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Synthetic bombesin (100 ng/min) was infused under pentobarbital anesthesia in normal dogs and in insulin deprived depancreatized dogs 4 days after surgery. The release of gut glucagon-like immunoreactive materials (gut GLI) calculated as the difference between the values measured using cross-reacting antiserum and a so-called pancreatic glucagon specific antiserum was markedly stimulated by bombesin infusion. Plasma glucagon immunoreactivity (GI) measured by pancreatic glucagon specific antiserum also showed a small increase, whereas plasma glucose decreased significantly with a transient rise in insulin. The plasma glucose level did not decrease in depancreatized dogs. Gut GLI response in the regional mesenteric vein to 5% glucose administered into the loop of the ileum was strongly augmented by bombesin infusion. It is concluded that (1) bombesin infusion decreased blood glucose level in normal dogs but not in depancreatized dogs. (2) Bombesin infusion markedly augmented the release of GLI from the intestine. (3) Bombesin also stimulated the release of glucagon which was probably of gastrointestinal origin. (4) Insulin release was stimulated transiently by bombesin infusion. Thus, a competition of gut GLI with glucagon at the glucagon receptor site may be an explanation of the reduction in blood glucose.

The antipyrine metabolizing capacity was studied in 12 patients with cirrhosis of the liver and 12 with cirrhosis and hepatocellular carcinoma (HCC). Antipyrine clearance (Cl) and liver volume (LV) were measured and the antipyrine clearance per unit liver volume (Cl/LV) was calculated. The patients with HCC showed a significantly lower Cl value than those without HCC but there was no significant difference in Cl/LV between the two groups. This suggested that the lower Cl values in the HCC patients resulted from a decrease in residual liver mass. Cl/LV showed positive correlation with % parenchymal cell mass as an indicator of residual parenchymal cell mass per unit volume of liver. This result showed a correlation of Cl/LV with histological change of the liver in cirrhotics.

A 55-year-old man with idiopathic Parkinson's disease developed myasthenia gravis shortly after taking trihexyphenidyl. The myasthenic weakness waxed and waned with rise and fall in serum levels of trihexyphenidyl, without marked change of anti-acetylcholine receptor antibody titer.

Using our electron microscopic method of polysome analysis we ascertained the numbers of membrane-bound polysomes and their constituent ribosomes in myeloma cells of J 606 (IgG3) and MOPC315 (IgA) parent cell lines and in their variants that did not produce and, accordingly, secrete either H- or L-chains. Both variants had far fewer membrane-bound polysomes than the respective parent lines. The polysome distribution curve drawn for each of these variants showed one peak at 5-6 ribosomes. In contrast to this finding, the distribution curves for the J 606 and MOPC315 parent lines gave two peaks. These observations on mouse myelomas strongly resembled those on human myelomas.

The true biological role of gut glucagon-like immunoreactive materials (gut GLI) is still unknown, although the stimulatory effect of intraluminal nutrients on the secretion of gut GLI has been described. The present authors, using the canine intestinal loop prepared from the terminal portion of the ileum, investigated how gut GLI would respond to digestive juice or its components. When bladder bile collected from another dog and diluted to 10% in saline was instilled into canine ileal loop, gut GLI in a branch of regional mesenteric vein was elevated significantly. Cholic acid suspended in saline (0.25 g/50 ml) also stimulated gut GLI secretion in the similar pattern to that of bile administration. On the other hand, 154 mM NaHCO3 which is a major inorganic component of pancreatic juice did not affect the venous level of gut GLI.

Cytochrome P-450-dependent N-demethylation of methylguanidine, a uremia toxin, was investigated. Methylguanidine was stoichiometrically converted into equal amounts of guanidine and formaldehyde by aerobic incubation with phenobarbital-induced microsomes and NADPH. The guanidine formation in the incubation mixture followed Michaelis-Menten kinetics and required the presence of molecular oxygen and NADPH. Methimazole, a non-formaldehyde-producing substrate specific for FAD-containing monooxygenase, did not inhibit significantly formaldehyde formation, suggesting that microsomal FAD-containing monooxygenase does not play a significant role in N-demethylation of methylguanidine. The direct involvement of cytochrome P-450 in the N-demethylation is supported by the observations that addition of methylguanidine to purified cytochrome P-450 preparation caused a type I spectral change and that inhibitors of cytochrome P-450, such as carbon monoxide and metyrapone, markedly decreased the rate of demethylation. Neither superoxide anion nor hydrogen peroxide was directly involved in the demethylation reaction. In addition, guanidine formation was observed in the reconstituted system containing purified cytochrome P-450. Thus, these findings indicate that the hepatic microsomal mixed function oxidase system catalyzes N-demethylation of methylguanidine to guanidine.

