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Biomedical subjects

K Takagi

Publications and source records attributed to K Takagi.

At least 19 recordsLinked to original sources
PubMed1992

Effects of alkyl substitutions of xanthine skeleton on bronchodilation.

Structure-activity relationships in a series of 1,3,7-trialkyl-xanthine were studied with guinea pigs. Relaxant actions in the tracheal muscle were increased with alkyl chain length at the 1- and 3-positions of the xanthine skeleton, but decreased by alkylation at the 7-position. Positive chronotropic actions in the right atrium were potentiated with 3-alkyl chain length but tended to decrease with 1-alkylation and diminish by 7-substitution. Consequently, while the 1- and 3-substitutions were equally important for the tracheal smooth muscle relaxation, the substitution at the 1-position was more important than the 3-substitution for bronchoselectivity. The 7-alkylation may be significant to cancel heart stimulation. There were good correlations between the smooth muscle relaxant action and the cyclic AMP-PDE inhibitory activity in 3-substituents and the affinity for adenosine (A1) receptors in 1-, 3-, and 7-substituents. This suggests that not only the cyclic AMP-PDE inhibitory activity but also the adenosine antagonistic activity is important in the bronchodilatory effects of alkylxanthines. Among these xanthine derivatives, 1-butyl-3-propylxanthine and its 7-methylated derivative showed high bronchoselectivity in the in vitro and in vivo experiments compared to theophylline and enprofylline and may be new candidates for bronchodilator.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Reversal of vinblastine resistance by a new staurosporine derivative, NA-382, in P388/ADR cells.

Activities of a newly synthesized compound, N-ethoxycarbonyl-7-oxo-staurosporine (NA-382), on cyclic AMP-dependent protein kinase (A-kinase), Ca2+/phospholipid dependent protein kinase (C-kinase), and drug resistance were investigated and compared with those of staurosporine. Protein kinase-inhibitory activity of NA-382 was lower but more selective to C-kinase than that of staurosporine. NA-382 was less toxic to P388 cells and at a non-cytotoxic concentration completely reversed the vinblastine (VBL) resistance of Adriamycin-resistant P388 (P388/ADR) cells without influence on the effect of VBL on the parental P388/S cells. However, the cytotoxicity of staurosporine was too high to give the combination effect with VBL. NA-382 dose-dependently increased VBL-accumulation and inhibited VBL-efflux in P388/ADR with higher potency than staurosporine. Both compounds inhibited the photolabeling of [3H]azidopine on 140-kDa P-glycoprotein in the plasma membrane from the resistant cells. These results suggest that a staurosporine analog, NA-382, reverses multidrug resistance by inhibiting the drug-efflux system or P-glycoprotein.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1992

Relaxant effect of pituitary adenylate cyclase-activating polypeptide on guinea-pig tracheal smooth muscle.

We investigated the relaxant effect of the pituitary adenylate cyclase-activating polypeptide with 27 residues (PACAP27) and with 38 residues (PACAP38) on guinea-pig tracheal smooth muscle. Both forms of PACAP showed dose-dependent relaxant effects. The EC50 of PACAP27 was 8.7 +/- 1.9 x 10(-8) M and that of PACAP38 was 6.8 +/- 1.0 x 10(-8) M. Both increased cyclic AMP levels dose dependently and the elevation of cyclic AMP preceded the relaxation of tracheal smooth muscle. There was a marked difference in the duration of action of the two peptides. PACAP38 showed a longer-lasting relaxation compared to PACAP27. Furthermore PACAP38 maintained significantly higher levels of cyclic AMP, with cyclic AMP levels at 60 min after a 5-min exposure to PACAPs (10(-6) M) being 14.0 +/- 1.4 pM/mg protein for PACAP27 and 35.9 +/- 2.4 pM/mg protein for PACAP38. These results suggest that PACAP27 and PACAP38 may be novel potent relaxants in tracheal smooth muscle and their relaxant effect might be mediated by cyclic AMP. However PACAP38 had a longer-lasting action on relaxation of tracheal smooth muscle and production of tissue cyclic AMP than PACAP27.

Animals↗
PubMed1992

Direct activation of phospholipase A2 by GTP-binding protein in human peripheral polymorphonuclear leukocytes.

In human peripheral polymorphonuclear leukocyte (PMN), 10% of PLA2 activity was found in the particulate fraction. In the particulate fraction, the activity of phospholipase A2 was enhanced 270% by 100 microM guanosine 5'-[gamma-thio]triphosphate, a hydrolysis-resistant analog of GTP. In the soluble fraction, such enhancement was not observed. Guanosine 5'-[beta-thio]diphosphate (2 mM), which irreversibly inactivates GTP-binding protein, blocked the enhancement in the particulate fraction. Membrane-binding phospholipase A2 activity of PMN would thus appear to be regulated directly by GTP-binding protein.

