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Biomedical subjects

K Tsunoda

Publications and source records attributed to K Tsunoda.

At least 127 records · Page 7Linked to original sources
PubMed1990

A new inhibitor of protein kinase C, RK-286C (4'-demethylamino-4'-hydroxystaurosporine). I. Screening, taxonomy, fermentation and biological activity.

In the course of our screening program using a bleb-forming assay, a new inhibitor of protein kinase C (PKC) was found in the fermentation of a streptomycete. The inhibitor, RK-286C (4'-demethylamino-4'-hydroxystaurosporine), inhibited the morphological change of K562 cells, a human chronic erythroleukemia cell, induced by phorbol 12,13-dibutylate at the concentration of 3 microM. The same concentration of the compound inhibited the activity of PKC in vitro and the aggregation of rabbit platelets induced by collagen and arachidonic acid.

Alkaloids↗
PubMed1990

Three main components in plasma proteases and their relation to the renin-angiotensin system.

The relation of plasma renin activity (PRA) and plasma levels of angiotensin I (AI) and II (AII) to those of various proteases, including eight endopeptidases and four aminopeptidases, was investigated in 51 normal control subjects. The multivariate study using factor analysis showed that the plasma proteases can be classified into three main components: the aminopeptidase, the plasmin, and the kinin-kallikrein. PRA and AI were related almost exclusively to the aminopeptidase component, while the AII level was related not only to the same component but also to the kallikrein-kinin component. This kind of multivariate study may help in the elucidation of the role of proteases and bioactive peptides, such as angiotensin derivatives, in essential hypertension through a comparison of multivariate relationships in controls and patients.

Amino Acid Sequence↗
PubMed1990

[The effect of captopril on proteinuria in glomerular diseases].

We evaluated the efficacy of an ACE inhibitor captopril (CAP) for the reduction of proteinuria in glomerular diseases, and tried to find the conditions in which urinary protein excretion was significantly decreased by this drug. Renin provocation test by CAP (C-test) was performed, and the result was compared to the effect on proteinuria. In 33 patients with proteinuria, ranging from 1.1 to 14.1 g/day, CAP was administered. Urinary protein excretion was reduced from 3.6 +/- 0.6 to 2.8 +/- 0.4 g/day (mean +/- SEM, p less than 0.01) after 2 weeks. The decrease in urinary protein was significant when renal function was moderately impaired (30 less than or equal to Ccr less than 60 ml/min) or patients were on a salt diet less than 7 g of NaCl daily. Reduction of urinary protein excretion by 2-week treatment of CAP was correlated with the result of C-test (r = 0.874, p less than 0.025). The long-term follow up for more than 6 months also suggested that CAP delayed the deterioration of renal function. Thus, CAP was proved effective in treating proteinuria, and C-test might give us an information of its proteinuria-suppressing effect in an individual case. But its efficacy was observed only in patients with moderately-reduced renal function or on low-salt diet. Therefore, we should select the cases carefully to expect the effect of CAP for the reduction of proteinuria.

Adult↗
PubMed1989

Comparison of immunoreactive renin and plasma renin activity in human plasma.

Measurement of immunoreactive plasma renin concentration (PRC) using direct radioimmunoassay (RIA) was compared with the common procedure, measurement of plasma renin activity (PRA). The sensitivity of the PRC assay was 5 pg/ml. In 67 normal subjects aged 45.2 +/- 1.2 year, the mean PRC value was 17.0 +/- 0.9 pg/ml in the recumbent position and 38.0 +/- 5.4 pg/ml in the upright position. In patients with high renin essential hypertension and renovascular hypertension, discrepancies were observed between changes in PRA and PRC at 60 min after the administration of captopril. In a patient with Bartter's syndrome PRC was markedly elevated (393 pg/ml) and the changes in PRA and in PRC after captopril were very different (452% vs. 1249%). In all 10 cases of primary hyperaldosteronism PRC was less than 5 pg/ml. The correlation coefficient between PRC and PRA was 0.85 (n = 227, p less than 0.01). The slope of the regression line between PRA and PRC decreased in proportion to PRC values. Direct RIA for PRC is likely to be useful for the determination of plasma active renin when renin levels are high or substrate concentrations are abnormal. Moreover, the combined use of PRA and PRC measurements might be useful in assessing abnormalities in renin substrate concentration as well as in PRC.