A case of malignant lymphoma with a helper activity of neoplastic cells is reported. On admission, a significant number of plasma cells of polyclonal nature were seen in the peripheral blood, and polyclonal hypergammaglobulinemia was seen. The biopsied lymph node showed poorly differentiated lymphocytic lymphoma with marked proliferation of plasma cells. At the terminal stage, the patient became leukemic in contrast with the disappearance of plasma cells from the peripheral blood. Although the leukemic cells failed to form sheep erythrocyte rosettes, they were considered to be of T-cell origin morphologically. Cytochemically, they had a "dot"-like pattern of alpha-naphthyl acetate esterase and acid phosphatase activity. Ultrastructurally, they had highly convoluted nuclei, and cytoplasmic clustered dense bodies. They showed marked helper activity on pokeweed mitogen-induced B-cell differentiation in vitro. This case may provide a novel view concerning the cause of hypergammaglobulinemia induced by lymphoproliferative disorders.

Summary Studies on hypouricaemia observed in a patient with 48, XXYY syndrome revealed an abnormality in renal urate handling. His renal urate clearance was abnormally increased. Inosine administration and provocative tests using probenecid and pyrazinamide identified an isolated renal tubular abnormality with increased urate secretion. Since the serum urate in his brother with a normal sex chromosome constitution was also low, the association of renal hypouricaemia and 48, XXYY syndrome in this patient is probably coincidental. Although the brother was not investigated, these siblings may be a previously unreported case of familial hypouricaemia due to isolated renal hypersecretion.

A novel system of low density lipoprotein (LDL) apheresis for familial hypercholesterolemia (FH) was developed, combining a centrifugal plasma separator (IBM-2997) with a new adsorption column specific to lipoproteins containing apolipoprotein B (apo-B), and its operation was compared to previous methods. The present system selectively removed LDL without the substantial reduction of high density lipoprotein that was seen with other methods using membrane filters. The capacity for LDL removal was slightly more reduced with the adsorption column than with the membrane filters when a single column was used. Since the ability to obtain plasma in the centrifugal system was much higher than in the system using membrane filters for plasma separation, efficient apheresis could be performed in a much shorter time, without making an arterio-venous shunt. Remixing of blood cells, such as platelets, with the separated plasma sometimes raises the pressure within the plasma component separator, but the problem could be avoided by withdrawing the buffy coat fraction, using the WBC pump of the IBM separator. In conclusion, the novel system, combining the centrifugal plasma separator with the adsorption column, has proved, in our hands, to be a more useful and more convenient method than those previously used for the treatment of severe FH.

Eight maturity-onset diabetic patients who had no infections, liver diseases or other endocrine diseases which might affect carbohydrate metabolism were treated with monocomponent lente insulin, which is known to have little antigenicity, until blood sugar was controlled. The diurnal values of the blood sugar (BS) and immunoreactive insulin (IRI) were obtained before treatment and on the third day after the withdrawal of insulin treatment. One patient was dropped from the study because of insulin antibody formation. The total integrated IRI area in the diurnal profile was increased from 98.9 +/- 23.7 to 186.1 +/- 37.7 muU.h/ml (p less than 0.05), while the total blood sugar area was decreased from 7,500 +/- 1,200 to 5,510 +/- 1,214 mg-h% (p less than 0.05). Oral Glucose Tolerance Test on the fourth day after the withdrawal of insulin treatment showed increased IRI response compared to pretreatment. It is concluded that endogenous insulin secretion could be increased in the diabetic patient by the metabolic control with exogenous insulin injections.

