Recent epidemiological studies have demonstrated that coffee drinking is associated with reduced mortality of cardiovascular disease. However, its precise mechanisms remain to be clarified. In this study, we examined whether single ingestion of caffeine contained in a cup of coffee improves microvascular function in healthy subjects. A double-blind, placebo-controlled, crossover study was performed in 27 healthy volunteers. A cup of either caffeinated or decaffeinated coffee was drunk by the subjects, and reactive hyperemia of finger blood flow was assessed by laser Doppler flowmetry. In an interval of more than 2 days, the same experimental protocol was repeated with another coffee in a crossover manner. Caffeinated coffee intake slightly but significantly elevated blood pressure and decreased finger blood flow as compared with decaffeinated coffee intake. There was no significant difference in heart rate between caffeinated and decaffeinated coffee intake. Importantly, caffeinated coffee intake significantly enhanced post-occlusive reactive hyperemia of finger blood flow, an index of microvascular endothelial function, compared with decaffeinated coffee intake. These results provide the first evidence that caffeine contained in a cup of coffee enhances microvascular function in healthy individuals.

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An elevation of oxidized forms of tetrahydrobiopterin (BH(4)), especially dihydrobiopterin (BH(2)), has been reported in the setting of oxidative stress, such as arteriosclerotic/atherosclerotic disorders, where endothelial nitric oxide synthase (eNOS) is dysfunctional, but the role of BH(2) in the regulation of eNOS activity in vivo remains to be evaluated. This study was designed to clarify whether increasing BH(2) concentration causes endothelial dysfunction in rats. To increase vascular BH(2) levels, the BH(2) precursor sepiapterin (SEP) was intravenously given after the administration of the specific dihydrofolate reductase inhibitor methotrexate (MTX) to block intracellular conversion of BH(2) to BH(4). MTX/SEP treatment did not significantly affect aortic BH(4) levels compared with control treatment. However, MTX/SEP treatment markedly augmented aortic BH(2) levels (291.1 ± 29.2 vs. 33.4 ± 6.4 pmol/g, P < 0.01) in association with moderate hypertension. Treatment with MTX alone did not significantly alter blood pressure or BH(4) levels but decreased the BH(4)-to-BH(2) ratio. Treatment with MTX/SEP, but not with MTX alone, impaired ACh-induced vasodilator and depressor responses compared with the control treatment (both P < 0.05) and also aggravated ACh-induced endothelium-dependent relaxations (P < 0.05) of isolated aortas without affecting sodium nitroprusside-induced endothelium-independent relaxations. Importantly, MTX/SEP treatment significantly enhanced aortic superoxide production, which was diminished by NOS inhibitor treatment, and the impaired ACh-induced relaxations were reversed with SOD (P < 0.05), suggesting the involvement of eNOS uncoupling. These results indicate, for the first time, that increasing BH(2) causes eNOS dysfunction in vivo even in the absence of BH(4) deficiency, demonstrating a novel insight into the regulation of endothelial function.

Abstract. Liposome-encapsulated hemoglobin (LEH) has been developed as a blood substitute. In spite of its size (1/30 -1/40 of erythrocytes), LEH has an oxygen-carrying capacity comparable to erythrocytes. Thus, LEH is expected to carry oxygen into vital organs via collateral routes during ischemia induced by vascular embolism. In the present study, we examined the therapeutic effects of LEH on behavioral impairments in rats after four-vessel occlusion (4VO) for 30 min. In the open-field test, locomotor activity in 4VO rats did not alter 7 days after ischemia. However, in the contextual fear conditioning (CFC) test, the freezing rate was significantly decreased in 4VO rats, although no behavioral changes in the Y-maze test and elevated plus-maze test were observed. Phosphorylation of the cyclic AMP response element-binding protein (CREB) in the hippocampal CA1 region after the CFC test was attenuated. These 4VO-induced impairments were significantly alleviated by the administration of LEH (5 ml/kg, i.v.) during occlusion. Moreover, LEH did not alter hippocampal blood flow and tissue oxygen pressure during 4VO, but it did suppress hyperoxia after ischemia-reperfusion. These findings suggest that LEH, an artificial oxygen carrier, could be a novel therapeutic agent for brain dysfunction after acute cerebral ischemia.

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Abstract. Shark liver oil (SLO) has long been used as a traditional health food, with a particular benefit for vascular health, in Japan. The aim of this study was to assess the effect of dietary supplementation with SLO on arterial stiffness and peripheral microvascular function in otherwise healthy middle-aged and older males with slightly increased arterial stiffness. A randomized, double-blind, placebo-controlled, parallel study design was used to assign 41 healthy males with a mean age of 59.0±4.0 years (range, 45-69 years) to either SLO (n=21) or placebo (n=20) treatment for eight weeks. The effects on arterial stiffness and peripheral microvascular function were assessed by the cardio-ankle vascular index (CAVI) and by measurement of hand blood flow to cutaneous tissues using a laser Doppler perfusion imaging (LDPI) technique, respectively. Although the magnitude of the changes in the CAVI value during the eight-week intervention for the SLO group did not significantly differ from that for the placebo group, the changes in the CAVI value for the former group were significantly associated (r=0.575, P<0.01) with age. It was also found that the LDPI values at week 8 were significantly lowered (P<0.05) compared with the baseline values in the placebo group, while no change was observed in the SLO group, resulting in a significant difference in the changes between the two groups (P=0.002). Neither SLO supplementation-related adverse side-effects nor any abnormal changes in routine laboratory tests, including lipid profiles and anthropometric and haemodynamic parameters, were observed throughout the intervention. SLO may have the potential to safely improve vascular health in middle-aged and elderly males. IntroductionShark liver oil (SLO) has long been used as a dietary supplement with health-promoting activities, particularly for cardiovascular health, in Japan. At present, several SLO-containing supplements are commercially available and their dietary consumption is increasing among the Japanese middle-aged and elderly populations, most likely due to the fact that there has been considerable interest in alternative therapies.SLO is known to contain large quantities of squalene and, thus, to be considered as the richest source of the compound. Squalene received its name as a result of its first isolation from liver oil of sharks (Squalus spp.) (1). Later, squalene was found in variety of vegetable oils, including olive, palm, wheat-germ and rice bran oils. Chemically, squalene is a polyprenyl compound, having a structural similarity with β-carotene, coenzyme Q10 and vitamins A, E and K (2). Among these squalene-related compounds, vitamin E, known as the most potent lipid-soluble antioxidant in vivo, has been most intensively studied for its effects on cardiovascular health; there have been a number of studies reporting that vitamin E is effective in decreasing arterial stiffening in overweight hypertensive patients (3,4), and others reporting that vitamin E supplementation improves peripheral vascular disease...