Adolescent↗
PubMed1989

Effects of antihypertensive drugs on renal function and atrial natriuretic polypeptide in spontaneously hypertensive rats with renal ablation.

To determine whether pharmacological control of blood pressure could affect the renal function and levels of atrial natriuretic polypeptide (ANP) in spontaneously hypertensive rats (SHR) with renal ablation, and to ascertain the benefits of antihypertensive drugs, we studied effects of oral administration of captopril (50 mg/kg/day), an inhibitor of angiotensin converting enzyme, benidipine (3 mg/kg/day) and nilvadipine (10 mg/kg/day), newly developed blockers of calcium channel, and indapamide (10 mg/kg/day) for 14 days on systolic blood pressure, serum creatinine, blood urea nitrogen, and plasma ANP concentration in SHR subjected to surgical removal of the left kidney and infarction of two-thirds of the right kidney (5/6 nephrectomy) a week before. Three weeks after the surgery, systolic blood pressure (mmHg) in the untreated group was 253 +/- 9 (n = 10), in the captopril group 156 +/- 9 (n = 7, p less than 0.05), in the benidipine group 197 +/- 9 (n = 7, p less than 0.05), in the nilvadipine group 146 +/- 9 (n = 7, p less than 0.05) and in the indapamide group 206 +/- 5 (n = 7, p less than 0.05). Serum creatinine (mg/100 ml) was lower in the captopril group (0.58 +/- 0.02, n = 7, p less than 0.05) and in the benidipine group (0.50 +/- 0.03, n = 7, p less than 0.05) but not in the nilvadipine group and in the indapamide group 3 weeks after 5/6 nephrectomy compared to the untreated group. Blood urea nitrogen was also lower in the captopril group and in the benidipine group but not in the nilvadipine group and in the indapamide group. Plasma ANP concentration was significantly reduced by the treatment with captopril and benidipine but not with nilvadipine and indapamide. These results suggest that the reduction of blood pressure by the inhibition of angiotensin converting enzyme with captopril has the potential to ameliorate renal function of the SHR with remnant kidney, a model of chronic renal failure with hypertension, associated with the decreased concentration of plasma ANP. However, it remains to be determined whether the reduction of blood pressure by calcium channel blockers may be involved in the delayed progression of renal failure in this model since there were disparate effects on renal function and plasma ANP concentration with these two calcium channel blockers.

Animals↗
PubMed1989

A new biological role of sangivamycin; inhibition of protein kinases.

During the screening for the inhibitors of protein kinase C (PKC), we found that a streptomycete produced an inhibitor in our bleb-forming assay (Osada et al., J. Antibiotics 41: 925, 1988). The inhibitor was isolated and identified as sangivamycin (4-amino-5-carboxamide-7-(D-ribofuranosyl)pyrrolo[2,3-d]pyrimidine). Biological activity of sangivamycin was compared with that of other 7-deazaadenosine group antibiotics, tubercidin and toyocamycin. Sangivamycin showed a strong inhibitory activity against bleb-formation of K562 cells and PKC. On the other hand, tubercidin and toyocamycin had only weak activities in both assays. This paper deals with a new biological activity of sangivamycin, that of an inhibitor of protein kinases, especially PKC.

Anti-Bacterial Agents↗
PubMed1989

Difference between the effects of atrial natriuretic peptide and calcium antagonist on cytosolic free calcium in cultured vascular smooth muscle cells.

