We investigated the effects of the adenosine type-1 receptor antagonist FK-838 on salt-induced hypertension in Dahl-Sea salt-sensitive (Dahl S) rats. Dahl S rats fed a high-salt (4% NaCl) diet for 4 weeks were treated with FK-838 or hydrochlorothiazide for 4 weeks and alterations in kidney function and morphologic changes were assessed. FK-838 attenuated the development of hypertension in Dahl S rats, and caused a decrease in aortic weight in a dose dependent fashion. The adenosine antagonist did not produce any detectable metabolic disturbance. The blood pressure reduction by FK-838 was associated with attenuation of glomerular and arterial injury in the kidney. The renal protective effect of FK-838 treatment was associated with a reduction of plasma renin activity and plasma aldosterone concentration. In contrast, the thiazide diuretic, which produced almost the same blood pressure reduction as FK-838, did not attenuate renal damage. These data indicate that adenosine A1 receptor antagonism reduces salt-induced hypertension and the consequent renal injuries.

Animals↗

PubMed1995

Stress-induced elevation of ouabainlike compound in rat plasma and adrenal.

Recent observations demonstrate the presence of neurosteroids and their rapid increase in response to acute stress. In view of a steroidal nature of ouabainlike compound, we tested the hypothesis that ouabainlike compound may participate in a homeostatic response to acute stress. Male Wistar rats were subjected to acute stress by swimming in water (22 degrees C) for 10 minutes. The levels of ouabainlike compound in plasma, hypothalamus, pituitary, and adrenal at 10, 40, and 70 minutes (n = 8 for each) after the end of swim stress were compared with nonstressed control levels (n = 10). Ouabainlike compound was measured by a radioimmunoassay for ouabain. Plasma levels of corticosterone and catecholamines were also measured. Plasma corticosterone concentrations increased rapidly at 10 minutes (P < .01) and then declined. A trend for a rise in plasma catecholamines was found at 10 minutes. Adrenal levels of ouabainlike compound concomitantly increased at 10 minutes (P < .01, control: 58.9 +/- 5.9 pmol ouabain equivalents per gram; 10 minutes: 92.5 +/- 4.8; 40 minutes: 47.3 +/- 9.6; 70 minutes: 45.1 +/- 6.3). In contrast, the response of plasma ouabainlike compound was slow and doubled at 40 minutes (P < .01, control: 115 +/- 12 pmol ouabain equivalents per liter; 10 minutes: 132 +/- 23; 40 minutes: 226 +/- 53; 70 minutes: 117 +/- 16). Ouabainlike compound levels in hypothalamus and pituitary remained unaltered. These findings suggest that ouabainlike compound may function as a stress hormone.

Acute Disease↗

PubMed1995

Effects of intracerebroventricular infusion of Fab fragments of digoxin antibody (Digibind) on development of reduced renal mass-saline hypertension in rats.

To clarify the role of brain ouabain-like compound in reduced renal mass-saline hypertension, we examined the effects of intracerebroventricular infusion of the Fab fragments of antidigoxin antibody (Digibind) on the change in blood pressure of saline-drinking subtotally nephrectomized rats. Twenty male Wistar rats weighing 250 g each underwent subtotal nephrectomy. Two groups of 10 rats received intracerebroventricular infusion of Digibind (20 mg/ml) or normal sheep IgG (20 mg/ml) at a rate of 0.5 microliters/h for 11 days. All rats began to drink 1% NaCl solution after two days of infusion. Systolic blood pressure was measured by the tail-cuff method on days 2, 6 and 9 of infusion. Two groups of saline-drinking rats with reduced renal mass developed hypertension. However, systolic blood pressure was significantly higher in Digibind-infused rats than in IgG-infused rats (day 2, 144 +/- 3(SEM) vs. 133 +/- 1 mmHg, p < 0.05; day 6, 161 +/- 4 vs. 151 +/- 2 mmHg, 0.05 < p < 0.1, day 9, 181 +/- 8 vs. 155 +/- 2 mmHg, p < 0.05). In spite of similar renal dysfunction, plasma aldosterone concentrations, and plasma OLC levels, the accelerated increase in blood pressure was accompanied by a significantly impaired pressure-natriuresis relationship (0.089 +/- 0.013 vs. 0.131 +/- 0.013 mmol/day/mmHg, p < 0.05). These results indicate that chronic intracerebroventricular infusion of Digibind augmented reduced renal mass-saline hypertension in rats and suggest that brain ouabain-like compound may play a protective role against the elevation of blood pressure, at least in this model of hypertension.

