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Biomedical subjects

J Higaki

Publications and source records attributed to J Higaki.

At least 235 records · Page 13Linked to original sources
PubMed1989

Metabolism of a thromboxane A2 antagonist in isolated rat hepatocytes.

Metabolism of a thromboxane A2 antagonist (+/-)-5-(Z)-7-(3-endo-phenylsulphonylaminobicyclo[2.2.1]hept-2- exoyl)- heptenoic acid (S-145) in isolated rat hepatocytes was examined by high-performance liquid chromatography and gas chromatography/mass spectrometry. As the hydrophobic metabolites, bis-nor S-145, tetra-nor S-145 and bis-nordihydro S-145 were identified, and two other products were estimated to be monohydroxylated S-145 and dehydrogenated S-145. On the basis of kinetics of S-145 metabolism, a metabolic pathway of S-145 in isolated hepatocytes is tentatively proposed.

Animals↗
PubMed1989

Stereoselective glutathione conjugation of a uricosuric diuretic.

A reduction of cellular glutathione (GSH) content was observed when isolated rat hepatocytes were incubated with a stereoisomer of a uricosuric diuretic (S-8666) at a high concentration. Subsequent studies have revealed it was due to conjugation of GSH and S-8666 (-)-enantiomer in the liver cytosol. The (+)-enantiomer strongly inhibited the conjugation reaction, therefore, GSH depletion did not take place when a racemic form of S-8666 was incubated with the liver cells. A possible chemical structure of the GSH-conjugate is tentatively proposed.

Animals↗
PubMed1989

Glutathione conjugation of synthetic steroids in isolated rat hepatocytes.

When designing steroid drugs with multiple double bonds, the influence of glutathione conjugation on the pharmacodynamics of drug action should be considered. We have examined the effect of canrenone, a mineralocorticoid receptor antagonist, on isolated rat hepatocytes and found that 1 mM canrenone injured the hepatocytes during shortterm incubation at 37 C, while an analogue of canrenone which bears 4 double bonds (delta 1,11-CAN) did not manifest such toxicity. To further pursue this, we prepared testosterone analogues comprising multiple double bonds as model compounds, and incubated them with freshly isolated rat hepatocytes. The viability of the hepatocytes was not influenced by any of the steroids, but some of them having a double bond at the C6-C7 position reduced the cellular glutathione levels. This was found to be due to conjugation of glutathione to the C7 position of the steroid molecule, and the rate of conjugation was accelerated when an additional double bond was introduced at C1-C2 or C11-C12 positions. The finding is interesting as glucuronidation or sulfation are common as conjugation processes of steroids.

Animals↗
PubMed1989

Chemical structure and toxicity of diuretics in isolated hepatocytes.

The effects of several diuretics, including tienilic acid and indacrinone, on isolated rat heaptocytes were examined. Addition of tienilic acid and indacrinone at 1 mM to a suspension of freshly isolated cells caused dose-dependent loss of cell viability as judged by the LDH-latency test. Survey of 19 structurally related compounds revealed that the extent of cell injury and chemical structure were correlated, and an intense adverse effect was attributed to the 2-thienylcarbonyl moiety. Several other factors influencing cell viability are also disclosed. Further study revealed that tienilic acid and indacrinone were toxic to the primary culture of hepatocytes at a lower dose than that a freshly isolated hepatocytes. Thus, an isolated hepatocyte system can be used to select compounds displaying low hepatotoxicity, as for example is needed when screening diuretics.

Animals↗
PubMed1989

Measurements of enzyme activity and immunoreactivity of plasma renin. Limitations of the conventional method for assay of plasma renin catalytic activity.

The values for "plasma renin activity", "plasma renin concentration" (both determined by the rate of angiotensin I generation) and the plasma active renin protein mass concentration (active enzyme protein measured by a direct radioimmunoassay) were compared. The values for "plasma renin activity" (angiotensin I generation from endogeneous renin substrate) and "plasma renin concentration" (angiotensin I generation from exogeneous excess of renin substrate) showed a significant correlation. However, the correlation was lost in samples with high (plasma renin activity greater than or equal to 10 micrograms/l.h) and low (plasma renin activity less than or equal to 1 microgram/l.h) renin contents. In another study, values for "plasma renin activity" were correlated with those for plasma active renin protein mass concentration, and values for "plasma renin concentration" were also correlated to those for plasma active renin protein mass concentration. However, in samples with low renin contents (plasma active renin protein mass concentration less than or equal to 20 ng/l), there was no correlation between values for "plasma renin activity" and plasma active renin protein mass concentration, although those for "plasma renin concentration" and plasma active renin protein mass concentration showed a significant correlation. These results suggest that the current method for the assay of plasma renin activity gives erroneous values for low and high plasma renin concentrations. The new radiometric method for the determination of the plasma active renin protein mass concentration seems to be applicable to plasma samples with a wide range of renin concentrations.

Angiotensin I↗
PubMed1989

Effects of aging on human plasma renin: simultaneous multiple assays of enzyme activity and immunoactivity of plasma renin.

