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In an animal preparation of congestive heart failure in the dog, during the development of cardiac failure due to rapid right ventricular pacing we observed significant decreases in cardiac output and arterial pressure and increases in pulmonary arterial and right atrial pressure. We also observed a related increase in right atrial pressure and increases in plasma levels of atrial natriuretic peptide (ANP) and cyclic guanosine monophosphate (c-GMP). Ultrastructure changes in the atrial myoendocrine cells indicated extreme stimulation of the secretory apparatus of ANP. The response of hemodynamic, renal, and hormonal variables was investigated after incremental infusions (0.01, 0.03, 0.1, 0.3, and 0.06 microgram/kg/min) of exogenous ANP. In healthy animals ANP significantly decreased mean arterial pressure, cardiac output, stroke volume, and right atrial pressure without changing heart rate or peripheral vascular resistance. As expected, we found a striking increase in urine flow and urinary excretion of sodium, chloride, magnesium and calcium and a smaller increase in potassium excretion. ANP suppressed renin secretion, and increased renal plasma flow, glomerular filtration rate, and filtration fraction. In dogs with heart failure ANP caused a small reduction in mean arterial pressure. No effect was seen on other hemodynamic variables or plasma renin concentration. The excretory effects on the kidneys were completely absent, and smaller increases in glomerular filtration rate and filtration fraction were observed. We found no difference between healthy dogs and animals with heart failure with respect to the secretion of c-GMP during ANP infusions in relation to the plasma levels of ANP. This suggests an intracellular defect that prevents the mediation of the hormonal signal into biological action in the presence of heart failure.

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We describe here a further Japanese family with pyrimidine 5'-nucleotidase (P5'N) deficiency diagnosed using a nuclear magnetic resonance (NMR) spectrum, in Kumamoto prefecture where two families having the disease have been reported before. The specific spectra in 1H-NMR of P5'N deficient erythrocytes were due to three methyl protons of CDP-choline at 3.22 ppm and to H-2, H-8 and ribose-1' of pyrimidine nucleotide phosphate(s) in the lower fields (at 5.82 and 8.00 ppm). The other specificities in 31P-NMR spectra were due to CDP-choline, CDP-ethanolamine and UDP-glucose. Those spectra were not detected in other types of hemolytic anemia.

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Pyrimidine 5'-nucleotidase deficient (PND) erythrocytes contain elevated levels of pyrimidine nucleotides and relatively normal purine nucleotide levels. The composition of this nucleotide pool has been examined by others, but not all of the abnormal red cell metabolites in this disorder were identified. We have isolated and positively confirmed the identity of cytidine diphosphate (CDP)-choline and CDP-ethanolamine from PND red cells using methods including proton FT-NMR, spectroscopy, and comparative mass spectrometry. The concentrations of these and other pyrimidine nucleotidase-deficient erythrocyte nucleotides were determined using anion-exchange high performance liquid chromatography and ultraviolet (u.v.) detection. The pyrimidine diphosphodiesters appear to be the most prominent abnormal pyrimidine nucleotides in PND red cells, accounting for 55% of the total red cell pyrimidine nucleotides in this disorder. It is proposed that these abnormal phosphodiesters may be related to the accelerated hemolysis in PND.

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The purine and pyrimidine nucleotides in the erythrocytes from two children with 5'-nucleotidase deficiency have been studied using HPLC-technique. The children belonged to the same Norwegian family. In addition to the conventional uracil and cytosine nucleotides relatively high concentrations of UDP-glucose, UDP-N-Ac-glucosamine, CDP-choline and CDP-ethanolamine were found.

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Children with elevated whole blood lead levels were treated for 4 days with EDTA. Changes in whole blood lead concentrations, erythrocyte zinc protoporphyrin concentrations, red cell pyrimidine 5'-nucleotidase activities, and erythrocyte cytidine triphosphate (CTP) levels were measured during the course of the EDTA therapy. EDTA treatment decreased blood lead levels by approximately 50% after 4 days. An inverse relationship existed between blood lead levels and erythrocyte pyrimidine 5'-nucleotidase activity. Despite reactivation of pyrimidine 5'-nucleotidase enzyme activity by EDTA, there was no decrease in erythrocyte cytidine triphosphate or in zinc protoporphyrin concentrations. The lack of change in these two parameters during EDTA treatment supports the concept that pyrimidine 5'-nucleotidase inhibition by lead in the reticulocyte cytidine phosphate accumulation in moderate lead poisoning may reflect chronic lead overburden analogous to prolonged elevation of erythrocyte zinc protoporphyrins.