Enzyme Activation↗
PubMed1992

Portal hypertensive gastropathy in patients with cirrhosis.

Portal hypertensive gastropathy is a recently recognized important complication of cirrhosis. In the present study, the clinical features, portohepatic hemodynamics, and hepatic function were investigated in a series of 47 patients with cirrhosis. Mild gastropathy was found in 15 patients (32%) and severe gastropathy in 17 patients (36%). The presence of gastropathy seemed to be independent of age, sex, cause of cirrhosis, or grade of gastroesophageal varices. However, severe gastropathy was associated with an increase in portal venous pressure gradient (vs. control, P less than 0.01; vs. mild gastropathy, P less than 0.01), an increase in hepatic sinusoidal resistance (vs. control, P less than 0.01; vs. mild gastropathy, NS), and a decrease in hepatic blood flow (vs. control, P less than 0.01; vs. mild gastropathy, NS). In addition, patients with severe gastropathy had impaired metabolic activity of the liver, which was assessed by intrinsic clearance of indocyanine green (vs. control, P less than 0.01; vs. mild gastropathy, NS). These observations may have important therapeutic implications in patients with cirrhosis and portal hypertensive gastropathy.

Aged↗
PubMed1992

Changes of superoxide dismutase activity and ascorbic acid in focal cerebral ischaemia in rats.

Free radical reactions are supposed to cause ischaemic brain damage, and active oxygens can initiate these chains reaction. If active oxygens play important roles in ischaemic brain damage, the activity of superoxide dismutase, scavenger of superoxide anion, is supposed to decrease in ischaemic brain. The reduced form of ascorbic acid also scavenges superoxide anion. In rat middle cerebral artery focal ischaemia, we investigated the changes in superoxide dismutase activity and the concentration of reduced ascorbate up to 48 hours. Middle cerebral artery territory of each cerebral hemisphere was homogenized. The supernatant was divided into two aliquots; one was dialysed to remove ascorbate and the other was not. The enzyme activity of the dialysed specimen from the ischaemic hemisphere did not decrease within 4 h after the arterial occlusion. The activity of the dialysed specimen from the nonischaemic side remained unchanged during the examination. Reduced ascorbate levels in nondialysed samples showed similar changes to the superoxide dismutase activities in the dialysed samples. Our data suggest that ascorbic acid may exert the enzyme activity and that the enzyme activity remains at the normal level in the early phase of ischaemia despite the irreversible ischaemic changes that take place within 4 h after the onset of ischaemia.

Animals↗
PubMed1992

Bronchodilatory activity and pharmacokinetics of new xanthines in guinea-pigs.

1. The in vitro biological activities and the effect of protein binding on the relaxant effects in vivo of N-3-alkylxanthine and N-3-alkyl-N-1-methylxanthine derivative were investigated in guinea-pigs. 2. A significantly positive correlation was observed among the in vitro muscle relaxant activity, the cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitory activity and the protein-binding potency of xanthine derivatives. However, there was a weak relationship between these activities and affinity for adenosine receptors. 3. When theophylline, enprofylline and 1-methyl-3-propylxanthine (MPX) were injected intravenously in guinea-pigs, their ED50 values were 6.1, 3.3 and 1.0 mg/kg, respectively. Plasma concentrations of these drugs obtained following the intravenous injection of the ED50 approximated the theoretically effective concentration (EC50) predicted from both the relaxant effects in vitro and the protein binding parameters. A good linear correlation was observed between bodyweight in four species (rats, guinea-pigs, rabbits and humans) and certain pharmacokinetic parameters of enprofylline and theophylline. 4. The present study indicates that differences in the relaxant effects of these drugs in vitro and in vivo can be explained in part by protein binding, and that the protein binding of these xanthine bronchodilators is an important determinant for their pharmacological activity. Guinea-pigs provide a useful model for studying pharmacodynamic-pharmacokinetic relationships of new bronchodilators.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Platelet-activating factor in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome.

