSH
• Diet * MeSH
• Humans MeSH
• Polyphenols chemistry   pharmacology   MeSH
• Gastrointestinal Microbiome drug effects   MeSH
• Vascular Stiffness drug effects   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH
• Names of Substances
• Polyphenols MeSH