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Biomedical subjects

E Kusano

Publications and source records attributed to E Kusano.

At least 73 records · Page 4Linked to original sources
PubMed1992

Elevation of levels of carcinogenic tryptophan pyrolysis products in plasma and red blood cells of patients with uremia.

The carcinogenic tryptophan pyrolysis products, 3-amino-1,4-dimethyl-5H-pyrido[4,3-b]indole (Trp-P-1) and 3-amino-1-methyl-5H-pyrido[4,3-b]indole (Trp-P-2), have been measured in plasma and red blood cells (RBC) of patients with uremia and normal subjects by using a high-performance liquid chromatography (HPLC) method. In both uremic patients and normal subjects, these carcinogens have been detected in RBC as well as plasma. Trp-P-1 and Trp-P-2 levels in plasma of uremic patients were significantly higher than those of normal subjects. Moreover, these carcinogen levels in RBC (per hemoglobin) were significantly elevated in uremic patients in spite of the presence of severe anemia. These results suggest that patients with uremia are continuously exposed to higher levels of these carcinogens as compared with normal subjects. Our data also support the idea that these carcinogens in plasma and RBC are suitable for monitoring exposure levels in humans.

Adult↗
PubMed1991

Subcellular distribution of thyroxine 5'-monodeiodinase activity in rabbit kidney.

Thyroxine 5'-monodeiodinase is located in the proximal tubules of the rabbit kidney. To estimate the subcellular distribution of 5'-monodeiodinase activity, we prepared subcellular fractions, a basolateral membrane fraction and a brush border membrane fraction, from kidneys of Japanese white rabbits. Each fraction (0.5 mg protein) was incubated at 37 degrees C for 60 min with 0.5 micrograms T4 in the presence of 5 mM DTT. The T3 generated in the reaction mixture was extracted with cold ethanol and measured by RIA. For analysis of propylthiouracil-insensitive thyroxine 5'-monodeiodinase, we examined its kinetic behavior at nanomolar concentrations of the substrate, T4, in the presence of 100 microM propylthiouracil. In order of decreasing activity, basolateral membrane, microsomal fraction, mitochondrial fraction, cytosolic fraction, brush border membrane and nuclear fraction were capable of converting T4 to T3. Upon addition of 10(-5) M propylthiouracil to the reaction mixture, 5'-monodeiodinase activities of basolateral membrane and brush border membrane were inhibited by more than 90%, but that of microsomes was inhibited by only about 50%. In addition, kinetic analysis of microsomal 5'-monodeiodinase activity at nanomolar T4 concentrations in the presence of 10(-4) M propylthiouracil suggested on apparent Km of 3.8 nmol. These results indicate that there is high-Km 5'-monodeiodinase activity (PTU-sensitive) in the basolateral and brush border membranes and also high-Km and low-Km 5'-monodeiodinase (PTU-insensitive) in the microsomes of rabbit kidney.

Animals↗
PubMed1991

Cellular mechanism of lithium-induced nephrogenic diabetes insipidus in rats.

One of the mechanisms by which Li evokes polyuria is thought to be impairment of arginine vasopressin (AVP)-sensitive adenylate cyclase (AdC) in cells of the renal collecting duct. To investigate how AdC is influenced by chronic administration of Li, we created nephrogenic diabetes insipidus (NDI) in rats and microdissected the medullary collecting tubule from both control and NDI rats. In the NDI group, the 10(-6) M AVP-stimulated cAMP contents failed to increase completely, and the levels were significantly lower than that of the control group (10.4 +/- 1.4 vs. 48.4 +/- 4.7 fmol/mm, P less than 0.001). Pretreatment with pertussis toxin (PT), an inhibitor of inhibitory G protein (Gi), did not affect the basal cAMP levels in both groups, although it increased AVP-stimulated cAMP production in the NDI group in a dose- and time-dependent manner. AVP-stimulated cAMP production with over 100 ng/ml PT in the NDI group reached the levels observed in the control group. Incubation with cholera toxin, an agonist of stimulatory G protein (Gs), increased the cAMP content in the two groups to almost equal levels. To exclude the possibility that prostaglandin E2 (PGE2) is involved in the cellular mechanism of Li-induced NDI, the effect of indomethacin (Indo) on PT action was examined. However, Indo (10(-5) M) did not influence either the basal or AVP-dependent cAMP contents. From these results it is suggested that Li impairs AVP-sensitive AdC not through inhibition of Gs but through activation of Gi and that PGE2 may not be involved in the cellular pathogenesis of NDI at least in the rat at the step of cAMP formation.