1. To clarify the role of platelet-activating factor (PAF) in the development of adult respiratory distress syndrome (ARDS), we performed bronchoalveolar lavage (BAL) in 19 patients with ARDS and examined cell populations, albumin concentrations and PAF levels. PAF levels were measured by a newly developed radioimmunoassay. 2. In the BAL fluid of ARDS patients, neutrophil percentages and albumin concentrations markedly increased compared with control subjects. 3. PAF was detected in 14 of 19 patients with ARDS, whereas it did not exist in the control subjects. 4. Furthermore, we investigated the priming effect of recombinant human tumour necrosis factor-alpha (TNF alpha), which is known to be one of the most important mediators in the development of ARDS, on PAF production induced by the calcium ionophore in neutrophils. 5. Pre-incubation with TNF alpha dose-dependently increased both extracellular and intracellular PAF production in neutrophils. 6. These results suggest that PAF might play an important role in the development of ARDS.

Adolescent↗
PubMed1992

Selective bronchodilators from 1-(5'-oxohexyl)xanthines.

A series of twenty one 1-(5'-oxohexyl)xanthines substituted with alkyl chains at the N3 and N7 positions of the xanthine nucleus were prepared and their relaxant activity in guinea-pig isolated tracheal muscle and positive chronotropic activity in isolated right atrium of guinea-pig were compared. The tracheal relaxant activities were markedly increased with alkyl chain length at the N3 position, but decreased by the N7 alkylation. The positive chronotropic activities in the right atrium were increased by introduction of an n-propyl group at the N3 position but decreased by substitution of longer alkyl chains, and the action on the heart was diminished by N7 substitution. The activities of compounds on cAMP-phosphodiesterase (PDE) and binding of [3H]8-cyclopentyl-1,3-dipropylxanthine were measured in the homogenate of tracheal muscle and the membrane preparation of cerebral cortex, respectively. No relationship among tracheal muscle relaxant activity, cAMP-PDE inhibitory activity and adenosine antagonism of these xanthines was observed, and other action mechanisms should be considered for their relaxant activities. This study indicated that N3 alkylation is important for the selectivity for tracheal muscle, while the introduction of long alkyl chains such as n-butyl and n-pentyl groups at the N3 and N7 positions diminished the potency for the right atrium in guinea-pigs. 3-n-Pentyl- and 7-methyl-3-n-pentyl-1-(5'-oxohexyl)xanthines showed much higher bronchoselectivity than oxpentifylline and theophylline.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1992

Interspecies differences and scaling for the pharmacokinetics of xanthine derivatives.

Pharmacokinetic characteristics of the new xanthine bronchodilators, enprofylline and 1-methyl-3-propylxanthine (MPX), were investigated in mice, rats, guinea-pigs, rabbits and dogs. The possibility of an interspecies pharmacokinetic scale was also evaluated. The concentration of these two drugs in plasma and urine was determined by HPLC. Pharmacokinetic parameters were calculated using model-independent methods. The disappearance curves of the two drugs from plasma varied markedly among animal species. Interspecies differences in the plasma protein binding of each drug were observed for all animals in the study. Differences in the biotransformation of enprofylline and MPX were also confirmed among the various animal species: enprofylline is mainly excreted in an unchanged form in urine while MPX follows a non-renal route of elimination. In all animals, the renal clearance for enprofylline was greater than the glomerular filtration rate, indicating active tubular secretion. Significant allometric relationships were seen between the values of total body clearance and steady state volume of distribution for both total and unbound enprofylline and species body weight, but similar correlations could not be recognized for MPX. Renal clearance of enprofylline was also closely correlated with species body weight, suggesting no interspecies difference with relation to affinity and/or capacity for the active tubular secretion mechanism of enprofylline. Our findings suggest that xanthine derivatives, including enprofylline, are mainly eliminated via the kidney, and an estimate of the basic pharmacokinetics in man can be obtained from data in experimental animals.

Animals↗
PubMed1992

Implication of oxygen radicals on airway hyperresponsiveness after ovalbumin challenge in guinea pigs.