Cardiovascular complications were examined in a 31-year-old woman with homozygous familial hypercholesterolemia (FH) (LDL receptor defective type), who had had no clinical symptoms of coronary artery disease. She had delivered 2 children without any cardiac complications, and her exercise electrocardiogram showed no positive findings for ischemic heart disease. Coronary angiography showed no significant arterial lesions, and left vent riculography revealed good contraction of the left ventricle (ejection fraction: 67%). This is considered to be a very rare case of homozygous FH without significant lesions in the coronary arteries. This might be attributed at least in part to her dietary regimen consisting of a very low fat and low calorie diet, to the residual LDL receptor activity or to the low value of prothrombin time.

Morphometric analysis of the hepatic endoplasmic reticulum and assays of drug-metabolizing enzymes in microsomes prepared from needle biopsy specimens were performed with samples from uremic patients on chronic hemodialysis and normal controls. The smooth endoplasmic reticulum (SER) morphometrically increased in the uremic patients, whereas the cytochrome P-450 content and the activity of p-nitroanisole O-demethylase per mg microsomal protein decreased in the uremic patients. This condition of SER corresponds to that of the so-called hypoactive hypertrophic smooth endoplasmic reticulum, which could suggest lower activity of hepatic microsomal drug oxidation in uremic patients. On the other hand, the P-450 content and the activity of p-nitroanisole O-demethylase per g liver were not significantly different between the uremic and the normal subjects. This seems to indicate that the capacity of drug oxidation is retained in whole livers of uremic patients. However, since some patients in this study showed markedly low activity of p-nitroanisole O-demethylase per mg microsomal protein and per g liver, lipophilic drugs metabolized in the liver as well as hydrophilic ones eliminated by the kidney should be carefully administered to uremic patients.

A case of chronic veno-occlusive disease of the liver manifested by ascites in a 59-year-old Japanese male is described. The patient had not been exposed to pyrrolizidine alkaloids, but had been receiving allopurinol for hyperuricemia, the only drug taken throughout the period in which the hepatic lesion developed. The hepatic veins and inferior vena cava were patent according to angiography. The first biopsy showed histological characteristics of the disease and the following two biopsies demonstrated the progression of the hepatic lesion from central fibrosis to non-portal cirrhosis. Morphometric analysis of the sublobular and central veins in the three serial biopsy specimens demonstrated stepwise decrease of the ratio of the veins per portal triad and stepwise increase of severely obliterative veins.

Long-term treatment with probucol induced marked regression of xanthoma in patients with both homozygous and heterozygous familial hypercholesterolemia despite a substantial accompanying decrease in high-density lipoprotein (HDL) cholesterol. Furthermore, a close correlation was found between the extent of the regression and the reduction of HDL cholesterol, which suggests that the probucol-induced decrease in HDL may not be an atherogenic change, but may reflect a favorable change for lipoprotein metabolism. The present study also evaluated the effects of probucol on HDL metabolism in patients with familial hyperHDL 2 cholesterolemia who had extremely high levels of HDL cholesterol ranging from 130 to 280 mg/dl. Premature corneal opacities were present in 2 patients, 1 of whom also had coronary artery disease despite high HDL cholesterol levels. In the 2 cases, the net transfer of cholesteryl ester from HDL to very low density lipoprotein and LDL was impaired, and low hepatic triglyceride lipase activity was observed, but cholesteryl ester transfer protein was not deficient. Administration of probucol to these patients caused a marked reduction of serum cholesterol, which was accounted for exclusively by a reduction in the HDL 2 fraction. The size of the HDL 2 particles, which had been much larger, decreased to normal, and the net transfer rate of cholesteryl ester was normalized. In the other 3 cases of hyperHDL 2 cholesterolemia, the cholesteryl ester transfer activity was completely deficient. Unlike its effect in the first 2 cases, probucol did not cause any change in lipid and apoprotein in the 3 patients with complete deficiency of cholesteryl ester transfer activity. These results suggest that probucol may accelerate cholesterol transport through HDL and other lipoproteins, enhancing reverse cholesterol transfer from peripheral tissues to the liver, and that it may need cholesteryl ester transfer protein to be effective.

This report describes studies of a man suspected of having primary cortisol resistance. This conclusion is based on his high plasma cortisol levels and high 24-h urinary 17-hydroxycorticosteroid and cortisol excretion, plus the fact that he had no manifestations of Cushing's syndrome. Among family members tested, his mother also had hypercortisolemia. Both mother and son had high levels of unbound plasma cortisol, but their plasma ACTH concentrations were within the normal range. Both were partially resistant to dexamethasone adrenal suppression, and both had mild hypertension without hypokalemia. To study this apparent end-organ resistance to cortisol, we examined the glucocorticoid receptors in peripheral mononuclear cells. Using whole cell assays, glucocorticoid receptors in both patients were found to have reduced total binding capacity. We conclude that these two patients, members of the same family, have primary cortisol resistance accompanied by a reduced number of glucocorticoid receptors.

