Abnormalities of autonomic control of the cardiovascular system are seen in chronic heart failure (CHF) and confer a poor prognosis. Nitric oxide appears to be important in the regulation of baroreflex control in health and in disease states. The antioxidant vitamin C increases nitric oxide bioavailability in CHF. We evaluated the effects of vitamin C on baroreceptor sensitivity (BRS) by sequence analysis in 100 CHF patients and 44 control subjects. Groups of 55 CHF patients and 22 controls were randomly allocated to receive a single intravenous injection of vitamin C (2 g) or placebo. In addition, 45 CHF patients were randomly allocated to receive a 4-week course of oral vitamin C (4 g/day) or placebo. An age-related reference range for BRS was developed in 22 healthy controls matched for age and gender to the CHF group. BRS was significantly impaired in the CHF group compared with age-matched older controls and young controls (6.9 ± 3.1, 12.5 ± 4.9 and 21.7 ± 9.1 mmHg/ms respectively; P < 0.001 between groups). Intravenous vitamin C acutely improved BRS in CHF patients by 24% (by 1.8 ± 4.1 mmHg/ms; P < 0.05), but not in controls. There was no improvement in BRS in CHF patients given chronic oral vitamin C. Thus acute intravenous, but not chronic oral, vitamin C improved BRS in CHF patients. There was no effect of intravenous vitamin C in healthy subjects, suggesting that the mechanism was either by free radical scavenging or due to central effects.

In various experimental models, S -adenosylmethionine (SAMe) has been shown to reduce liver injury by preventing depletion of glutathione, one of the antioxidant systems that plays a critical role in defence against oxidative stress. On the other hand, α-tocopherol may be decreased in liver diseases, and treatment with this vitamin reduces liver injury in CCl 4 -treated rats. Since there is a close relationship among the different antioxidant systems (mainly glutathione, α-tocopherol and ascorbic acid), we have assessed whether, as well as restoring hepatic glutathione content, SAMe has any effect on liver α-tocopherol and ascorbic acid levels in CCl 4 -injured rats. Four groups of seven male Wistar rats treated for 9 weeks were studied: rats induced to cirrhosis with CCl 4 , rats induced to cirrhosis plus SAMe administration (10 mgċkg -1 ċday -1 ) and their respective controls. Liver samples were obtained for measuring levels of glutathione, α-tocopherol, ascorbic acid and thiobarbituric acid-reactive substances (TBARS), and hydroxyproline concentration as an index of collagen content. The hydroxyproline content was higher in CCl 4 -injured rats than in the control group (4.4±1.8 and 1.1±0.3 μ mol/g respectively; P < 0.05). In CCl 4 -injured rats, SAMe administration decreased collagen content (2.7±1.0 μ mol/g; P < 0.05) and TBARS, and corrected glutathione depletion. α-Tocopherol was significantly lower in CCl 4 -injured rats than in controls (17.3±4.9 and 23.0±4.0 μ mol/g respectively; P < 0.05). By contrast, α-tocopherol levels were similar (23.8±5.1 μ mol/g) in CCl 4 -injured rats receiving SAMe and in controls. In CCl 4 -injured rats, liver ascorbic acid was decreased in comparison with controls (4.9±1.8 and 8.2±1.0 μ mol/g respectively; P < 0.05), levels which were not replenished by SAMe (4.6±0.4 μ mol/g). In conclusion, SAMe not only decreases fibrosis and protects against hepatic glutathione depletion, but has a further antioxidant effect of preventing α-tocopherol depletion in CCl 4 -injured rats.