We elucidated the implication of oxygen radicals on airway hyperresponsiveness after ovalbumin (OA) challenge in guinea pigs. Ten days OA exposure increased airway responsiveness, i.e., a significant decrease in log [acetylcholine (Ach) PC200] (2.445 +/- 0.227) was observed compared with the control group (3.398 +/- 0.269). After OA exposure, the number of beta-adrenoceptors decreased by 38%, and adenylate cyclase activity decreased by 36% (isoproterenol stimulated) and 28% (basal). Significant increases in xanthine oxidase activities in lung tissue, bronchoalveolar lavage fluid (BALF), and serum were observed after the tenth OA exposure (49.1 +/- 11.7 mU/g tissue, 12.6 +/- 3.16 mU/ml, and 11.5 +/- 2.66 mU/ml, respectively) compared with those in the control group (7.35 +/- 6.48 mU/g tissue, 2.85 +/- 1.17 mU/ml, and 3.51 +/- 1.15 mU/ml, respectively). Administration of long-acting superoxide dismutase (SOD) (5,000 U/kg twice a day intraperitoneally) or gamma-glutamylcysteine ethyl ester (gamma-GCE) (10 mg/kg, twice a day, intraperitoneally), a prodrug of glutathione, maintained log [Ach PC200] (3.248 +/- 0.415 and 3.298 +/- 0.246, respectively) in spite of 10 days OA exposure. Decreases in the number of beta-adrenoceptors and adenylate cyclase activity were prevented by long-acting SOD or gamma-GCE. In contrast, long-acting SOD or gamma-GCE inhibited significantly, but not completely, the elevation of xanthine oxidase activities. These results support suggestions that oxygen radicals might be involved in the underlying mechanism of airway hyperresponsiveness after OA challenge in guinea pigs.

Adenylyl Cyclases↗
PubMed1992

Age-related decrease in respiratory muscle mitochondrial function in rats.

The purpose of this study was to elucidate the effects of aging on diaphragmatic mitochondrial function. Diaphragm mitochondria were prepared from specific pathogen-free rats aged 7 wk (n = 7), 35 wk (n = 7), and 55 wk (n = 7). The activities of various portions of the mitochondrial electron transport chain, i.e., complexes I, II, III, and IV, were measured enzymatically. The specific activities of complex I decreased significantly (P less than 0.01) in 35-wk-old rats (726 +/- 90 nmol/min/mg protein) compared with 7-wk-old rats (1,018 +/- 121), and the decrease was more remarkable in 35-wk-old rats (565 +/- 64; P less than 0.01 versus 35-wk-old). The activities of complex IV also decreased significantly (P less than 0.01) in 55-wk-old rats (1,222 +/- 191) compared with 7-wk-old rats (1,797 +/- 208); however, no significant changes in complex IV activities between 7-wk-old rat and 35-wk-old rats were observed. In contrast, the activities of complex II and III were not affected by aging. Limb muscle, heart, and liver mitochondria were also prepared from the same rats. The same tendency was observed in limb muscle mitochondria; however, in heart and liver mitochondria, activities of all four complexes were not changed in rats of all age groups. These results indicate that vulnerability of mitochondrial electron transport chain to aging differs from organ to organ and that it also differs from portion to portion in the electron transport chain and the most vulnerable site was complex I.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Aging-associated deletions of human diaphragmatic mitochondrial DNA.

It is known that respiratory function deteriorates with age. Endogenous damage to DNA is thought to contribute to the aging process. The mitochondrial oxidative phosphorylation system, a bio-engine, consists of five complexes, and 13 subunits of those complexes are biosynthesized from information encoded in mitochondrial DNA. Mitochondrial DNA is shown to have a much higher mutation rate than nuclear DNA. We examined the diaphragms obtained at autopsy from 34 humans, 23 men and 11 women, ranging in age from 25 to 85 yr, for mitochondrial DNA deletions using the polymerase chain reaction method. Multiple mitochondrial DNA deletions were detected particularly among the elderly; the number of deletions in those over age 70 was significantly higher than in those under age 40. The occurrence of a 3.4-kbp deletion of mitochondrial DNA increased with age, i.e., 0% of those under age 30, 20.0% of those in their forties, 25.0% of those in their fifties, 28.6% of those in their sixties, 72.7% of those in their seventies, and in all of those over age 80. The mutation was based on the directly repeated sequence, 5'-TCACCCC-3', which exists in both the CO3 gene and the ND5 gene. Replication impairment occurred at that directly repeated sequence, which caused the elimination of a genome between the CO3 gene and the ND5 gene, and information for biosynthesis of four subunits in complex I (ND3, ND4L, ND4, and ND5), one in complex IV (CO3), and five transfer RNA genes was missing.(ABSTRACT TRUNCATED AT 250 WORDS)

Aging↗
PubMed1992

Effect of nitrite on cell growth and antibody production in mouse splenic B cells stimulated with lipopolysaccharide and B cell hybridomas.