The effect of atrial natriuretic peptide (ANP) on cytosolic free calcium ([Ca2+]i) was studied in monolayers of cultured vascular smooth muscle (VSM) cells loaded with a fluorescent calcium indicator, fura-2. ANP (atriopeptin III, 10(-8) M) decreased the resting level of [Ca2+]i and sustained rises in [Ca2+]i following peak levels induced by vasoconstrictive hormones (angiotensin II or vasopressin). ANP also decreased a rise in [Ca2+]i induced by high potassium (high K+) depolarization. The initial rise in [Ca2+]i induced by vasopressin was not inhibited by ANP. On the other hand, calcium antagonists (nicardipine or nifedipine) inhibited the high K+-induced rise in [Ca2+]i, whereas there was no effect on rises in [Ca2+]i induced by vasopressin. These results suggest that calcium antagonists inhibit voltage-dependent calcium channels, while ANP can decrease [Ca2+]i presumably through a stimulation of calcium-extrusion active transports in vascular smooth muscle cells.

Animals↗
PubMed1989

Inhibitory effect of cicletanine on vascular smooth muscle cell proliferation.

We investigated the effect of cicletanine on vascular smooth muscle cell proliferation. In cultured vascular smooth muscle cells from rat mesenteric artery, cicletanine (10(-5) to 10(-4) M) increased prostacyclin synthesis (measured as 6-keto-PGF1 alpha by radioimmunoassay) dose-dependently. When added to cells in which mitogenesis was activated by 10% fetal bovine serum, cicletanine (3.3 x 10(-5) to 10(-4) M) inhibited [3H] thymidine incorporation up to 31% of the control level. Inhibitory effect of cicletanine on mitogenesis was also confirmed at 48 h by cell counts (control: 18965 +/- 629, cicletanine 10(-4) M: 14840 +/- 430, n = 6). The effect of cicletanine on platelet-derived growth factor (PDGF)-stimulated [3H] thymidine incorporation was not abolished by prostaglandin synthesis inhibition with aspirin, but the prostacyclin analogue OP-41483 (125-1000 ng/ml) inhibited it dose-dependently. Calcium entry blockers, nifedipine (3.3 x 10(-6) M) and diltiazem (10(-4) M), inhibited both [3H] thymidine incorporation and cell proliferation, while furosemide did not affect it. Cicletanine also inhibited PDGF-stimulated [3H] thymidine incorporation in cultured glomerular mesangial cells. We conclude that cicletanine stimulates prostacyclin synthesis and inhibits cell proliferation in cultured vascular smooth muscle cells, which may possibly be related to the intracellular calcium mobilization. Such a property might be contributory to the antihypertensive activity of cicletanine.

Animals↗
PubMed1989

A rare fast variant of red cell 6-phosphogluconate dehydrogenase found in Japanese.

In a Japanese family, we discovered by starch-gel electrophoresis a fast variant of 6-phosphogluconate dehydrogenase (PGD) in red blood cells. This variant is described here for the first time and temporarily named AX. It showed three PGD bands, the usual PGD A band and two faster-moving bands than PGD A. The ratio of the staining intensity of these bands was 2:2:1 in the order of increasing mobility, and negative sensitivity was noted toward 2-mercaptoethanol. Its genotype appeared to be heterozygous PGDA/PGDX, based on examinations of the PGD band composition and the pedigree of the family. It may possibly correspond to the PGD "Kadar" variant (PGDA/PGDKadar), with which it was quite similar, in electrophoretic mobility, staining intensity and sensitivity to 2-mercaptoethanol.

Asian People↗
PubMed1989

[Experimental studies on stress hormones at the time of sudden death (II)--Differences in adrenocortical hormone levels of cardiac arrest-preceding type and apnea preceding type sudden death under cerebral ischemia or aortic stenosis].

Under cerebral ischemia or aortic stenosis, changes in plasma and adrenal corticosterone (CS) levels before and after cardiac arrest-preceding type (CPT) and apnea-preceding type (APT) sudden death were examined to determine the response of the hypophyseal adrenocortical system in Wistar rats. The plasma CS value at 1.5 hours after cerebral ischemia treatment was about 3 times that of pretreatment under non-anesthesia. With the occurrence of CPT and APT sudden death during cerebral ischemia, a difference between CS levels before and after death was more pronounced in the adrenals than in the plasma. The adrenal CS value after death was significantly lower than that before death in APT sudden death (P less than 0.05), though the CS value in adrenals after death was the same as that of living animals with cerebral ischemia in CPT sudden death. APT sudden death may thus be concluded to have a lower CS level in the adrenals than CPT sudden death (P less than 0.01). In the case of aortic stenosis, the effect of this treatment on plasma CS level was not as distinct as in the case of cerebral ischemia. Only a slight increase in plasma CS was noted on the 6th day from treatment. Under this condition, a difference between plasma or adrenal CS levels before and after CPT and APT sudden death was similar to the case of cerebral ischemia. The adrenal CS value after death in both sudden death types was also the same case of cerebral ischemia.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Glands↗
PubMed1988

Regulation of cardiac preload by atrial natriuretic peptide in congestive cardiac failure.