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The erythrocyte nucleotides of 25 children, 1-5 years old, with normal and increased blood leads, were assayed by anion-exchange high-performance liquid chromatography. Red blood cells of the 12 children with blood lead (PbB) below 30 micrograms/dl (20.3 +/- 6 micrograms/dl, mean +/- S.D.) had normal levels of activity of pyrimidine 5'-nucleotidase (P5N) and their erythrocytes were virtually free of pyrimidine nucleotides except for small amounts of UMP and UDP. The purine nucleotides, predominantly ATP and GTP, were present at values similar to adults. In the 13 children with PbB 30-72 micrograms/dl (45.3 +/- 14.3 micrograms/dl), total cytidine phosphates (CMP, CDP, CTP) were significantly (P less than 0.001) increased from trace values to 8.31 +/- 6.21 nmoles/10(10) erythrocytes. The purine nucleotides were unchanged. P5N activity was 143.3 +/- 22.0 units/g hemoglobin in children with PbB less than 30 micrograms/dl and 75.4 +/- 24.2 units (P less than 0.001) in the high lead subjects. There was a logarithmic correlation of erythrocyte cytidine phosphates with PbB (r = 0.89, P less than 0.001) and an inverse correlation of cytidine phosphates with ln P5N activity (r = 0.59, P less than 0.001), of ln P5N with PbB (r = 0.64, P less than 0.001) and of ln P5N with ln erythrocyte zinc protoporphyrin (Protoporphyrin IX) (r = 0.57, P less than 0.001).

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GTP levels were low and NAD+ levels high in purine nucleoside phosphorylase (PNP) deficient erythrocytes, in addition to the raised deoxy-GTP (dGTP) levels previously noted by others. dGTP was also identified in the PNP deficient child's lymphocytes. A further novel finding was the conversion of hypoxanthine to inosine by the PNP deficient red cells, as compared to inosine monophosphate (IMP) in controls. This has been attributed to IMP formation with subsequent breakdown, and raises interesting questions regarding the controls which normally maintain erythrocyte nucleotide pools. These findings may also explain the gross purine overproduction seen in this defect; they may likewise be related to the associated immunodeficiency, anaemia, and other clinical manifestations. The results may also have important implications for the development and clinical use of PNP inhibitors.

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The effects of various metabolic activators on the glucose metabolism of the perfused cat brain have been investigated. (1) When the perfusion is done with the blood containing cytidine monophosphate, the glucose metabolism of the brain is enhanced, as compared to the perfusion with the blood without cytidine monophosphate. There is no marked change in the cerebral metabolic rate and in the contents of intermediate metabolite of glucose in the brain. (2) Citicoline enhances the incorporation of blood glucose into the brain and its metabolism in the brain. It increases slightly the cerebral blood flow rate and decreases the accumulation of lactate in the brain. (3) Either Pyrithioxin or Meclophenoxate has no effect on the glucose metabolism of the brain nor on the cerebral metabolic rate.

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A severe deficiency of a red cell pyrimidine 5'-nucleotidase was found to be associated with hereditary hemolytic anemia in four members of three kindreds. The syndrome was characterized by marked increases above normal in red cell basophilic stippling, total nucleotides, and GSH and by a fairly severe deficiency of ribosephosphate pyrophosphokinase (EC 2.7.6.1.). Patient erythrocytes uniquely contained large amounts of pyrimidine 5'-ribonucleotides. In earlier studies, these were erroneously considered to be adenosine phosphates, since all previous investigations of the nucleotides of human red cells and reticulocytes have shown 97% or more to contain adenine. Total nucleotides in patient cells were present in amounts 3-6 times greater than normal, and approximately 80% contained pyrimidine. The ultraviolet spectral curves of deproteinized red cell extracts exhibited a shift in maximum absorbance from the usual 256-257 nm to approximately 266-270 nm, and absorbance at 250, 270, 280, and 290 nm, expressed as a ratio of that at 260 nm, differed greatly from normal. The spectral characteristics of extracts provide the basis of a readily performed screening procedure, which does not require enzyme assay. The nucleotidase activity in deficient red cells assayed less than 14%, and usually less than 10%, of normal and much less in terms of reticulocyte-rich blood, where it was consistently found to be increased. The enzyme has a pH optimum of 7.5-8.0, is inhibited by EDTA, and does not utilize purine 5'-ribonucleotides or beta-glycerophosphate as substrates. While comparatively few family members have been available thus far for study, initial data are compatible with an autosomal, recessive mode of transmission of the deficiency. The pyrimidine 5'-ribonucleotides are presumably derived from RNA degradation and, not being diffusible, accumulate when the enzyme catalyzing their dephosphorylation is deficient. It is postulated that the prominent basophilic stippling results from retarded ribosomal RNA degradation secondary to accumulation of degradation products, namely pyrimidine 5'-ribonucleotides. Ribosephosphate pyrophosphokinase deficiency is considered to be an epiphenomenon. The mechanism responsible for increased red cell GSH is unknown.

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