SUMMARY Clinical observations and serial determinations of serum thyroglobulin (Tg) were made in five patients with acute haemorrhage into the thyroid gland. Fever, local pain and acceleration of erythrocyte sedimentation rate were minimal or were not observed, and serum T4 and T3 were normal. Although all patients showed an increase in serum Tg, this was most obvious in three subjects and it gradually decreased as the nodule became smaller. There was no correlation between the serum Tg concentration and the nodular size. Acute haemorrhage into the thyroid gland should be added as one of the causes to increase serum Tg concentrations.

Hereditary diabetic mice (NSY) were inbred from original streptozotocin diabetic ICR mice for 8-9 generations using hyperglycemia as an index. The normoglycemic ICR mice were used as controls for the NSY line. The nonfasting blood sugar level of the NSY mice was 305 +/- 14 mg/100ml, while their immunoreactive insulin level was 30 +/- 4 microU/ml (the values of the controls were 165 +/- 12 mg/100 ml and 79 +/- 14 microU/ml, respectively). beta-N-Acetylglucosaminidase [EC 3.2.1.29], beta-galactosidase [EC 3.2.1.23], alpha-glucosidase [EC 3.2.1.21], and alpha-mannosidase [EC 3.2.1.24] activities were determined in the 1,000 X g supernatant of the liver and the kidney of control and streptozotocin diabetic ICR mice and their NSY line. In the kidneys of the insulinopenic NSY mice, the beta-galactosidase and alpha-mannosidase activities were significantly decreased. No significant changes were found in liver enzyme activities. Insulin treatment increased the kidney beta-galactosidase activity signficantly. The insulinopenic state, which caused a decrease in the glycosidase activities in the kidney, could induce retarded breakdown of glycoprotein.

We cloned cDNA of gastrin mRNA from human gastric antrum. First we obtained a porcine gastrin precursor cDNA clone using a synthetic oligodeoxyribonucleotide, d(A-A-A-G-T-C-C-A-T-C-C-A-T-C-C-A-T) as a hybridization probe. Then, using this porcine clone as a hybridization probe, human gastrin precursor cDNA clones were obtained. Sequence analysis revealed 4, 303, and 98 nucleotides, respectively, in the 5' untranslated region, in the amino acid coding region, and in the 3' untranslated region. The deduced precursor molecule codes for big and small gastrin, surrounded by pairs of basic amino acids. When the sequences of porcine and human gastrin precursor are compared, a high degree of homology in the active peptide region and lower homology in other regions are observed.

Zinc metabolism in diabetes was studied in depancreatized dogs and alloxan diabetic rabbits.Urinary zinc excretion was markedly increased 4 or 5 days after the onset of diabetes and it maintained a relatively constant value of a five-to eight-fold increase so long as the diabetic state lasted. The magnitude of an increase of urine zinc in the experimetal animals was approximately equal to that observed in severe diabetic patients. Improvement of diabetic conditions tended to regain a normal pattern of zinc excretion.There was also obtained the finding of an early and transient increase in zinc excretion which occurred immediately after administration of alloxan. Evidence has been obtained that such early and transient increase is not related to alloxan per se but to metabolites of alloxan such as purpureate and alloxanic acids. The diabetogenic action of alloxan has been discussed in the light of the present experimental findings.

The effects of a soluble insulin—dextran complex on the distribution of l-14C—L—arabinose and on the incorporation of U—14C—D—glucose into glycogen were examined in rat “intact” hemidiaphragm preparations. The complex was prepared by coupling crystalline bovine insulin covalently with dextran (av mol wt, 40,000). The insulin—dextran caused the acceleration of glycogen formation in parallel with the facilitation of sugar transport in quite a similar manner to that of native insulin, although insulin—dextran was to some extent less potent than native insulin in both of the above actions. The present results indicate that insulin exerts its effects on glycogenesis under conditions precluding the entry of the hormone into the cell. The binding of insulin with the cell membrane structures not only stimulates transmembrane sugar transport but initiates a propagation of events by which glycogen formation system is directly stimulated within the cell. (Endocrinology 91: 1442, 1972)