1-Methyl-3-isobutylxanthine↗
PubMed1991

Application of plasma perfusion in hepatic failure.

To evaluate the efficacy of plasma perfusion as a liver-assistance system, 17 patients with hepatic failure were treated with a total 37 sessions of plasma perfusion and 43 sessions of plasma exchange. For plasma perfusion, Plasma-flo AP-08-H was used as a plasma separator, and the separated plasma was passed through an adsorber, Bespore UPC-III (Jap.Med.Suppl., Hiroshima) or BR 350 (Asahi Med. Co., Tokyo). The mean treated plasma volume was 5.0 liters. The mean proportion of bilirubin removed by routine plasma exchange was 29% with a mean of plasma exchange volume of 2.1 L. In the plasma perfusion with Bespore and BR, the removal rates were 37% and 42%, respectively. The plasma ammonia level decreased by 16% (from 121 to 97 mumol/L) with plasma exchange. Likewise, plasma perfusion decreased the plasma ammonia level from 75 to 56 mumol/L with an average decrement rate of 23%. The capacity for removal of amino acids was analyzed in terms of the change in the Fisher score ([Val+Leu+Ileu]/[Tyr+Phe]). The Fisher score was improved by plasma perfusion from 1.8 to 2.4. Thus, we concluded that in terms of removal of bilirubin, ammonia and amino acids, plasma perfusion was as efficient a therapy as plasma exchange. However, further clinical evaluation will be required before this procedure can be applied for the treatment of hepatic failure.

Adult↗
PubMed1989

Production of renin, angiotensin II, and aldosterone by adrenal explant cultures: response to potassium and converting enzyme inhibition.

The existence of renin in a number of extrarenal tissues has been well documented, but the physiological role of extrarenal renin remains unknown. To study the physiological role of adrenal renin, we developed a serum-free culture system for adrenal capsular/zona glomrulosa explants. Explants showed good viability in culture (greater than 80%), and demonstrated net production of aldosterone, angiotensin II, and prorenin. Aldosterone production was consistently stimulated by an increase in potassium (6 mM) in the culture medium. Both aldosterone and angiotensin II production could be attenuated by adding the angiotensin converting enzyme inhibitor lisinopril to the culture medium (0.1 mM). These data suggest that rat adrenal explants are capable of producing all of the components of a functional renin-angiotensin-aldosterone system and that these components can interact in response to physiological stimuli. These findings support the hypothesis that a local adrenal renin system may play a physiological role in the control of adrenal aldosterone production.

Adrenal Glands↗
PubMed1989

[Evaluation of antimicrobial schemes in episodes of fever and granulocytopenia in children with cancer].

The efficacy of two antibiotic regimens used as initial empiric therapy was evaluated in 299 episodes of fever and granulocytopenia in children with cancer. Of these, 148 were treated with the combination cefoxitin-amikacin-carbenicillin and the remaining 151 with ceftriaxone-amikacin. All of the patients were evaluated at the beginning and 72 hours after starting treatment with laboratory tests and based on their clinical condition. Each was classified according to the type of infection. A few modifications were made to the initial treatment plan and in accordance with the clinical condition of each patient. Over 52% of the episodes were due to fever of unknown origin and 47.2% due to infections, of which 33.8% proved to be positive blood cultures mainly for Staphylococcus aureus and Pseudomonas aeruginosa. The modifications made to the basic treatment regimens were the addition of amphotericin B, clindamycin or vancomycin. An 89.2% therapeutic index percentage was obtained, independent from the use of either antibiotic scheme. The total therapeutic index for the study was 83.6%.

Adolescent↗
PubMed1988

Adrenal renin: a possible local hormonal regulator of aldosterone production.

The complete renin-angiotensin system is present in the adrenal cortex: prorenin, renin, angiotensinogen, angiotensin I and II, and converting enzyme. Most of the renin found is probably synthesized there since the renin concentration increases after nephrectomy, and the mRNA for renin is present. The renin-angiotensin system has the highest activity in the zona glomerulosa cells, the site of aldosterone formation. A low-sodium diet or a high-potassium diet, or nephrectomy markedly increases the adrenal renin concentration in the zona glomerulosa cells without any effect on the fasciculata-medullary cells. There is a close correlation between adrenal renin and aldosterone production. The adrenal renin angiotensin system may be a local regulator of aldosterone production.

Adrenal Glands↗
PubMed1987

Dynamics of NAD in cortical nephron segments: effect of nicotinamide and of dietary phosphate intake.

