Background-In patients with chronic heart failure (CHF), hyperuricemia is a common finding and is associated with reduced vasodilator capacity and impaired peripheral blood flow. It has been suggested that the causal link of this association is increased xanthine oxidase (XO)-derived oxygen free radical production and endothelial dysfunction. We therefore studied the effects of XO inhibition with allopurinol on endothelial function and peripheral blood flow in CHF patients after intra-arterial infusion and after oral administration in 2 independent placebo-controlled studies. Methods and Results-In 10 CHF patients with normal serum uric acid (UA) levels (315Ϯ42 mol/L) and 9 patients with elevated UA (535Ϯ54 mol/L), endothelium-dependent (acetylcholine infusion) and endothelium-independent (nitroglycerin infusion) vasodilation of the radial artery was determined. Coinfusion of allopurinol (600 g/min) improved endothelium-dependent but not endothelium-independent vasodilation in hyperuricemic patients (PϽ0.05). In a double-blind, crossover design, hyperuricemic CHF patients were randomly allocated to allopurinol 300 mg/d or placebo for 1 week. In 14 patients (UA 558Ϯ21 mol/L, range 455 to 743 mol/L), treatment reduced UA by Ͼ120 mol/L in all patients (mean reduction 217Ϯ15 mol/L, PϽ0.0001). Compared with placebo, allopurinol improved peak blood flow (venous occlusion plethysmography) in arms (ϩ24%, Pϭ0.027) and legs (ϩ23%, Pϭ0.029). Flow-dependent flow improved by 58% in arms (Pϭ0.011). Allantoin, a marker of oxygen free radical generation, decreased by 20% after allopurinol treatment (PϽ0.001). There was a direct relation between change of UA and improvement of flow-dependent flow after allopurinol treatment (rϭ0.63, PϽ0.05). Conclusions-In hyperuricemic CHF patients, XO inhibition with allopurinol improves peripheral vasodilator capacity and blood flow both locally and systemically.

Familial hypercholesterolemia carries a marked increase in the risk of coronary heart disease (CHD), but there is considerable variation between individuals in susceptibility to CHD. To investigate the possible role of lipoprotein(a) as a risk factor for CHD, we studied the association between serum lipoprotein(a) levels, genetic types of apolipoprotein(a) (which influence lipoprotein(a) levels), and CHD in 115 patients with heterozygous familial hypercholesterolemia. The median lipoprotein(a) level in the 54 patients with CHD was 57 mg per deciliter, which is significantly higher than the corresponding value of 18 mg per deciliter in the 61 patients without CHD. According to discriminant-function analysis, the lipoprotein(a) level was the best discriminator between the two groups (as compared with all other lipid and lipoprotein levels, age, sex, and smoking status). Phenotyping for apolipoprotein(a) was performed in 109 patients. The frequencies of the apolipoprotein(a) phenotypes and alleles differed significantly between the patients with and those without CHD. The allele LpS2, which is associated with high lipoprotein(a) levels, was found more frequently among the patients with CHD (0.33 vs. 0.12). In contrast, the LpS4 allele, which is associated with low lipoprotein(a) levels, was more frequent among those without CHD (0.27 vs. 0.15). We conclude that an elevated level of lipoprotein(a) is a strong risk factor for CHD in patients with familial hypercholesterolemia, and the increase in risk is independent of age, sex, smoking status, and serum levels of total cholesterol, triglyceride, or high-density lipoprotein cholesterol. The higher level of lipoprotein(a) observed in the patients with CHD is the result of genetic influence.

1. The liberation of the vesicles of the mesosomes from protoplasts of Bacillus licheniformis strain 6346 is controlled by the Mg(2+) concentration present during the removal of the walls by lysozyme. 2. The functioning of the cytoplasmic membranes is also critically controlled by the Mg(2+) concentration. 3. The isolated mesosomes and the cytoplasmic membranes differ in their enzymic activities. Both succinate dehydrogenase and NADH oxidase activities are very low or absent from the mesosomes. 4. The cytoplasmic membranes can also be separated into materials of different density. 5. Distribution of the membranes between these fractions is controlled by the Mg(2+) concentration and the growth conditions of the microorganisms.

L-Arginine is metabolized by two pathways: 1) by nitric oxide synthase (NOS) to nitric oxide (NO) and 2) by arginase forming urea and L-ornithine. Inflammatory responses may involve a balance between the pathways, as NO is cytotoxic and vasodilatory and L-ornithine is a promoter of cell proliferation and matrix synthesis. In experimental glomerulonephritis we have previously shown that NOS is activated in nephritic glomeruli. We have now examined both pathways of L-arginine metabolism to study competition for L-arginine, temporal variation, and the sources of NOS and arginase. Acute in situ glomerulonephritis was induced in rats, and glomeruli were studied at 1, 4, and 7 days. Both NOS and arginase activities were present. There was temporal variation: NOS activity was highest on day 1 and arginase activity on day 4; both declined by day 7. Competition between the pathways was demonstrated by increased urea synthesis in the presence of NG-monomethyl-L-arginine, an inhibitor of NOS. Measurement of NOS and arginase activities in macrophages isolated from nephritic glomeruli showed that these cells were a major source of glomerular NOS but not arginase activity. In contrast, high arginase activity but low NO production was identified in cultured rat glomerular mesangial cells. These studies show differential temporal variation in expression of NOS and arginase pathways of arginine metabolism in experimental glomerulonephritis. We have found two factors that may contribute to this: 1) competition for substrate L-arginine between the two pathways and 2) different cellular sources. We hypothesize that the balance between these pathways is a mechanism regulating injury, hemodynamics, and mesangial cell proliferation.