Selection of liquid chromatographic adsorbents was studied for the separation and determination of uric acid in body fluids and mammalian tissues. A solution containing norepinephrine, epinephrine, dopamine, ascorbic acid and uric acid was used as a test solution for optimizing chromatographic conditions. Eluate from a column was electrochemically monitored by aid of an electrochemical detector set at +800mV vs Ag/Ag Cl. Five column systems were examined for the complete separation of catecholamines, ascorbic acid and uric acid. All the column systems examined in this study allowed the determination of uric acid in body fluids such as serum, cerebrospinal fluid and urine under the present chromatographic conditions. The reversedphase column systems examined in this study have been found to allow the quantitative determination of uric acid in mammalian tissues as well as in body fluids.

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To elucidate conditions of gout, thirty Wistar strain hyperuricemic rats were fed a commercially available chow containing 2% oxonic acid and 3% uric acid. Uric acid concentrations were measured in the kidney and abdominal aorta after two and four fed weeks. The uric acid concentrations in the renal cortex, outer medulla, inner medulla and papillarly tips were significantly increased compared with control rats, and this tendency was greater in the medulla than cortex. Uric acid concentrations in the kidney were higher after four weeks rats than after two weeks. The uric acid concentrations in aorta were also increased in hyperuricemic rats as compared with control. rats, however, the values were lower than those in the inner medulla and papillary tips. A positive correlation was found between the value of uric acid concentrations in the kidney tissues and urinary excretion of uric acid, and serum uric acid levels. This correlation was more significant in the inner medulla and papillary tips. The same correlation was also noticed between the level of uric acid concentration in aorta and serum uric acid. Our findings suggest that persistent manifestation of hyperuricemia and hyperuricosuria causes the deposition of uric acid and urate in various internal organs.

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We investigated luminol - dependent chemiluminescence (LDCL) of peripheral blood PMNs from gouty patients. The reaction mixture consisted of PMNs, luminol solution and synthetic monosodium urate (MSU) crystals.
MSU crystals and inactivated serum-treated MSU crystals did not generate LDCL of PMNs from normal individuals and gouty patients, but fresh serumtreated MSU crystals did. In acute gouty arthritis, LDCL of PMNs was enhanced more prominently than in patients without attacks whose LDCL showed higher levels than those of normal individuals. Even in patients with acute attacks of gouty arthritis administered colchicine, LDCL of PMNs was prominently suppressed by MSU. Moreover, compared to LDCL induced by opsonized zymosan, LDCL of PMNs from patients with acute gouty arthritis showed low levels.
The present study demonstrates that MSU crystals treated with fresh serum evoked LDCL of peripheral blood PMNs in gouty patients.

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This study was performed to elucidate the mechanism of dimethylxanthine (theophylline)induced reduction of the maximum rate of rise (Vmax) of action potentials in guinea pig papillary muscle perfused with Tyrode's solution of different K⁺ concentrations(2.7-13.5mM). At. relatively high [K⁺]o concentrations(8.1-13.5mM), the Vmax is composed of 2 components, i. e., the Vmax, fast followed by the Vmax, slow. The Vmax, fast was a measure of the residual (partly inactivated) fast channel while the Vmax, slow represents the slow channel. Theophylline depressed Vmax, fast with and increase in Vmax, slow in a concentrationdependent manner (1-4mM). The depression of Vmax, fast by this agent was remarkable in more depolarized membranes and was attributed to the negative shift of the curve relating Vmax, fast to the resting potentials along the voltage axis. A similar shift occurred in the presence of dibutyryl- cAMP(3mM).
These results suggested that theophylline blocks the residual Na⁺ channel in depolarized ventricular muscle via an increase of cellular cAMP.

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In this report, we compared lipid and lipoprotein levels between two groups with and without gouty arthritis matching the uric acid levels. There was no difference in age, percent of ideal body weight or blood pressure between these two groups. Serum total -cholesterol and (VLDL + LDL)-cholesterol levels were slightly lower in the symptomatic group than in the asymptomatic group, while serum triglyceride and HDL - cholesterol levels showed no difference between two groups. The subjects were divided into two groups with regard to serum uric acid concentrations, (>=, or <8.0 mg/dl). In the group with high serum uric acid values, there was no difference in serum lipids and lipoproteins, whereas in the group with low values, totalcholesterol and (VLDL + LDL) - cholesterol levels were significantly (p<0.05) lower in the symptomatic group than in the asymptomatic group (195+39mg/dl vs 214+48mg/dl and 142 +38mg/dl vs 162+47mg/dl respectively). In contrast, serum triglyceride and HDL- cholesterol levels were similar between symptomatic and asymptomatic groups. We further divided subjects into five subgroups according to serum uric acid levels and found that the difference of both total - cholesterol and (VLDL + LDL) -cholesterol between symptomatic and asymptomatic subjects were more prominent in the lower uric acid group. Our findings support the concept that apoprotein B - containing lipoproteins (VLDL and LDL) are involved in the inhibition of gouty arthritis.