The effects of aging on plasma renin in normotensive volunteers were evaluated by conventional indirect RIA of angiotensin I and a newly developed direct RIA. Plasma renin activity and the plasma concentration of active renin measured by radiometric assay with monoclonal antibody were significantly lower in 14 subjects over 60 years than in 15 subjects under 60 years (plasma renin activity: 0.5 +/- 0.1 vs 1.7 +/- 0.4 nmol.1-1.h-1, P less than 0.01; plasma active renin: 0.50 +/- 0.05 vs 0.87 +/- 0.13 pmol/l, P less than 0.01, means +/- SEM), whereas neither the total renin activity nor the total plasma renin concentration measured by the newly developed immunometric assay were different in the two groups. In another study, the plasma renin concentration, total renin concentration and immunoreactive total renin concentration measured by direct RIA with polyclonal antibody were determined in 17 young (less than 60 years) and 12 elderly (greater than or equal to 60 years) subjects. Plasma renin concentration was significantly lower in the elderly subjects (1.7 +/- 0.2 nmol.l-1.h-1) than in young subjects (3.2 +/- 0.7 nmol.l-1.h-3, P less than 0.05), but the total renin concentration and immunoreactive total renin concentrations in the two groups were not significantly different. These results indicate that the total renin content of the plasma does not change, whereas the active renin content decreases with age in normal subjects, and suggest that activation of prorenin to active renin may be impaired in elderly subjects.

Adult↗
PubMed1989

Proteolytic activation of aldosterone biosynthesis in rabbit adrenal capsular cells by alpha-chymotrypsin.

The effect of chymotrypsin on aldosterone biosynthesis by dispersed rabbit adrenal capsular cells was examined. Bovine alpha-chymotrypsin at concentrations of 10(-7) to 10(-5) M stimulated aldosterone production, and human chymotrypsin had an even stronger stimulatory effect. Bovine trypsin had no effect on aldosterone production by adrenal cells. Chymotrypsin treatment did not change the sensitivity of the adrenal cells to ACTH or angiotensin II. These results suggest the existence of unique chymotrypsin-susceptible sites on rabbit adrenal capsular cells, the digestion of which results in stimulation of aldosterone biosynthesis.

Adrenal Glands↗
PubMed1989

Changes in plasma active renin and prorenin after endoscopic retrograde pancreatography.

Plasma active renin, total renin (active renin plus prorenin) and immunoreactive trypsin were measured simultaneously before and after endoscopic retrograde pancreatography (ERP) in 9 subjects suspected of having pancreatic or biliary disease. After ERP, their plasma immunoreactive trypsin level increased significantly (p less than 0.02) from 12.4 +/- 1.5 to 163 +/- 57 ng/ml (means +/- SEM), while their plasma renin activity, total renin activity and ratio of active renin to total renin did not change. Individual values for the ratio of active renin to total renin correlated significantly (p less than 0.01) with those for immunoreactive trypsin in the basal condition (before ERP), but not after ERP. These results suggest that plasma trypsin is involved in activation of prorenin to active renin in the basal condition, and that ERP-induced increase in plasma trypsin has no effect on activation of prorenin.

Blood Pressure↗
PubMed1988

Endothelin inhibits renin release from isolated rat glomeruli.

The effect of endothelin on renin release from isolated rat glomeruli was examined. Endothelin inhibited basal renin release in a dose-dependent manner with an IC50 of 1.0 x 10(-9) M. Endothelin also inhibited renin release stimulated by isoproterenol (10(-5) M). Nifedipine (10(-5) M), a calcium channel blocker, induced an increase in renin release. Endothelin did not affect this nifedipine-induced renin release. These results suggest that endothelin inhibits renin release via a calcium entry mechanism and increases intracellular calcium.

Animals↗
PubMed1988

Effects of frusemide and captopril on the relationship between biologically and immunologically active renin in human plasma.

1. The plasma renin concentration (PRC) and active renin concentration determined by radioimmunometric assay (ARC) were measured before and after administration of frusemide or captopril to normal volunteers. 2. Injection of 40 mg of frusemide followed by 1 h in the upright position significantly increased both PRC (P less than 0.001) and ARC (P less than 0.001). Oral administration of 50 mg of captopril also increased PRC (P less than 0.05) and ARC (P less than 0.05). 3. ARC and PRC were linearly correlated in the basal supine position [y = 0.635x - 0.048 (y = PRC, x = ARC), r = 0.958, P less than 0.001], after frusemide injection and standing (y = 0.800x + 0.359, r = 0.793, P less than 0.02) and after captopril administration in the supine position (y = 0.938x - 0.555, r = 0.998, P less than 0.001). 4. A cross-calibration study in which pure human renin was added to pooled plasma and PRC and ARC were measured showed linearity between the values obtained by the two methods. 5. The regression line for values of PRC and ARC in the supine position after captopril administration had a significantly greater slope (P less than 0.001) and that for values after frusemide injection and standing was significantly elevated (P less than 0.001) compared with the regression line for basal values in the supine position. 6. These results show that the biological activity of renin may be increased by various acute stimulations of renin to inappropriately high levels compared with the immunological activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗
PubMed1988

Effect of beta-lactam antibiotics on hepatocellular glutathione levels in vitro and in vivo.

