Tea-induced improvement of endothelial function in humans: No role for epigallocatechin gallate (EGCG).

Consumption of tea is inversely associated with cardiovascular diseases. However, the active compound(s) responsible for the protective effects of tea are unknown. Although many favorable cardiovascular effects in vitro are mediated by epigallocatechin gallate (EGCG), its contribution to the beneficial effects of tea in vivo remains unresolved. In a randomised crossover study, a single dose of 200 mg EGCG was applied in three different formulas (as green tea beverage, green tea extract (GTE), and isolated EGCG) to 50 healthy men. Flow-mediated dilation (FMD) and endothelial-independent nitro-mediated dilation (NMD) was measured before and two hours after ingestion. Plasma levels of tea compounds were determined after each intervention and correlated with FMD. FMD significantly improved after consumption of green tea containing 200 mg EGCG (p < 0.01). However, GTE and EGCG had no significant effect on FMD. NMD did not significantly differ between interventions. EGCG plasma levels were highest after administration of EGCG and lowest after consumption of green tea. Plasma levels of caffeine increased after green tea consumption. The results show that EGCG is most likely not involved in improvement of flow-mediated dilation by green tea. Instead, other tea compounds, metabolites or combinations thereof may play a role.

The activity of catechol-O-methyltransferase (COMT) is not impaired by high doses of epigallocatechin-3-gallate (EGCG) in vivo.

Catechol-O-methyltransferase (COMT) inactivates many endogenous and exogenous compounds by O-methylation. Therefore, it represents a major enzyme of the metabolic pathway with important biological functions in hormonal and drug metabolism. The tea catechin epigallocatechin-3-gallate (EGCG) is known to inhibit COMT enzymatic activity in vitro. Based on beneficial in vitro results, EGCG is extensively used in human intervention studies in a variety of human diseases. Owing to its low bioavailability, rather high doses of EGCG are frequently applied that may impair COMT activity in vivo. Enzymatic activities of four functional COMT single-nucleotide polymorphisms (SNPs) were determined in red blood cells (RBCs) in 24 healthy human volunteers (14 women, 10 men). The subjects were supplemented with 750 mg of EGCG and EGCG plasma levels and COMT enzyme activities in erythrocytes were measured before and 2 h after intervention. The homozygous Val→Met substitution in the SNP rs4680 resulted in significantly decreased COMT activity. Enzymatic COMT activities in RBCs were also affected by the other three COMT polymorphisms. EGCG plasma levels significantly increased after intervention. They were not influenced by any of the COMT SNPs and different enzyme activities. Ingestion of 750 mg EGCG did not result in impairment of COMT activity. However, COMT activity was significantly increased by 24% after EGCG consumption. These results indicate that supplementation with a high dose of EGCG does not impair the activity of COMT. Consequently, it may not interfere with COMT-mediated metabolism and elimination of exogenous and endogenous COMT substrates.

Effects of lycopene on the initial state of atherosclerosis in New Zealand White (NZW) rabbits.

BACKGROUND: Lycopene is the main carotenoid in tomatoes, where it is found in high concentrations. Strong epidemiological evidence suggests that lycopene may provide protection against cardiovascular diseases. We therefore studied the effects of lycopene on diet-induced increase in serum lipid levels and the initiation of atherosclerosis in New Zealand White (NZW) rabbits. METHODOLOGY/PRINCIPAL FINDINGS: The animals, divided into four groups of 9 animals each, were fed either a standard diet, a high-cholesterol diet containing 0.5% cholesterol, a high-cholesterol diet containing placebo beadlets, or a high-cholesterol diet plus 5 mg/kg body weight/day of lycopene (in the form of lycopene beadlets), for a period of 4 weeks. We found significantly elevated lycopene plasma levels in the animal group treated with lycopene beadlets. Compared to the high-cholesterol and the placebo group, this was associated with a significant reduction of 50% in total cholesterol and LDL cholesterol serum levels in the lycopene group. The amount of cholesteryl ester in the aorta was significantly decreased by lycopene. However, we did not observe a significant decrease in the extent of aortic surface lipid accumulation in the lycopene group. In addition, no differences in the intima-media thickness among groups were observed. Endothelial-dependent and endothelial-independent vasodilation in isolated rabbit aortic and carotid rings did not differ among any of the animal groups. CONCLUSIONS: Lycopene supplementation for 4 weeks increased lycopene plasma levels in the animals. Although we found strongly reduced total and LDL cholesterol serum levels as well as significantly lower amounts of cholesteryl ester in the aortae in the lycopene-treated group, no significant differences in initial lesions in the aortae were detected.

Green and black tea are equally potent stimuli of NO production and vasodilation: new insights into tea ingredients involved.