Plasma atrial natriuretic peptide levels are increased in heart failure. In rats with experimental heart failure, the elevation in plasma atrial natriuretic peptide bore a close relationship to the size of the myocardial infarct and the degree of ventricular dysfunction. Sodium retention, assessed by changes in exchangeable body sodium, could not be demonstrated in this model of cardiac dysfunction. Even rats receiving a low-sodium diet had increased plasma atrial natriuretic peptide levels following coronary artery ligation despite a significant decrease in exchangeable body sodium. This establishes that the elevated plasma atrial natriuretic peptide levels found in heart failure are a consequence of ventricular dysfunction and increased intracardiac pressures rather than a reflection of the salt and water status. Alternatively, the elevated plasma atrial natriuretic peptide may limit salt and water retention in this model. In these animals with high circulating atrial natriuretic peptide levels, "down-regulation" of renal atrial natriuretic peptide receptors could be demonstrated. This decrease in renal atrial natriuretic peptide receptor numbers may, in part, explain the blunted response to infused atrial natriuretic peptide in heart failure. However, changes in renal atrial natriuretic peptide receptors alone would appear to be insufficient to lead to salt and water retention without the activation of other sodium-retaining mechanisms that occur with the progression of cardiac failure. Nevertheless, this down-regulation of renal atrial natriuretic peptide may then contribute to the salt and water retention that occurs in congestive biventricular heart failure. The close relationship between increases in atrial natriuretic peptide and ventricular dysfunction rather than sodium balance suggests that atrial natriuretic peptide's primary role in the circulation may be to produce venodilation and increase capillary permeability. This may act rapidly to reduce cardiac preload and prevent pulmonary congestion. Vasodilation and natriuresis may then become supplementary actions to maintain cardiac output and remove the excess fluid.

Animals↗
PubMed1988

Neurohumoral responses to chronic myocardial infarction in rats.

In chronic cardiac failure, various neurohumoral mechanisms are activated to sustain blood volume, blood pressure, and organ perfusion. Using the coronary artery ligation model of heart failure in the rat, we have measured changes in vasoactive hormone secretion and related these changes to salt and water status during a 1-month period. When compared with controls, rats with infarction had a marked rise in plasma atrial natriuretic peptide (294 +/- 59 vs. 79 +/- 10 pg/ml, p less than 0.001) although there was no increase in total exchangeable body sodium. Plasma renin activity and plasma aldosterone concentrations were the same for both rats with infarction and controls. Similarly, there were no significant differences in plasma arginine vasopressin, plasma osmolality, or plasma sodium concentration in rats with infarction. Ventricular norepinephrine levels were reduced in animals with infarction (p less than 0.01). Plasma atrial natriuretic peptide levels were raised in this model of chronic left ventricular failure. However, there was no salt retention and little stimulation of the renin-angiotensin-aldosterone system or vasopressin. The results suggest that high circulating atrial natriuretic peptide levels may prevent or limit salt and water retention, either directly or indirectly, by inhibiting the renin-angiotensin-aldosterone system.

Aldosterone↗
PubMed1988

Role of thromboxane A2 in the hypotensive effect of captopril in essential hypertension.