NAD content and the rate of NAD hydrolysis were determined in proximal convoluted tubules (PCT), proximal straight tubules (PST), and adjacent cortical nephron segments microdissected from kidneys of thyroparathyroidectomized (TPTX) rats. In the basal state, rats fed a normal phosphate diet had an NAD content higher in PCT, PST, and in cortical ascending limb (CAL) than in glomeruli. After intraperitoneal injection of nicotinamide, the NAD content increased significantly in all nephron segments except CAL; the greatest (delta + 277%) increase was found in PCT, with less (delta + 82%) in PST. In experiments conducted on TPTX rats stabilized on a low-phosphorus diet, NAD content increased in response to a nicotinamide injection in PCT (delta + 197%), but did not change significantly in PST. The catabolism of NAD was determined by generation of [3H]adenosine, a major metabolite of [adenine-2,8-3H]NAD. The rate of [3H]adenosine generation from [3H]NAD was significantly (P less than 0.001) higher in PST than in PCT. We conclude that, in response to nicotinamide administration in vivo, the NAD content increases more in PCT than in PST and that this difference may be, at least partly, due to a lower rate of NAD breakdown in PCT. In a state of dietary phosphate deprivation, NAD also increases significantly in response to intraperitoneal nicotinamide in PCT, but it does not increase significantly in PST. The nicotinamide-elicited increase of NAD content in proximal tubules, mainly in PCT, may be related to inhibition of Na+-gradient-dependent inorganic phosphate (Pi) reabsorption across the brush-border membrane of proximal tubules and to the phosphaturic effect of nicotinamide in rats fed normal-Pi diet.

Animals↗
PubMed1986

Atrial natriuretic peptide elevates cGMP contents in glomeruli and in distal tubules of rat kidney.

Effect of synthetic rat atrial natriuretic peptide (1-28) (ANP) on the cGMP content was studied using defined nephron segments of rat kidney. ANP elevates cGMP contents in glomeruli in a concentration and time-dependent manner. The increase of cGMP was observed in glomeruli, distal convoluted tubule (DCT) and cortical collecting tubule (CCT) (delta %; 279 +/- 35, 148 +/- 10 and 152 +/- 18, respectively), and no effect was observed in proximal convoluted (PCT) and straight tubule (PST). These results suggest that ANP may act directly on the tubular cells as well as glomeruli. In glomeruli, effects of ANP and carbamylcholine on cGMP contents were additive suggesting that these two agents may act on different receptors. Angiotensin II and norepinephrine failed to affect the ANP-induced cGMP production in the glomeruli.

Angiotensin II↗
PubMed1986

Dynamics of nucleotides in distal nephron of mice with nephrogenic diabetes insipidus.

In mice with hereditary nephrogenic diabetes insipidus (NDI), the high activity of cAMP-phosphodiesterase (cAMP-PDIE) in medullary collecting tubules (MCT) prevents the increase in cAMP content in response to vasopressin [Arg8]vasopressin (AVP). Even when the cAMP response to AVP is partly corrected by cAMP-PDIE inhibitor 1-methyl-3-isobutylxanthine (MIX), under all tested conditions the cAMP levels in MCT of NDI mice remained much lower than in controls (B. A. Jackson, R. M. Edwards, H. Valtin, and T. P. Dousa, J. Clin. Invest. 66: 110-122, 1980). In the present study, we explored which factors may account for this defect. We determined contents of ATP, nicotinamide adenine dinucleotide (NAD), and the levels of cAMP in MCT and in medullary thick ascending limb of Henle's loop (MAL) microdissected from control and NDI mice. In the presence of 1 microM AVP and 0.05 mM MIX, the cAMP levels accumulated in MCT of NDI mice were four times lower compared with controls, but the levels of ATP and NAD were not different. ATP levels in MAL of NDI mice were slightly (delta -23%) lower than in MAL from controls, and in distal convoluted tubules (DCT) of NDI mice the ATP levels were also decreased (delta -49%). Although AVP alone had little effect on cAMP levels in mouse MAL in the presence of 0.1 mM forskolin, the AVP elicited a 20-fold increase of cAMP of both the control and NDI mice. Addition of 0.1 mM forskolin further increased the cAMP accumulation in MCT incubated with AVP.(ABSTRACT TRUNCATED AT 250 WORDS)

1-Methyl-3-isobutylxanthine↗
PubMed1985

ATP and cAMP system in the in vitro response of microdissected cortical tubules to PTH.