Animals↗

PubMed1995

Possible linkage between renal injury and cardiac remodeling in Dahl salt-sensitive rats treated with the calcium channel antagonist benidipine.

Interest in cardiovascular protection by calcium channel antagonists has grown over the past decade. We investigated the prevention of cardiac remodeling and renal injury by the long-acting calcium channel antagonist benidipine using 12 week-old Dahl salt-sensitive (Dahl S) rats fed a high-salt (4% NaCl) diet. Six-week benidipine treatment (10 mg/kg chow) decreased systolic blood pressure by 22% in Dahl S rats. This blood pressure reduction was associated with decreases in cardiac mass and weight of the aortic wall. Collagen content in the left ventricle tended to decline with benidipine treatment. In addition, glomerular filtration rate increased by 33% and arterial and glomerular lesions improved morphologically with this treatment. Regression of cardiac mass and collagen content in the left ventricle was due mainly to blood pressure reduction; however, collagen content in the low-pressure right ventricle was not only related to systemic blood pressure but to the severity of renal lesions. These data suggest that the calcium channel antagonist benidipine attenuates cardiac and renal injury in hypertensive Dahl S rats, and that part of the cardiac hypertrophy is due to a non-hemodynamic mechanism that might be responsible for, or be a consequence of, the lesions in the kidney.

Animals↗

PubMed1995

[Effects of glucose ingestion on urinary excretion of electrolytes: comparison between patients with chronic glomerulonephritis and diabetes mellitus].

We investigated the effects of ingesting 75g of glucose on urinary excretion of electrolytes in patients with chronic glomerulonephritis (CGN) and diabetes mellitus (DM) over a 4-hour period. Creatinine clearance did not change in patients with either disease following glucose ingestion. Fractional excretion of sodium (Na), chloride (Cl) and potassium (K) decreased significantly, while that of calcium (Ca) and magnesium (Mg) increased significantly in both groups. The change in fractional excretion of phosphorus (P) differed between patients with CGN and DM. Fractional excretion of P increased initially, then decreased significantly in patients with CGN, while it decreased steadily in patients with DM. In diabetic patients, significant positive relationships were observed between cumulative filtered glucose and cumulative urinary excretion of Ca (r = 0.47, p < 0.05) and P (r = 0.54, p < 0.05). In addition, cumulative plasma IRI concentration was correlated inversely with cumulative urinary excretion of K (r = -0.54, p < 0.05) in diabetic patients. In nephritic patients. however, no significant relationship was observed among these variables. In conclusion, renal tubular reabsorption of Na, K and Cl was enhanced, while that of Ca and Mg was inhibited after glucose ingestion in both CGN and DM patients. Moreover, filtered glucose may be involved partially in the inhibitory effect on tubular reabsorption of Ca and P in diabetic patients.

Administration, Oral↗

PubMed1995

[Radiotherapy for myeloma].

The quality of life, as well as the length of survival, in patients with myeloma has improved since the introduction of melphalan chemotherapy. Although myeloma is a radio-responsive disease, radiotherapy should be chosen for relapsed and refractory myeloma, because prolongation of overall survival is not improved. The aim of radiotherapy for solitary plasmacytomas is to mainly relieve pain, rather than the curative local therapy. On the other hand, total body irradiation has been used, as palliative therapy, for relapsed and refractory myeloma but treatment related toxicity is commonly. The hemibody irradiation and whole bone marrow irradiation developed to decrease radiation pneumonitis and hematologic toxicity. On the other hand, the results of radiotherapy in combination with chemotherapy shows no better survival than that of chemotherapy alone. Radiotherapy should be used for severe intractable bone pain and should be employed, using a limited field in lytic lesions.

Adult↗

PubMed1995

[Acquired amylase production induced by radiotherapy in a myeloma patient].