Epidemiological studies suggest that consumption of tea is associated with beneficial cardiovascular effects. Since different types of tea are consumed throughout the world, a question of much interest is whether green tea is superior to black tea in terms of cardiovascular protection. We therefore compared the effects of green and black tea on nitric oxide (NO) production and vasodilation and elucidated the tea compounds involved. We chose a highly fermented black tea and determined concentrations of individual tea compounds in both green and black tea of the same type (Assam). The fermented black tea was almost devoid of catechins. However, both teas stimulated eNOS activity and phosphorylation in bovine aortic endothelial cells (BAEC) as well as vasorelaxation in rat aortic rings to a similar extent. In green tea, only epigallocatechin-3-gallate (EGCG) resulted in pronounced NO production and NO-dependent vasorelaxation in aortic rings. During tea processing to produce black tea, the catechins are converted to theaflavins and thearubigins. Individual black tea theaflavins showed a higher potency than EGCG in NO production and vasorelaxation. The thearubigins in black tea are highly efficient stimulators of vasodilation and NO production. Green and black tea compounds induced comparable phosphorylation of eNOS and upstream signalling kinases. Whereas stimulation of eNOS activity by EGCG was only slightly affected by pretreatment of cells with various ROS scavengers, TF3(theaflavin-3',3-digallate)-induced eNOS activity was partially inhibited by PEG-catalase. These results implicate that highly fermented black tea is equally potent as green tea in promoting beneficial endothelial effects. Theaflavins and thearubigins predominantly counterbalance the lack of catechins in black tea. The findings may underline the contribution of black tea consumption in prevention of cardiovascular diseases.

Green tea and cardiovascular disease: from molecular targets towards human health.

PURPOSE OF REVIEW: To summarize current knowledge of the protective effects of green tea and green tea constituents, particularly catechins, on the cardiovascular system. RECENT FINDINGS: Consumption of green tea has been inversely associated with the development and progression of cardiovascular diseases and cardiovascular risk factors. Mechanisms that have been suggested as being involved in the antiatherosclerotic effects of green tea consumption primarily entail antioxidative, antiinflammatory, antiproliferative, and antithrombotic properties, as well as beneficial effects on endothelial function. Moreover, evidence exists for myocardial effects of tea constituents, including positive inotropic and antihypertrophic effects, and beneficial impact in myocardial ischaemia-reperfusion injury. SUMMARY: Green tea represents a promising tool for the prevention of cardiovascular disorders.

Characteristics of catechin- and theaflavin-mediated cardioprotection.

Catechins and theaflavins-the main polyphenolic substances of green and black tea, respectively-exert a plethora of beneficial effects on the cardiovascular system. In a model of H(2)O(2)-mediated oxidative stress, we investigated the effects of epigallocatechin-3-gallate (EGCG) and theaflavin-3,3'-digallate (TF3) on neonatal rat cardiomyocytes. Pretreatment with EGCG or TF3 1 hr prior to induction of oxidative stress by H(2)O(2) effectively protected cardiac myocytes as determined by measuring release of lactate dehydrogenase after 24 hrs. Longer pre-incubation times resulted in significant loss of protection. To enable further mechanistic insight, we investigated expression of antioxidative enzymes and activation of prosurvival signaling cascades. Whereas mRNA levels of glutathione peroxidase 3, superoxide dismutase 1, and catalase were not influenced by both polyphenols, heme oxygenase (HO-1) was selectively upregulated by EGCG-but not by TF3. However, inhibition of HO-1 did not diminish polyphenol-mediated cardioprotection. While EGCG and TF3 activated Akt, extracellular signal-regulated kinase 1/2, and p38 mitogen-activated protein kinase, inhibition of these kinases did not attenuate polyphenol-mediated protection. Loading of cardiomyocytes with dichlorofluorescein revealed that intracellular levels of reactive oxygen species were significantly reduced after treatment with EGCG or TF3 as early as 30 mins after induction of oxidative stress. In conclusion, activation of prosurvival signaling kinases and upregulation of antioxidative enzymes do not play a major role in tea polyphenol-mediated cardioprotection.

The efficacy of black tea in ameliorating endothelial function is equivalent to that of green tea.

Consumption of tea has been shown to improve endothelial function. It is assumed that catechins are the tea components responsible for these beneficial effects. In black tea, catechin concentrations are significantly lower than in green tea. The present study was designed to compare green and black tea with regard to amelioration of endothelial function. Endothelial function in response to both teas was assessed in bovine aortic endothelial cells (BAEC) and rat aortic rings. To elucidate whether these findings are also applicable to humans, flow-mediated dilation (FMD) and nitro-mediated dilation (NMD) were assessed by ultrasound in twenty-one healthy women before and 2 h after consumption of green and black tea (2 h of FMD and NMD), in comparison with water (control). In BAEC, green and black tea significantly increased endothelial NO synthase activity to the same extent. Similarly, both teas induced comparable endothelial-dependent vasodilation in rat aortic rings. In human subjects, ingestion of green and black tea led to significant increases in FMD: from 5.4 (sd 2.3) to 10.2 (sd 3) % (baseline-adjusted difference (BAD) for 2 h of FMD, green tea v. water: 5.0 (95 % CI 3.0, 7.0) %; P < 0.001) and from 5 (sd 2.6) to 9.1 (sd 3.6) % (BAD for 2 h of FMD, black tea v. water: 4.4 (95 % CI 2.3, 6.5) %; P < 0.001), respectively. The increase in FMD was not significantly different between the two tea preparations (BAD for 2 h of FMD, green tea v. black tea: 0.66 (95 % CI - 0.76, 2.09) %; P = 0.36). NMD did not vary between any of the groups. In conclusion, green and black tea are equally effective in improving endothelial function.