The effect of differing crossreactivities of antiglucagon sera with pancreatic and gut glucagon on the content of immunoreactive glucagon (IRG) in plasma has been investigated.Two types of antisera employed in the study gave identical dilution curves for pancreatic glucagon, but different ones for gut glucagon. The mean value of IRG of seven plasma samples determined using antiserum less reactive to gut glucagon was 0.57±0.19 mμg/ml, but 0.77±0.22mμg/ml when measured with another antiserum. Similar findings were observed in IRG determination in the plasma samples obtained from a pancreatectomized patient containing gut glucagon alone. The recovery of gut glucagon added to plasma assayed with one antiserum differed from that using another, but those of pancreatic glucagon were the same without reference to antiserum employed.These facts suggest a possible explanation for the widely divergent results reported for circulating glucagon levels.

A new type of glycogenosis due to deficiency of muscle phosphofructokinase is described. It occurred in three siblings from a single family, who had suffered from intolerance of exercise since childhood. This disease is characterized by the marked accumulation of hexose monophosphates and moderate glycogen deposition in skeletal muscles. Erythrocyte phosphofructokinase is only partially affected in this disease in contrast to the almost complete lack of muscle phosphofructokinase.

The in vitro effect of Kunitz pancreatic trypsin inhibitor (KPTI) on the release of corticosterone from rabbit adrenals in the presence of three different preparations of corticotropins has been investigated. These preparations include highly purified porcine corticotropin, Pcorticotropin and Gly^a-*^ corticotropin. The effect of KPTI was found to be more marked in sustaining the action of corticotropin with shorter peptide chain than that with longer peptide chain. KPTI per se did not show any stimulatory effects on steroidogenesis. It may be concluded that KPTI protects shorter chain corticotropin against digestion by proteolytic enzymes. The above mentioned effect of KPTI was not demonstrated, however, with soybean trypsin inhibitor. (Endocrinology 90: 1652, 1972) T T HAS BEEN known that corticotropins are •*• inactivated by proteolytic enzymes. White and Gross (1) reported that plasmin inactivated corticotropins in blood. Other proteolytic enzymes, such as trypsin, pepsin and liver cathepsin have been also recognized as corticotropin inactivators (1). However, little is known as to whether corticotropins could be inactivated in the adrenal, during exerting their hormone action in adrenal. In the present report we employed proteolytic enzyme inhibitors to evaluate the possible influence of tissue proteolytic activities on the maintenance of steroidogenic action of corticotropins including synthetic analogues with shorter chain peptides. Our data suggest that the action of synthetic corticotropin analogue with 18 amino acids is markedly augmented by protecting against the degradation of the peptide. Materials and Methods A highly purified porcine corticotropin (HP corticotropin) with a potency of 120 U/mg was purchased from Calbiochem; synthetic P* corticotropin from Organon-Daiichi; Kunitz pancreatic trypsin inhibitor and soybean trypsin inhibitor from Worthington Biochemical Corp.; bovine serum albumin (Fr. V) from Armour Pharm. Co.; synthetic Gly-a-2 Received November 17, 1971, corticotropin was a gift from Dr. Otsuka of Shionogi Laboratory, Osaka. Adrenals were obtained from male rabbits weighing 2.0-2.5 kg. They were washed exhaustively by Krebs-Ringer bicarbonate buffer, pH 7.4 (KRB) and quadricepted after removal of thin fibrous capsules. Each adrenal preparation weighed 30-50 mg. Two pieces of quadricepted tissue from a pair of adrenal glands were placed in each incubation vessel containing 5 ml KRB with glucose (2 mg/ml) and bovine serum albumin (5 mg/ml) (G-KRB) in the presence or absence of trypsin inhibitors. The vessels were preincubated for 60 min in an atmosphere of 95% O2—5% CO2 at 37 C with shaking at 100 cycles/min. After preincubation, corticotropin preparations were added and incubation was continued for another 120 min under the same condition. The steroidogenic action was followed by measuring the amount of corticosterone released into the incubation medium. 0.5 ml aliquots of medium were removed at 0, 20, 40, 60 and 120 min for the assay of corticosterone which was performed by the method of Guillemin (2). Results Effect of KPTI on steroidogenic action of corticotropins The effect of three different corticotropin preparations on corticosterone production in rabbit adrenals were tested. As shown in Fig. 1A, HP corticotropin (0.04 y-g/ml), synthetic J3" NOTES AND COMMENTS 1653 FIG. 1. The effect of HP corticotropin, P' corticotropin and Gly-a-2 corticotropin on the corticosterone production in rabbit adrenals in the presence or absence of proteolytic enzyme inhibitors (KPTI or STI). Quadricepted adrenals were preincubated for 60 min with or without proteolytic enzyme inhibitors, each preparation of corticotropins was then added to incubation vessels as indicated with an arrow and incubation was continued for 120 min. Each value is the mean ± SE of four or five experiments. 12.0