Incubation of isolated rat hepatocytes with high concentration of beta-lactam antibiotics, cephaloridine (CER), flomoxef (FMOX) or cephamandole (CMD), resulted in significant reduction of cellular glutathione (GSH) levels, though cell viability was not affected during the incubation period. I.v. injection of a large dose, 300 mg/kg, of these beta-lactam antibiotics to rats did not affect the hepatic GSH levels. The concentration of beta-lactam antibiotics in the body fluid of the rats were found to be much lower than the amounts which causes GSH depletion in vitro.

Animals↗
PubMed1987

Hemodynamic, renal, and hormonal responses to alpha-human atrial natriuretic peptide in patients with congestive heart failure.

Hemodynamic, renal, and hormonal effects of intravenous bolus injection of 50 micrograms synthetic alpha-human atrial natriuretic peptide (alpha-hANP) were studied in eight patients with congestive heart failure. alpha-hANP caused significant reductions in mean blood pressure and systemic vascular resistance. These responses were sustained up to 90 minutes and not accompanied by reflex tachycardia. Cardiac index and stroke volume index increased significantly at 90 minutes and pulmonary capillary wedge pressure, pulmonary arterial pressure, and mean right atrial pressure remained unchanged. Urine volume, urinary sodium excretion, creatinine clearance, and fractional excretion of sodium increased significantly, but fractional excretion of potassium and phosphate did not change. Elevated plasma renin activity, plasma aldosterone, and norepinephrine were suppressed after the injection of alpha-hANP. The bolus injection of this peptide has moderately hypotensive, vasorelaxant, and natriuretic effects in patients with congestive heart failure.

Aged↗
PubMed1986

Induction of 2-carboxybenzaldehyde reductase by phenobarbital in primary culture of rat hepatocytes.

When rats were treated with phenobarbital (PB), the activity of CBA reductase, which catalyzes the conversion of 2-carboxybenzaldehyde (CBA) to 2-hydroxymethylbenzoic acid (HMB), in the liver was markedly enhanced. Likewise, addition of PB to the primary culture of rat hepatocytes increased the activity of CBA reductase. The enzyme recovered from cell lysate of cultured cells showed the same characteristics in molecular and catalytic properties as the enzyme purified from the livers of the rats treated with PB. Experiments with cycloheximide suggest that de novo synthesis of the enzyme protein is enhanced by PB in primary culture.

Alcohol Oxidoreductases↗
PubMed1985

Calmodulin levels in hypertensive rats.

Intracellular calmodulin levels were measured by direct radioimmunoassay in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY). Decreased calmodulin levels were demonstrated in the brain, heart, aorta and kidney of spontaneously hypertensive rats compared with those in Wistar-Kyoto rats. Calmodulin levels in the brain were also decreased in deoxycorticosterone acetate (DOCA)-salt rats, but not changed significantly in the heart, aorta and kidney compared with those in Wistar-Kyoto rats. These findings suggest that intracellular calcium-dependent regulatory systems are genetically disrupted in spontaneously hypertensive rats, but this is probably not an important factor in the development of hypertension.

Animals↗
PubMed1984

Synergic effects of kallikrein-kinin and prostaglandins on renin release on infusion of isolated hog kidney with aldosterone.

The effects of infusion of a large amount of aldosterone into the renal artery of isolated perfused hog kidney on the release of renin, prostaglandins (PG) and kinin and the excretion of urinary kallikrein were investigated. Infusion of aldosterone at a rate of 100 ng/min (100 to 800 ng/ml of perfusate) resulted in significant releases of renin, PG (PGE2 , 6-0-PGF1 alpha), and kinin and increase in urinary kallikrein. Infusion of aldosterone and an inhibitor of kallikrein, aprotinin, decreased the releases of renin, PG and kinin and infusion of aldosterone with indomethacin decreased the release of PG but increased that of kinin and urinary kallikrein without significant change in renin releases. These findings suggest that the release of renin by aldosterone may result from synergic effects of renal PG and the kallikrein -kinin system.

Aldosterone↗
PubMed1984

Responses of active and inactive plasma renin to insulin-induced hypoglycemia in normal subjects.

To examine the in vivo activation mechanism for the conversion of inactive to active renin in human plasma, we measured active, inactive and total plasma renin activity during an insulin tolerance test in normal subjects. Total renin was measured after trypsin activation of inactive renin. Inactive renin was calculated as the difference between total and active renin. With a decrease in the blood glucose level from 92 +/- 8 to 22 +/- 6 mg/dl (p less than 0.01), active renin increased significantly (p less than 0.01) from the basal level of 1.9 +/- 0.6 to 6.0 +/- 1.9 ng/ml.hr at 60 min after insulin injection. Total renin increased and inactive renin decreased slightly, but the changes were not statistically significant. The ratio of active to total renin showed a significant increase (p less than 0.01) at 60 min. These results suggest that stimulation of the endogenous sympathetic nervous system is involved in the in vivo activation of inactive renin.

Adult↗