Peripheral endothelial function can be improved by daily consumption of water containing over 7 ppm of dissolved hydrogen: A randomized controlled trial.

BACKGROUND: Measurement of the reactive hyperemia index (RHI) using peripheral arterial tonometry (PAT) has shown benefits in the evaluation of vascular endothelial function and prediction of cardiovascular disease prognosis. Thus, it is important to examine the factors that promote the RHI. In this study, we aimed to investigate the effect of molecular hydrogen (H2) on reactive hyperemia-PAT of the small arteries of fingers in healthy people. METHODS: To determine the efficacy of H2 for improving peripheral vascular endothelial function, water containing high H2 concentrations was administered to participants, and the Ln_RHI was measured in the finger vasculature. Sixty-eight volunteers were randomly divided into two groups: a placebo group (n = 34) that drank molecular nitrogen (N2)-containing water and a high H2 group (n = 34) that drank high H2 water (containing 7 ppm of H2: 3.5 mg H2 in 500-mL water). The Ln_RHI was measured before ingesting the placebo or high H2 water, 1 h and 24 h after the first ingestion, and 14 days after daily ingestion of high H2 water or the placebo. The mixed effects model for repeated measures was used in data analysis. RESULTS: The high H2 group had a significantly greater improvement in Ln_RHI than the placebo group. Ln_RHI improved by 22.2% (p<0.05) at 24 h after the first ingestion of high H2 water and by 25.4% (p<0.05) after the daily consumption of high H2 water for 2 weeks. CONCLUSIONS: Daily consumption of high H2 water improved the endothelial function of the arteries or arterioles assessed by the PAT test. The results suggest that the continuous consumption of high H2 water contributes to improved cardiovascular health.

Replacement of connexin 43 by connexin 32 in a knock-in mice model attenuates aortic endothelium-derived hyperpolarizing factor-mediated relaxation.

Previous studies demonstrated that intercellular communication through endothelial, smooth muscle or myoendothelial connexin channels contributes to the control of vascular tone. At least four connexin types are present in the arterial wall. The aim of the present work was to assess the role played by connexin 43 (Cx43)-formed gap junctions on vessel function. Aortic reactivity to noradrenaline, acetylcholine and sodium nitroprusside, and endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations, were analysed in a Cx43KI32 mouse model in which the coding region of Cx43 was replaced by that of connexin 32 (Cx32). Aortic rings were placed in organ baths containing a Krebs solution oxygenated at 37 degrees C (pH 7.4). Confocal images of aortic rings confirmed connexin substitution in mutant mice. In control conditions, replacement of Cx43 by Cx32 in homozygous mutant mice did not modify endothelium-independent contractile responses to noradrenaline, or relaxations in response to sodium nitroprusside (endothelium independent) or acetylcholine (endothelium dependent). However, residual endothelium-dependent relaxations in response to acetylcholine after nitric oxide synthase and cyclooxygenase inhibition (EDHF type) were significantly reduced in homozygous Cx43KI32 mice (maximal effect values: 4.86 +/- 0.37% of noradrenaline precontraction versus 7.06 +/- 0.31% in wild-type, n = 8, P < 0.05). This attenuation was mimicked by treatment of rings from wild-type animals with the connexin-mimetic peptide (37,43)Gap27 (5 x 10(-6)m). In conclusion, replacement of Cx43 by Cx32 attenuates EDHF-mediated relaxations in mice aortic rings, suggesting that they are, at least in part, dependent on Cx43-formed gap junctions. In contrast, aortic responses to tested endothelium-independent agonists were not modified in knock-in animals.

Dietary soy modulates endothelium-dependent relaxation in aged male rats: Increased agonist-induced endothelium-derived hyperpolarising factor and basal nitric oxide activity.

We examined the effects of dietary soy on the contributions of endothelium-derived hyperpolarising factor (EDHF), nitric oxide (NO), and oxidative stress to vascular tone in isolated aortic rings and small mesenteric and pulmonary arteries in vitro. Male Wistar rats were either continuously fed a soy-deficient diet (SD) or switched from a soy-deficient diet to a soy-rich one for 6 months (SW). Contractile responses were generally smaller in arteries from SW rats. In mesenteric arteries, this difference was blunted by L-NAME, but not by charybdotoxin and apamin. Preconstricted SW mesenteric arteries were more sensitive to acetylcholine (ACh) than SD ones. This difference was unaffected by L-NAME but was abolished by charybdotoxin and apamin. Exogenous superoxide dismutase (SOD) and catalase induced powerful relaxations in aortic rings, which were smaller in those from SW rats. In mesenteric and pulmonary arteries, however, they partially inhibited ACh-mediated relaxation, and enhanced PGF(2alpha)-mediated contraction, respectively. Our results suggest that feeding aging male rats a soy-rich diet results in improved agonist-mediated EDHF production and a generalized reduction in contractile force, which is partly due to elevated basal NO. Our data also suggest a prorelaxant role for endogenous H(2)O(2) in small arteries, which is modulated by a soy diet.

EDHF: new therapeutic targets?

Besides cyclooxygenase and NO-synthase, another distinct endothelial pathway, endothelium-dependent hyperpolarization (EDHF), is involved in the relaxation of the vascular smooth muscle cells. EDHF has been demonstrated unequivocally in various blood vessels from different species, including human, and is likely to play an important role in cardiovascular physiology. This alternative pathway involves the activation of two populations of endothelial potassium channels, the small conductance and intermediate conductance calcium-activated potassium channels (SK(Ca) and IK(Ca), respectively). EDHF-mediated responses are clearly altered in various pathological conditions (ageing, hypertension, atherosclerosis, hypercholesterolemia, heart failure, ischemia-reperfusion, angioplasty, eclampsia, diabetes, sepsis). Therapeutic or adjutant interventions (angiotensin converting enzyme inhibitors, antagonist of the angiotensin receptor, estrogen, omega-3 polyunsaturated fatty acids, polyphenol derivatives, potassium and/or calcium intake) can restore these responses, suggesting that the improvement of the EDHF pathway contributes to the observed beneficial effect of these various substances. However, the improvement or restoration of EDHF responses has not been, yet, the direct purpose of any pharmaceutical effort. Activating endothelial IK(Ca) and/or SK(Ca) or increasing their expression as well as improving myo-endothelial communication, for instance by increasing the expression of connexin(s), could become interesting therapeutic targets.