A 55-year-old patient with multiple myeloma (IgG-lambda) diagnosed in November 1988 was admitted because of bone pain throughout the body. After plasmapheresis and several courses of chemotherapy, a massive tumor of the left thoracic wall involving the rib appeared. Radiotherapy was performed to ameliorate the severe chest pain, after which myelomatous pleural effusion appeared on the left side. The serum, urine and pleural effusion revealed increased activity of amylase of the salivary type. Amylase activity was also detected in the supernatant of myeloma cells cultured from pleural effusion. We reviewed 12 cases of ectopic amylase-producing multiple myeloma. All the cases except one have been reported from Japan, and hyperamylasemia in these cases was detected at diagnosis or during course of the illness. Moreover, cytogenetic analysis of myeloma cells of previous reports revealed structural abnormalities including chromosome 1, near the amylase gene locus. This case also showed t (1; 10) (q 21?; q 26) by examination of 8 metaphase derived from bone marrow. These observations suggested that ectopic amylase production was induced by irradiation to the plasmacytoma of thoracic wall.

Amylases↗

PubMed1994

Role of ouabainlike compound in rats with reduced renal mass-saline hypertension.

Ouabainlike compound (OLC) has recently been identified as a likely mammalian endogenous digitalis-like factor (EDLF) from human plasma. In this study, plasma levels of OLC were determined to assess the role of OLC in a model known as volume-expanded, reduced renal mass (RRM)-saline (S) hypertension in rats with use of a newly developed radioimmunoassay for ouabain. In the first experiment, at 3 wk after subtotal nephrectomy and drinking 1% saline solution, sysolic blood pressure (SBP) of 18 rats with reduced renal mass (RRM-S rats) was significantly higher than in 17 sham-operated saline-drinking control (C-S) rats [154 +/- 4 (SE) vs. 132 +/- 2 mmHg; P < 0.01]. Plasma OLC levels were 355 +/- 68 pmol/l in RRM-S rats, sevenfold higher than in C-S rats (54 +/- 4 pmol/l; P < 0.01). In the second experiment, we measured plasma OLC levels of 10 RRM-S, 12 sham-operated control (C), and 10 subtotally nephrectomized rats drinking distilled water (RRM rats). Concomitant with a marked increase in blood pressure (203 +/- 5 mmHg), RRM-S rats showed significantly higher plasma OLC levels compared with C and RRM rats (RRM-S 114 +/- 24, C 47 +/- 11, and RRM 52 +/- 9 pmol/l; P < 0.05). In both experiments, plasma OLC levels correlated significantly with SBP (P < 0.05). These findings suggest that plasma OLC shows a similar behavior to that of EDLFs or Na(+)-K(+)-adenosinetriphosphatase inhibitors reported in previous publications and may play a role in hypertensive mechanisms in rats with RRM and excess Na intake.

Animals↗

PubMed1994

Participation of ouabainlike compound in reduced renal mass-saline hypertension.

We examined the role of ouabainlike compound in reduced renal mass-saline hypertension using a population of rats immunized with ouabain. To develop ouabain-immunized rats, ouabain-bovine serum albumin conjugates were injected subcutaneously three times at 4-week intervals. Titer determinations were made 2 weeks after the third immunization, and rats with high titers were used in the study. Immunoglobulin G fractions from ouabain-immunized rats effectively inhibited the contractile response of guinea pig aorta to exogenous ouabain (150 nmol). Fourteen ouabain-immunized and seven nonimmunized control rats underwent subtotal nephrectomy. An additional eight ouabain-immunized and six nonimmunized rats served as sham-operated rats. Four groups of rats drank 1% NaCl solution for 3 weeks, and systolic blood pressure was measured weekly by the tail-cuff method. Two groups of sham-operated rats remained normotensive. In contrast, two groups of subtotally nephrectomized rats developed hypertension. However, among these rats, systolic blood pressure was significantly lower in ouabain-immunized rats than in nonimmunized rats (161 +/- 5 versus 180 +/- 3 [+/- SEM) mm Hg, P < .01). The decrease in blood pressure was accompanied by a significant inhibition of aortic hypertrophy (P < .05). These results indicate that chronic blockade of circulating ouabainlike compound partly ameliorates reduced renal mass-saline hypertension and suggest that circulating ouabainlike compound may be involved in the pathophysiology in this model of hypertension.

Adrenal Glands↗

PubMed1994

Role of brain ouabainlike compound in central nervous system-mediated natriuresis in rats.