Responsiveness of proximal convoluted tubule (PCT) and distal convoluted tubule (DCT) microdissected from mouse kidney to PTH, in terms of cAMP accumulation and stimulation of adenylate cyclase, was examined. In both PCT and DCT, the cell-free adenylate cyclase was stimulated at least 10-fold by the same dose (10 U/ml) of PTH, and activity of cAMP phosphodiesterase was about 80% higher in DCT than in PCT. In intact tubules, while the incubation with PTH increased cAMP content in DCT more than 10-fold, it failed to increase the cAMP levels in PCT. To explain discrepancies between cell-free and intact cell incubations, ATP content in microdissected tubules was determined with use of a microbioluminescence assay. ATP content in PCT (4.0 +/- 1.3 fmol/mm, n = 30) was dramatically lower than ATP content of DCT (376.8 +/- 54.3 fmol/mm, n = 25). Incubation with 1 microM rotenone reduced markedly (delta -98%) the ATP content in DCT. In DCT, with ATP depleted by 1 microM rotenone, PTH failed to increase the cAMP, although 1 microM rotenone did not inhibit the adenylate cyclase activity. When 0.1 mM of 1-methyl-3-isobutylxanthine (MIX) was added to the incubation medium, PTH caused a marked elevation in tubular cAMP in PCT and to even a greater degree in DCT. Present results show that various segments of microdissected tubules differ greatly in their ability to maintain adequate ATP levels for cAMP generation in vitro.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine Triphosphate↗
PubMed1985

Effects of calcium on the vasopressin-sensitive cAMP metabolism in medullary tubules.

The modulatory effect of Ca on [Arg8]vasopressin-dependent (AVP) cAMP metabolism was studied in medullary collecting tubules (MCT) and medullary ascending limbs (MAL) microdissected from rat kidney. In MCT segments incubated in vitro with AVP, the accumulation of cAMP was enhanced (delta +59%) when Ca was omitted from the incubation medium compared with a medium with 2 mM of ionized calcium (Ca2+). Ionophore A23187 caused a decrease in AVP-stimulated cAMP accumulation in MCT in the presence of 2 mM Ca2+ but not in a Ca2+-free medium. Diltiazem and verapamil enhanced the AVP-stimulated cAMP accumulation in MCT; PTH had no detectable effect. A23187 caused a dose-dependent inhibition of cAMP accumulation stimulated by AVP with forskolin in both MCT and in MAL. However, in MAL the A23187 concentration needed for half-maximum inhibition (6.3 X 10(-6) M) was higher than for MCT (3.9 X 10(-7) M). The maximum inhibition in MAL (-65%) was less than in MCT (-97%). In the presence of 3-isobutyl-1-methylxanthine, AVP-stimulated cAMP accumulation was inhibited by A23187 in MCT (-45%) but not in MAL. Naproxen or ibuprofen did not relieve the inhibitory action of A23187 in MCT. Added Ca2+ inhibited the AVP-stimulated adenylate cyclase in MCT and MAL (half-maximum approximately equal to 5 X 10(-4) M Ca2+) and stimulated cAMP phosphodiesterase (cAMP-PDIE) in both MCT and in MAL (half-maximum approximately equal to 9 X 10(-5) M Ca2+). Incubation of MCT and MAL with A23187 decreased (-50%) the content of ATP. Results suggest that increased influx of extracellular Ca2+ inhibits the AVP-stimulated cAMP accumulation in MCT and to a much lesser degree in MAL. Deceased cAMP accumulation in MCT is probably due to both stimulation of cAMP-PDIE and the inhibition of adenylate cyclase, whereas in MAL it is due to stimulation of cAMP-PDIE. The results suggest that Ca2+ influx exhibits a negative modulatory effect on AVP-dependent cAMP metabolism mainly in MCT.

1-Methyl-3-isobutylxanthine↗
PubMed1985

Human alpha 1-microglobulin and its relationship to renal function.