Addition of milk prevents vascular protective effects of tea.

AIMS: Experimental and clinical studies indicate that tea exerts protection against cardiovascular diseases. However, a question of much debate is whether addition of milk modifies the biological activities of tea. We studied the vascular effects of tea, with or without milk, in humans and elucidated the impact of individual milk proteins in cell culture experiments, with isolated rat aortic rings and by HPLC analysis. METHODS AND RESULTS: A total of 16 healthy female volunteers consumed either 500 mL of freshly brewed black tea, black tea with 10% skimmed milk, or boiled water as control. Flow-mediated dilation (FMD) was measured by high-resolution vascular ultrasound before and 2 h after consumption. Black tea significantly improved FMD in humans compared with water, whereas addition of milk completely blunted the effects of tea. To support these findings, similar experiments were performed in isolated rat aortic rings and endothelial cells. Tea induced vasorelaxation in rat aortic rings and increased the activity of endothelial nitric oxide synthase by phosphorylation of the enzyme in endothelial cells. All effects were completely inhibited by the addition of milk to tea. Of the various kinds of milk proteins, the caseins accounted for these inhibiting effects of milk, probably by formation of complexes with tea catechins. CONCLUSION: Milk counteracts the favourable health effects of tea on vascular function. This finding indicates the need for particular awareness in the interpretation and design of studies comprising nutritional flavonoids.

Thoracic spinal cord stimulation improves functional status and relieves symptoms in patients with refractory angina pectoris: the first placebo-controlled randomised study.

BACKGROUND: Spinal cord stimulation (SCS) is an alternative treatment option for refractory angina. Controlled trials demonstrate symptom relief and improvement in functional status. Since patients experience retrosternal prickling during active SCS, there is no option for blinding patients to active treatment or for placebo control. OBJECTIVE: To examine the therapeutic effects of subthreshold SCS in patients with refractory angina in a placebo-controlled study. METHODS: 12 responders to treatment who had already been treated with SCS for refractory angina were enrolled. Patients were randomised into four consecutive treatment arms, each for 4 weeks, with various stimulation timing and output parameters: 3 x 2 h/day (phase A) and 24 h/day with conventional output (phase B); 3 x 2 h/day with a subthreshold output (phase C); and 24 h/day with 0.1 V output, which served as control (phase D). Functional status, quality of life, Canadian Cardiovascular Society classification and nitrate usage were assessed at the end of each 4-week period. RESULTS: In phase D, patients showed a significant reduction in walking distance compared with phases A and C. Canadian Cardiovascular Society classification worsened in phase D compared with phases A-C. Frequency of angina attacks and the visual analogue scale were significantly worse in phase D than in phases A-C. In three patients, it was necessary to prematurely terminate phase D owing to intolerable angina attacks. CONCLUSIONS: In this first placebo-controlled trial to apply SCS in patients with refractory angina, improvement in functional status and symptoms was revealed in phases with conventional or subthreshold stimulation, in comparison to a low-output (placebo) phase.

The tea flavonoid epigallocatechin-3-gallate reduces cytokine-induced VCAM-1 expression and monocyte adhesion to endothelial cells.

Attachment of leukocytes to the vascular endothelium and the subsequent migration of cells into the vessel wall are early events in atherogenesis. This process requires the expression of endothelial adhesion molecules. Since tea catechins are reputed to promote antiatherogenic activities, we investigated the effects of various tea catechins-i.e., epicatechin (EC), epicatechin gallate (ECG), epigallocatechin (EGC), and epigallocatechin-3-gallate (EGCG)-on cytokine-induced expression of intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), and endothelial leukocyte adhesion molecule-1 (E-selectin) in HUVECs by ELISA. EGCG and to a lesser extent ECG prevented the induction of VCAM-1 expression in a concentration-dependent manner after stimulation with TNF-alpha, whereas EC and EGC were without effect. EGCG also inhibited the IL-1beta-induced induction of VCAM-1 expression. Inhibition of cytokine-induced VCAM-1 expression was manifested already on the transcriptional level. Furthermore, EGCG reduced the TNF-alpha-induced adhesion of THP-1 cells to HUVECs. EGCG did not influence TNF-alpha-stimulated NF-kappaB activation.