Both neutrophil margination and increases in the non-invasively assessed parameter, isovolumetric venous congestion cuff pressure ( P v i ), are symptomatic of some inflammatory diseases. Neutrophil margination occurs primarily, though not exclusively, at the post-capillary endothelial surface. The local haemodynamic changes resulting from margination may be responsible for the observed increases in P v i . Smoke inhalation has been shown in animal studies to cause an increase in post-capillary neutrophil margination by mechanisms that can be blocked by oral vitamin C administration. We looked for indices of a relationship between margination and P v i in man, using cigarette smoke inhalation as a pathophysiological challenge. We also examined the effect of prophylactic vitamin C on the response. Smoke inhalation was associated with highly significant increases in both P v i and heart rate. After vitamin C pre-treatment, no increase in P v i was observed in response to the smoke inhalation; however, whilst heart rate still increased significantly, the duration of this response was attenuated. The results suggest that vitamin C affords protection against some of the cardiovascular and microvascular changes associated with cigarette smoke inhalation in man. They also support the notion that non-invasive assessment of changes in P v i may provide a measurable index of systemic changes in inflammatory conditions.

The tissue concentration of lipid hydroperoxides, which was determined by a specific method involving chemical derivatization and HPLC, increased significantly in the heart, liver, kidney and muscle of diabetic rats 8 weeks after the intraperitoneal injection of streptozotocin compared with that of the control group. These results demonstrate that an enhanced oxidative stress is caused in these tissues by diabetes. Vitamin C concentrations of the brain, heart, lung, liver, kidney and plasma of the diabetic rats decreased significantly after 8 weeks compared with those of the control group. Vitamin E concentrations of the brain, heart, liver, kidney, muscle and plasma of the diabetic rats increased significantly after 4 weeks compared with the control group. After 8 weeks, an elevation in vitamin E concentration was observed in the heart, liver, muscle and plasma of the diabetic rats.

1. Hypertension affects 30% of adults and low intakes of antioxidants have been associated with increased risk of hypertension and cardiovascular disease. To investigate the effect of short-term high-dose antioxidant supplementation on blood pressure in hypertensive and normotensive outpatients, we undertook a randomized, double-blind, crossover design placebo-controlled study. 2. Forty subjects were recruited from medical outpatient clinics, of whom 38 completed the study. Twenty-one were attending for treatment of hypertension and 17 were normotensive, attending for minor gastrointestinal complaints. Subjects were randomly assigned to receive either 8 weeks placebo followed by 2 weeks washout then 8 weeks antioxidants or vice versa. The combination of antioxidants consisted of 200 mg of zinc sulphate, 500 mg of ascorbic acid, 600 mg of α-tocopherol (sodium succinate salt) and 30 mg of β-carotene daily. 3. Systolic blood pressure fell at the end of the antioxidant phase compared with the placebo phase both in subjects receiving anti-hypertensive therapy ( P < 0.01) and those who were normotensive ( P = 0.067). Circulating levels of β-carotene and α-tocopherol increased in all subjects during supplementation ( P < 0.01) and urine nitrite increased in hypertensive patients ( P < 0.05). 4. Short-term oral high-dose combination antioxidant therapy reduces blood pressure, possibly via increased availability of nitric oxide. This study may have implications for the innovative use of antioxidants as an adjunct to anti-hypertensive therapy.

1. Plasma and buffy-coat vitamin C, urinary proline, hydroxyproline, creatinine and total amino acid concentrations were measured in 23 healthy elderly subjects at intervals of 3 months. 2. There was a strong positive correlation between plasma vitamin C and buffy-coat vitamin C. 3. There were no significant correlations between plasma or buffy-coat vitamin C and total urinary hydroxyproline, whether expressed on a creatinine basis or on a total amino acid basis. Similarly, no significant correlations could be detected involving the proline/hydroxyproline ratio in urine hydrolysates. 4. There was a significant negative correlation between plasma or buffy-coat vitamin C and total urinary proline, when expressed per unit of total amino acids in the hydrolysates. This correlation was not observed with unhydrolysed urine, and it appeared to reside in the diffusible fraction, part of whose proline could be liberated by prolidase digestion. In addition, in the men, there was some evidence for a positive correlation between plasma or buffy-coat vitamin C and the ratio of total urinary amino acids to creatinine. 5. These results support the view that poor vitamin C status in elderly humans may be associated with a defect in collagen proline hydroxylation, reflected by increased excretion of proline-rich, collagen-derived peptides. If this interpretation is correct, it indicates a potential defect in connective tissue repair, and could form the basis of a functional test for subclinical vitamin C deficiency.