Passage of sugars and polyols across the cell membrane is the first rate-limiting step in metabolism of these substances and, in particular, glucose transport in some tissues is a site of hormonal regulation. Some tissues show active transport for glucose; that is, a process which must be maintained by energy derived from metabolism in order to move sugars from a lower into a higher concentration. Generally speaking, the tissues having a specialized system of active transport for glucose are situated on the boundary between internal and external environments. Intestinal absorption or tubular reabsorption of glucose is known to be an active transport process. However, up to the present, these systems of active transport for glucose have not been shown to be influenced directly by any hormones. The hormone-sensitive sugar transfer is, so far, limited to a process of downhill transport and the stereospecificity of the hormone effect provides evidence for the existence of a transport carrier system.

We investigated the expression, degree of phosphorylation, and activation of the proto-oncogene c-kit product before and after stimulation with the c-kit ligand in a human factor-dependent myeloid leukemia cell line, MO7E. The culture supernatant of the BALB/3T3 fibroblast cell line, which contains the ligand for the murine c-kit product, was found to stimulate proliferation of the MO7E cell line in a dose-dependent manner. The proliferation was significantly inhibited by a tyrosine kinase inhibitor, genistein. An immunoblot technique with a monoclonal antibody specific for phosphotyrosine, showed that there was rapid, dose-dependent tyrosine-phosphorylation of the c-kit product in response to murine c-kit ligand. Furthermore, the murine c-kit ligand increased autokinase activity of the c-kit product in vitro. Similar results were obtained with human stem cell factor (SCF), a recombinant human ligand for the c-kit product. These results suggest that the phosphorylation and activation of the c-kit product are involved in proliferative signals of some human leukemia cells, as well as of normal hematopoietic cells.

症例, 33才,男性. 29才よりBehcet病にて治療中.緩徐に進行する右心不全にて入院.精査にて左肺動脈基始部の完全閉塞,右肺動脈の高度の狭窄が判明,直ちに血栓除去術を施行.術後,右心不全症状は完全に消失した.手術時の肺動脈組織診により,肺動脈炎に伴う肺動脈血栓症の存在が確認された.本例は両側性肺動脈基始部にBehcet病に基づく閉塞病変を有するも,救命しえたまれな症例と考えられる.

Myogenic hyperuricemia is caused by increased production of uric acid secondary to enhanced release of inosine and hypoxanthine from exercising muscles into blood. This novel mechanism is evident in glycogenosis types VII (muscle phosphofructokinase deficiency), III (debranching enzyme deficiency), and V. In this study, we examined the effect of muscular exercise on the glycolysis of circulating erythrocytes in glycogenosis types VII and III. The concentration of erythrocyte 2,3-bisphosphoglycerate, which had decreased because of genetic partial deficiency of erythrocyte phosphofructokinase, was further decreased after prolonged bed rest in patients with type VII. Ergometric exercise rapidly increased fructose-1,6-P2, dihydroxyacetone-P plus glyceraldehyde-3-P, and 2,3-bisphosphoglycerate in circulating erythrocytes. Similar changes were observed after exercise in patients with type III. The exercise-induced metabolic alteration of erythrocytes was reproduced in vitro by incubating normal erythrocytes in the presence of inosine. We conclude that physical activity affects glycolysis in erythrocytes in glycogenosis types VII and III, and that myogenic factors including inosine are responsible for this change.