We have previously reported that captopril stimulates thromboxane A2 synthesis in patients with essential hypertension. In the present study, the hypotensive effects of captopril and OKY-046, a selective inhibitor of thromboxane A2 synthetase, were studied in nine patients with essential hypertension to determine whether thromboxane A2 is involved in the regulation of blood pressure. A single oral dose of OKY-046 (400 mg) decreased urinary thromboxane B2 (a stable metabolite of thromboxane A2) excretion significantly (from 113 +/- 19.0 to 51.0 +/- 6.1 pg/min; p less than 0.01) and increased urinary sodium excretion significantly (from 73.0 +/- 15.3 to 113.0 +/- 14.4 microEq/min; p less than 0.01), but no change was observed in mean arterial pressure. The administration of OKY-046 (600 mg/day) for 3 days induced a significant and sustained decrease in urinary thromboxane B2 excretion, but it did not affect the mean arterial pressure. Although captopril (50 mg) alone induced a significant increase in urinary thromboxane B2 excretion (from 91.4 +/- 11.0 to 297.3 +/- 30.8 pg/min; p less than 0.001) and a significant decrease in mean arterial pressure (from 97.0 +/- 4.7 to 88.1 +/- 5.1 mm Hg; p less than 0.01), captopril in combination with OKY-046 induced a decrease both in urinary thromboxane B2 excretion (from 70.8 +/- 12.3 to 54.2 +/- 14.7 pg/min; p less than 0.01) and in mean arterial pressure (from 105.1 +/- 3.8 to 84.2 +/- 3.6 mm Hg; p less than 0.01). Thus, the hypotensive effect of captopril was potentiated by OKY-046. OKY-046 did not affect the changes in plasma renin activity and plasma aldosterone concentration and blunted urinary prostaglandin E2 and 6-keto-prostaglandin F1 alpha excretion in response to captopril. These results indicate that thromboxane A2 counteracts the hypotensive effect of captopril in patients with essential hypertension.

Adult↗
PubMed1988

Decreased atrial natriuretic peptide binding in renal medulla in rats with chronic heart failure.

The relations between atrial natriuretic peptide (ANP) binding sites in the renal medulla, plasma ANP concentration, and ventricular dysfunction have been studied in rats 4 weeks after myocardial infarction induced by left coronary artery ligation. Plasma ANP concentration was measured by radioimmunoassay, and quantitation of receptors was performed by computerized in vitro autoradiography with 125I-labeled alpha-rat ANP (1-28) as the radioligand. When compared with controls, rats with myocardial infarction had markedly elevated plasma immunoreactive ANP concentrations (462 +/- 82 versus 124 +/- pg/ml, p less than 0.01) and reduced densities of ANP binding in the inner renal medulla (2.93 +/- 0.19 versus 3.53 +/- 0.22 fmol/mg protein, p less than 0.01). Extensive myocardial infarction was associated with a significant decrease in receptor numbers in the inner medulla (33.6 +/- 5.7 versus 95.6 +/- 9.6 fmol/mg protein, p less than 0.01) without significantly altering the affinity constant (1.76 +/- 0.51 versus 1.03 +/- 0.15 x 10(9) M-1, p greater than 0.05). Right ventricular weight increased in proportion to infarct size (r = 0.71, p less than 0.01), and both were correlated with plasma immunoreactive ANP levels (r = 0.74, p less than 0.01 and r = 0.75, p less than 0.01, respectively). Binding densities in the inner medulla of rats with infarcts were negatively correlated with right ventricular weight, plasma immunoreactive ANP concentrations, and also with infarct size (r = -0.92, p less than 0.001; r = -0.78, p less than 0.001; r = -0.77, p less than 0.01, respectively).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1987

Interactions of renal prostaglandins, renin-angiotensin system and renal kallikrein-kinin system in human hypertension.

Dietary sodium deprivation lowered blood pressure in patients with essential hypertension, while indomethacin induced a rise in blood pressure with significant decreases in plasma angiotensin II concentration and urinary excretion of sodium and PGE. In contrast, captopril lowered blood pressure in them with significant decrease in plasma angiotensin II concentration and significant increase in urinary excretion of sodium and PGE. These data strongly indicate that the decreased PG generation in the nephron could elevate blood pressure by means of sodium retention caused by the reduced renal excretory function in spite of the decreased R-A system in human, suggesting the involvement of renal tubular PGE2 in the regulation of blood pressure.

Adult↗