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We studied hyperuricemia associated with familial hypercholesterolemia (FH). Eighty-seven subjects with FH (47 males and 40 females) including five FH-homozygotes were investigated for serum uric acid. Serum uric acid levels were significantly higher than normal controls in male FH-heterozygotes(6.4±1.6mg/dl vs 5.1±1.0mg/dl, p<0.001)and also in female FH-heterozygotes(4.9±1.5mg /dl vs 4.1±1.0mg/dl, p<0.001). Three out of five FH-homozygotes showed hyperuricemia. The distribution curve of serum uric acid concentrations in FHsubjects was shifted to the right and the incidence of hyperuricemia (designated as. more than 7.0 mg/dl in male and 6.0 mg/dl in female ) was also high in both sexes. Serum uric acid levels did not correlate with the degree of hypercholesterolemia, but rather with the serum triglyceride values in female. Especially in female FH- subjects, serum levels of uric acid had a tendency to increase in WHO - phenotype II b and III. The underlying mechanism of hyperuricemia in FH is yet to be elucidated, but since HMG- CoA reductase activity is considerably elevated in FH, the de novo synthesis of uric acid might be linked together with the pathway for cholesterol de novo synthesis.
The incidence of gouty arthritis was unexpectedly low in FH inspite of hyperuricemia, which was considered to be in part due to the inhibition of gouty attack by elevated serum apolipoprotein B levels.

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We measured serum uric acid (SUA) in adults and the following results were obtained:
1) In adults who were diagnosed as normal with normal body weight and who were not heavy drinkers, the mean SUA value was 5,22±1.05mg/dl in 197 male subjects and 3.76±0.73mg/dl in 61 female subjects. The sex difference was statistically significant.
2) A total of 53 males had asymptomatic hyperuricemia (7.1%) and 5 females (2.5%). The prevalence of hyperuricemia in men and women was highest for those in their sixties.
3) In men, obesity was a distinct factor in hyperuricemia.

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Zotepine(2-chloro-11-(2-diethyl-aminoethoxy)dibenzo[b.f.]thiepin)has been reported to decrease serum uric acid levels in schizophrenics. We have investigated its uricosuric effect by uric acid clearance, inosine loading test, and PZA suppression test.
Oral administration of 20 mg of zotepine to 3 normal volunteers resulted in moderate uricosuria in 2 or 3 hours, which paralleled the increase of the serum concentration of the drug. In 20 gouty subjects, after administration of zotepine 20mg/day for 14 days, uric acid clearance revealed a decrease of uric acid (1.5±1.8mg/dl). Inosine loading test showed increases of SUA, UUA and CUA. These changes were similar to those of benzbromarone (potent uricosuric agent), but different from those of allopurinol (uric acid production inhibitor), and suggested that zotepine is an uricosuric agent.
In a normal volunteer, who was given 4g of PZA previously, zotepine- induced uricosuria disappeared. PZA is a potent tubular secretion inhibitor. Therefore, zotepine may inhibit tubular secretion, or postsecretory tubular reabsorption.

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We investigated the effect of zotepine on uric acid, xanthine and hypoxanthine in patients with schizophrenia. In addition, we performed pyrazinamide - suppression test and phenolsulfophthale in test to identify the site of its uricosuric action in the kidney.
Zotepine had a hypouricemic effect in patients with schizophrenia as reported previously, although the effect was not dose-dependent. In 6 patients treated with zotepine (40 mg/day), the serum uric acid value rose quickly one week after discontinuation of zotepine and returned close to the pretreatment level after two weeks.
Pyrazinamide blocked the uricosuric action of zotepine to the same degree as it did the uricosuric action of benzbromarone but phenolsulfophthale in excretion was not inhibited by zotepine as by benzbromarone. These findings indicate that zotepine exerts its uricosuric action at postsecretory sites. Zotepine increased the xanthine clearance/creatinine clearance ratio significantly. but decreased the hypoxanthine clearance /creatinine clearance ratio significantly. These results suggest that the renal transport mechanisms of uric acid and xanthine are similar to each other but are different from that of hypoxanthine.

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We present evidence demonstrating the importance of tissue uric acid determination by liquid chromatography. Uric acid in mammalian tissues was determined by reversed-phase high-performance liquid chromatography (RPHPLC) with electrochemical detection (ECD) recently developed by us. The chromatographic examinations revealed marked over-production of uric acid in human malignant tumor tissues and also regional over-production in the left hemisphere following left middle cerebral artery occlusion. In some diseases, hyperuricemia may result in marked over-production of uric acid in tissues. Therefore, uric acid levels in body fluids were investigated in relation to diseases. The HPLC-ECD method allows determination of uric acid levels in body fluids as well as in mammalian tissues up to 10 pg. We are now investigating the relationship between abnormalities in purine metabolism in mammalian tissues and diseases.

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