Intracerebroventricular infusion of artificial sodium-rich cerebrospinal fluid induces increases in blood pressure and urinary sodium excretion. To examine the role of brain ouabainlike compound in these central nervous system-mediated responses, we evaluated the effects of prior intracerebroventricular injection of the Fab fragments of digoxin-specific antibody (Digibind, 10 mg/mL, 10 microL) on changes in blood pressure and urinary sodium excretion after intracerebroventricular infusion of high-sodium (323 mmol/L, 150 microL/kg per 15 minutes) cerebrospinal fluid in anesthetized rats. Antiouabain action of Digibind was revealed by the inhibition of a contractile response to ouabain in guinea pig aorta. Similar significant increases in blood pressure were found in rats that received preinjection of Digibind (n = 14) compared with control rats that received injection of saline (n = 5) or normal sheep IgG (n = 8). In rats pretreated with Digibind the natriuretic responses to central high sodium were significantly diminished by 68% (P < .05) or 82% (P < .05) compared with rats treated with saline or normal IgG, respectively. In contrast, Digibind did not affect either pressor or natriuretic responses to intracerebroventricular angiotensin II (600 ng/30 microL per 10 minutes). These data indicate that Digibind significantly inhibits increases in renal sodium excretion in response to high central sodium and suggest that brain ouabainlike compound may be involved in central nervous system-mediated natriuresis with nonpressor mechanisms.

Animals↗

PubMed1993

Digitalis-like factors from human urine.

We isolated two candidates for endogenous digitalis-like factors from human urine based on the inhibition of [3H]ouabain binding to intact human erythrocytes. The more-polar ouabain-displacing compound-1 (ODC-1) closely resembled ouabain in biological, physicochemical, and chromatographic properties. Moreover, anti-ouabain IgG dose-dependently neutralized the action of ODC-1. The less-polar ODC-2 behaved identically to digoxin in three analytical high-performance liquid chromatography and thin layer chromatography systems. Fast atom bombardment mass spectrum and proton nuclear magnetic resonance spectrum supported the notion that ODC-2 may be indistinguishable from digoxin. The possibility that substances quite similar to cardenolides are synthesized in the mammalian body must be seriously considered.

Binding Sites↗

PubMed1989

An interindividual variability in the sensitivity of atrioventricular node to diltiazem in patients with paroxysmal supraventricular tachycardia.

To study the sensitivity of atrioventricular (AV) node to diltiazem in seven patients with paroxysmal supraventricular tachycardia (PSVT), we analyzed the plasma concentration-response relationship of this Ca-antagonist using AH interval as an index for assessing its Ca channel blocking effect on the AV node after an IV infusion (0.4 mg/kg). The postdose AH intervals were prolonged compared with the baseline, and their percentage changes correlated significantly (P less than 0.01) with log-diltiazem concentrations in all patients. However, drug concentrations associated with a 20% prolongation of AH interval differed considerably among the patients (range; 65 to 260 ng/ml), indicating a large interindividual variability in the sensitivity of AV node to diltiazem. These results suggest that the interindividual difference in the responsiveness of AV node to diltiazem-induced Ca channel blocking effect may be one of the possible explanations for the therapeutic failure of this Ca-antagonist for terminating PSVT or preventing its recurrences in certain patients.

Adult↗

PubMed1989

[Megakaryocyte proportion versus nucleated cells in the peripheral blood showing leukoerythroblastosis].

Megakaryocytes in the peripheral blood in which leukoerythroblastosis was recognized were studied by electron microscopy on the vertically cut section of the buffy coat of the blood, and percentages of them in 10,000 nucleated cells distributed from the top of the bottom of the buffy coat were counted. In 15 of 31 patients, percentages of peripheral blood megakaryocytes ranging from 0.01% to 0.64% were seen. There was difference of the result among diseases shown peripheral blood megakaryocytes. Namely, in patients with myelofibrosis and CML, in whom extramedullary hematopoiesis was predominant, many cases ascertained peripheral blood megakaryocytes were demonstrated. Because of this result, the extramedullary hematopoiesis appears to play an important role to the presentation of megakaryocytes in the peripheral blood. On the other hand, patients indicating both megakaryocytes and abnormal sideroblasts in the peripheral blood had sideroblastic anemia marrow. This result seems to show that a part of megakaryocytes are directly flowed out from the marrow into the blood simultaneously accompanied with abnormal sideroblasts.

Adolescent↗

PubMed1988

[Clinical means of measurement of urinary polyamines in chronic renal failure by method of enzymatic assay].

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Chromatography, High Pressure Liquid↗