Degradation of purine nucleotides was evaluated in different types of rat skeletal muscle during ischemic and non-ischemic contraction. Extensor digitorum longus (EDL, fast) and soleus (slow) muscles were stimulated electrically via the sciatic nerve (5 Hz, 10 min). Under non-ischemic condition, the concentrations of IMP, inosine, adenosine, and hypoxanthine increased in EDL muscles but not in soleus muscles during stimulation. Under ischemic condition, these metabolites increased in both EDL and soleus muscles and the changes in concentrations of IMP and inosine were greater in ischemic EDL muscles. The increase in inosine had a strong positive correlation with that in IMP in ischemic EDL and soleus muscles, but the ratio, Δinosine/ΔIMP was smaller in EDL muscles. The increase in adenosine under ischemic condition was not significantly different between the two muscles. These findings suggest that ischemia enhances overall degradation of purine nucleotides in contracting fast and slow muscles, and that although the degradation of adenine nucleotides to IMP is greater in fast muscles than in slow muscles, the relative degradation rate of IMP to inosine with respect to the intramuscular IMP concentration is rather smaller in fast muscles.

We studied two brothers with hereditary xanthinuria (xanthine oxidase deficiency) and their family members. The two brothers had extremely low concentrations of urate but markedly high concentrations of xanthine and hypoxanthine in plasma and urine. Xanthine oxidase activities were virtually absent in the duodenal mucosa. In their parents (presumed obligate heterozygotes), the activities of xanthine oxidase were about half that of normal subjects. Although plasma xanthine and hypoxanthine concentrations of the parents were normal, urinary xanthine and hypoxanthine excretions were significantly higher than those of normal subjects (xanthine, father 17.1 mg/g creatinine and mother 27.4 vs. normal controls 5.7 to 11.0; hypoxanthine, father 14.0 and mother 27.3 vs. controls 4.0 to 8.4). Similar changes in the metabolite concentrations were seen in at least 6 other relatives, suggesting they were heterozygotes. This study indicates that the presumed obligate heterozygotes of xanthine oxidase deficiency retained about half normal enzyme activities causing the partial metabolic blockage in vivo at this enzyme step.

In a patient with Kearns-Sayre syndrome, concentration of coenzyme Q l0 , a component of the mito-chondrial electron transport system, was decreased in serum and in the mitochondrial fraction of skeletal muscle. Serum concentrations of lactate and pyruvate were abnormally high, especially after exercise or oral glucose loading. Levels of folic acid in plasma and CSF were decreased. ECG showed a first-degree atrioventricular block. After administration of coenzyme Q l0 60 to 120 mg daily for 3 months, serum levels of lactate and pyruvate became normal, with improvement of atrioventricular block and ocular movements.

Type VII glycogenosis (muscle phosphofructokinase deficiency) is attended by hyperuricemia and hyperuricosuria. In one patient, we found that exercise on a bicycle ergometer increased plasma uric acid, inosine, and hypoxanthine levels. Forearm exercise also markedly increased venous inosine, hypoxanthine, and ammonia in the exercising arm of two patients. Exaggerated release of precursors for uric acid synthesis from exercising muscle may be related to the hyperuricemia.

Excess purine degradation in exercising muscle due to impaired glycolysis causes hyperuricemia in muscle glycogenoses (myogenic hyperuricemia). However, hyperuricemia has been seen more frequently in Type VII than in Type V. This study was designed to clarify a metabolic basis for the different frequency of hyperuricemia between the diseases. 5 patients (2 males, 3 females) with Type V and 4 (3 males, 1 female) with Type VII participated in the study. 1) In every patient, semi ischemic forearm exercise caused no increase in lactate but exaggerated increases in ammonia, inosine and hypoxanthine in cubital venous blood. The ammonia increase was not different between Type V and Type VII, but it was greater in male than female patients. 2) Semiischemic forearm exercise performed after glucagon injection showed that lactate production was induced by exercise in Type V but not in Type VII. 3) Saline or glucose solution was infused in a patient with Type V during exercise on a bicycle ergometer. With saline infusion, ammonia and hypoxanthine in systemic circulation increased greatly after exercise. Conversely, with glucose infusion there were no increases in these metabolites. These findings indicated that blood glucose can be available as metabolic fuel through muscle glycolysis in Type V but not in Type VII. Thus, muscle purine degradation may be accelerated more in Type VII than in Type V, leading to a higher frequency of hyperuricemia.