Nitric oxide, nitrite and nitrate are released by activated macrophages in an immune response. We showed here that nitrite influenced cell growth and antibody production in mouse lipopolysaccharide (LPS)-stimulated splenic B cells and B cell hybridomas. The addition of 10(-7) and 10(-6) M nitrite enhanced deoxyribonucleic acid (DNA) synthesis of LPS-stimulated splenic B cells. However, DNA synthesis and antibody production in the case of total spleen cells stimulated with LPS were suppressed by nitrite in a dose dependent-manner. These phenomena were also observed in a similar experiment involving mouse B cell hybridomas. Antibody production of all B cell hybridomas was significantly suppressed by the addition of nitrite. This suppressing effect could not be explained by changes in viable cell yields. This data suggests that the antibody production and cell proliferation of B cells may be influenced by nitrite from activated macrophages in the immune response.

Animals↗
PubMed1992

Effects of a new histamine H2-receptor antagonist, Z-300, on gastric secretion and gastro-duodenal lesions in rats: comparison with roxatidine.

We examined the effects of a new compound, N-[3-[3-(piperidinomethyl)phenoxy]-propyl]-2-(2-hydroxyethyl-1- thio)acetamido.2-(4-hydroxy benzoyl)benzoate (Z-300), on the histamine H2-receptor, gastric secretion in rats and dogs, and acute gastro-duodenal lesions or chronic gastric ulcers in rats. Roxatidine acetate hydrochloride (roxatidine), a known histamine H2-receptor antagonist, was used as a reference compound. The pA2 values for Z-300 and roxatidine for the isolated guinea pig atrium were 6.8 and 7.0, respectively. These agents at less than 10(-5) M did not affect the contraction of guinea pig ileum in response to carbachol. Z-300, administered either orally or parenterally, significantly inhibited the basal and histamine-stimulated gastric acid secretion in rats. Gastric acid secretion stimulated by histamine, pentagastrin or carbachol in Heidenhain pouch dogs was also significantly inhibited by the compound. The effect persisted for greater than 7 hr in the case of histamine-stimulation. Oral Z-300 significantly protected the gastric mucosa from water-immersion stress-, indomethacin-, aspirin- and HCl.ethanol-induced lesions and protected the duodenal mucosa against mepirizole- and cysteamine-induced ulcers. These effects on gastric secretion and lesion formation were, as a whole, stronger than those observed with roxatidine. Z-300, but not roxatidine, significantly accelerated the spontaneous healing of acetic acid ulcers induced in rats and prevented the delay in ulcer healing caused by indomethacin. The mechanism of action of Z-300 on acute lesions and chronic ulcers appears to be mostly related to its potent antisecretory and mucosal-protective activities.

Acetamides↗
PubMed1992

7S collagen in bronchoalveolar lavage fluid of patients with adult respiratory distress syndrome.

To evaluate the disruption of the basement membrane in the pathogenesis of adult respiratory distress syndrome (ARDS), we measured the level of 7S collagen in the bronchoalveolar lavage (BAL) fluid of patients with ARDS and normal control subjects by using a radioimmunoassay method. Twelve of 14 patients with ARDS had evidence of 7S collagen in the BAL fluid, but no 7S collagen was detected in the BAL fluid of the controls. The mean 7S collagen concentration of the BAL fluid in patients with ARDS was 19.6 +/- 9.4 ng/ml. In patients with ARDS, the BAL levels of 7S collagen correlated strongly with neutrophil counts (r = 0.813; p less than 0.01) and with elastase-complex (r = 0.914; p less than 0.01). We conclude that 7S collagen may be an index of leukocyte-mediated lung injury in patients with ARDS, and detection of 7S collagen in BAL fluid is useful for evaluating the disruption of basement membrane.

Adult↗
PubMed1992

[Upper gastrointestinal bleeding in the elderly].

Due to increasing number of the elderly, cases of hematemesis and melena in the aged have been increasing. The authors evaluated 69 such cases over 60 years old in whom emergency endoscopy of the upper digestive tract was carried out because of hematemesis and melena. Twenty cases are diagnosed as gastric ulcer (29%), 12 cases as esophageal ulcer and esophageal erosion (17.4%), 9 as duodenal ulcer (13.0%), 7 as gastric cancer (10.1%), 6 as Mallory-Weiss syndrome (8.7%), 6 as esophageal and gastric varices (8.7%), 4 as acute hemorrhagic gastritis (5.8%), 3 as Dieulafoy's ulcer (4.3%), and one case each of chronic pancreatitis (hemosuccus pancreaticus) and hemorrhage due to gastric angiodysplasia (1.4%). Of these cases, blood transfusion was performed in 46 cases (66.7%), and shock occurred in 27 cases (39.1%). The endoscopical hemostatic procedure was effective for detection of underlying diseases in the aged. Surgery was often impossible because of the rapid deterioration of the systemic condition due to the hemorrhage of the digestive tract.

Aged↗