To evaluate the clinical usefulness in terms of estimation for glomerular filtration rate (GFR), we determined the levels of alpha 1-microglobulin (alpha 1m) in the serum and urine of patients with various renal diseases and compared with those of beta 2-microglobulin (beta 2m) and creatinine. Serum and urinary alpha 1m levels were measured by using single-radial immunodiffusion method. 24-hour creatinine clearance (Ccr) was used as a indicator of GFR. There was a significant positive correlation between serum alpha 1m and creatinine levels (r = 0.75, p less than 0.001). Serum alpha 1m, beta 2m and creatinine inversely correlated and logarithmically correlated to Ccr as shown in the following equations: log alpha 1m = 2.30 - 0.42 X log Ccr (r = -0.74); log beta 2m = 2.06 - 0.91 X log Ccr (r = -0.92); log creatinine = 1.57 - 0.78 X log Ccr (r = -0.94). Both correlation coefficient and regression coefficient for alpha 1m were rather poor compared to those for beta 2m and creatinine. However, alpha 1m levels started to increase over normal range when Ccr fell below 80 liters/day, while beta 2m and creatinine remained within normal ranges. The daily urinary excretion of alpha 1m was increased in the patients whose Ccr was within normal limits compared to that of healthy control subjects (15.2 +/- 3.2 mg/day, n = 19, vs. 5.7 +/- 0.7, n = 7, p less than 0.001). Fractional clearance of alpha 1m increased proportionally to the decrease of Ccr. These data suggest that combined measurements of alpha 1m in the serum and urine seem to be useful to estimate GFR, especially to detect the mild reduction of CFR.

Adolescent↗
PubMed1985

Pathogenesis of nephrogenic diabetes insipidus due to chronic administration of lithium in rats.

A polyuric syndrome with nephrogenic diabetes insipidus (NDI) is a frequent consequence of prolonged administration of lithium (Li) salts. Studies in the past, mainly the acute and in vitro experiments, indicated that Li ions can inhibit hydroosmotic effect of [8-arginine]vasopressin (AVP) at the step of cAMP generation in vitro. However, the pathogenesis of the NDI due to chronic oral administration of low therapeutic doses of Li salts is not yet clarified. We conducted a comprehensive study to clarify the mechanism by which Li administered orally for several weeks induces polyuria and NDI in rats. Albino rats consuming a diet which contained Li (60 mmol/kg) for 4 wk developed marked polyuria and polydipsia; at the end of 4 wk the plasma Li was 0.7 +/- 0.09 mM (mean +/- SEM; n = 36). Li-treated rats had a significantly decreased (-33%) tissue osmolality in papilla and greatly reduced cortico-papillary gradient of urea (cortex--43%; medulla--64%; papilla--74%). Plasma urea was significantly (P less than 0.001) lower in Li-treated rats (5.4 +/- 0.2 mM) compared with controls (6.8 +/- 0.3 mM). Medullary collecting tubules (MCT) and papillary collecting ducts (PCD) microdissected from Li-treated animals had higher content of protein than MCT and PCD from the control rats. The cAMP accumulation in response to AVP added in vitro was significantly (delta = -60%) reduced. Also, the cAMP accumulation in MCT and PCD after incubation with forskolin was markedly lower in Li-treated rats. Addition of 0.5 mM 1-methyl,3-isobutyl-xanthine did not restore the cAMP accumulation in response to AVP and forskolin in MCT from Li-treated animals. In collecting tubule segments from polyuric rats with hypothalamic diabetes insipidus (Brattleboro homozygotes) the AVP-dependent cAMP accumulation was not diminished. The activity of adenylate cyclase (AdC) in MCT of Li-treated rats, both the basal and the activity stimulated by AVP, forskolin, or fluoride, was significantly (delta approximately equal to -30%) reduced, while the activity of cAMP phosphodiesterase (cAMP-PDIE) in the same segment showed no significant difference from the controls. Also, the content of ATP in MCT microdissected from Li-treated rats and incubated in vitro did not differ from controls. The rate of [14C]succinate oxidation to 14CO2 in MAL was inhibited (-77%) by 1 mM furosemide, which indicates that this metabolic process is coupled with NaCl cotransport in MAL. The rate of (14)CO(2) production from [14C]succinate in MAL was not significantly different between control and Li-treated rats. In MCT of control rats, the rate of [14C]succinate oxidation was approximately 3 times lower than in MAL. The rate of (14)CO(2) production from [(14)C]succinate in MCT of Li-treated rats was significantly (delta +33%) higher than in MCT dissected from control rats. Based on these results, we conclude that at least two factors play an important role in the pathogenesis of NDI consequent to chronic oral administration of Li: (a) decreased ability of MCT and PCD to generate and accumulate cAMP in response to stimulation by AVP; this defect is primarily due to diminished activity of AdC in these tubular segments caused by prolonged exposure to Li; and (b) lower osmolality of renal papillary tissue, due to primarily to depletion of urea, which decreases osmotic driving force for water reabsorption in collecting tubules. On the other hand, NaCI reabsorption in MAL is apparently not affected by chronic Li treatment.

3',5'-Cyclic-AMP Phosphodiesterases↗