Renal tubular acidosis with autoantibody directed to renal collecting-duct cells.
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Acidosis, Renal Tubular↗
Biomedical subjects
T Saruta
Publications and source records attributed to T Saruta.
Efficacy and safety of amlodipine in hypertensive patients with renal dysfunction.
Amlodipine, a dihydropyridine calcium antagonist, was administered at 2.5-5.0 mg/day for 8 weeks to 35 hypertensive patients with renal dysfunction, and its efficacy and safety were evaluated. The target reduction in blood pressure was achieved in 28 of the 35 patients (80%), while blood pressure was decreased in 4 patients (11.4%) and unchanged in 3 patients (8.6%). A side effect of mild headache was reported by one patient (2.9%). In addition, abnormal changes in laboratory values were observed in five patients, but all of the changes were mild. Blood urea nitrogen and serum creatinine levels both increased in two of these five patients, and serum creatinine levels increased in another two patients. Serum amlodipine concentration was 4.86 +/- 2.57 ng/ml (n = 8) and 3.01 +/- 1.02 ng/ml (n = 8) in patients receiving a daily dose of 2.5 mg for 2-5 weeks and 8-10 weeks, respectively. Serum concentration in patients receiving 5 mg from Weeks 2-6 was 9.72 +/- 6.89 ng/ml (n = 6) after 7-9 weeks, suggesting no tendency for the accumulation of this drug. The drug was rated as of clinical benefit in 27 of the 35 patients (77.1%), and as slightly beneficial in another 5 patients (14.3%). Thus, amlodipine significantly decreased the blood pressure while causing little or no aggravation of renal dysfunction in hypertensive patients with renal impairment.
Adult↗
Effects of diazoxide on alpha- and beta-cell function in isolated perfused rat pancreas.
To elucidate the effects of diazoxide on insulin and glucagon secretion at normal, high and low glucose concentrations and 10 mmol/l arginine, we performed pancreatic perfusion experiments. The insulin secretion rate in response to 16.7 mmol/l glucose was dose-dependently suppressed by concomitant infusion of diazoxide (100 and 300 mumol/l). Both the first and second phases of glucose-stimulated insulin secretion were significantly reduced in the presence of diazoxide as compared with controls. Basal glucagon secretion rate at 5.6 mmol/l glucose was significantly reduced by the administration of both 100 and 300 mumol/l diazoxide. Furthermore, the glucagon secretion rate at a high glucose concentration (16.7 mmol/l) was significantly lower with 300 mumol/l diazoxide than in the control. The glucagon secretion rate with glucopenia (1.4 mmol/l) was also significantly lower with 100 and 300 mumol/l diazoxide than in the control. The insulin secretion rate in response to 10 mmol/l arginine was also dose-dependently suppressed by concomitant infusion of diazoxide. The glucagon secretion rate in response to 10 mmol/l arginine was, however, significantly higher with 100 mumol/l diazoxide while not being significantly different with 300 mumol/l diazoxide. These findings suggest that some mechanism(s) which can be inhibited by diazoxide is involved in glucagon, as well as insulin, secretion in isolated perfused rat pancreas.
Analysis of Variance↗
WBN/Kob rat: a new model of spontaneous diabetes, osteopenia and systemic hemosiderin deposition.
A long-term investigation of bone mineral metabolism in a newly developed strain, the WBN/Kob rat, which spontaneously develops diabetes, possibly due in part to hemosiderin deposition, was conducted. WBN/Kob rats used in this study developed diabetes after 9 months of age. Bone mass peaked at 6 months or 8 months of age, and femoral breaking strength was maximal at 8 months of age, declining rapidly after the development of diabetes. In contrast, both the bone mass and the mechanical strength increased up to 14 months of age in controls. The serum osteocalcin (BGP) levels were lower at 4 months of age and serum 1.25(OH)2D levels were significantly lower throughout the study in WBN/Kob rats than in controls. These results suggest that abnormal bone and mineral metabolism is present in WBN/Kob rats before the onset of diabetes, and that bone strength and BMD decrease simultaneously with the development of diabetes. This strain can serve as a useful model, not only of hemosiderosis and diabetes, but also of osteopenia.
Absorptiometry, Photon↗
Interleukin-4 expression in mesangial proliferative glomerulonephritis.
Several cytokines are known to play roles in the pathogenesis of human glomerulonephritis. Recently, some studies proposed a possible relationship between interleukin-4 (IL-4) and glomerulonephritis. To investigate the involvement of IL-4 in human glomerulonephritis, we evaluated renal biopsy specimens using immunohistochemical procedures. Our study revealed that the glomeruli in immunoglobulin A nephropathy and lupus nephritis (World Health Organization grades II and IV) contained IL-4-positive cells, which were CD-3- and CD-4-positive T lymphocytes. CD-8-, CD-14-, CD-19-, or CD-56-positive cells did not react with anti-IL-4. CD-23-positive cells were not observed in the sections used in this study. Interleukin-4-positive cells were not found in the normal control kidney tissues. The degree of the glomerular IL-4-positive cell index correlated well with the glomerular hypercellularity index, but not with any other clinical or histopathologic parameters. Therefore, the present study offers more reliable evidence concerning the association between IL-4 and human glomerulonephritis.
Adult↗
Angiotensin II type 1 receptor gene abnormality in a patient with Bartter's syndrome.
Administration of a selective angiotensin I type 1 receptor (AT1) antagonist in animals not only nullifies the vasopressor action of angiotensin II, but also induces chloriduria and kaliuria, juxtoglomerular apparatus (JGA) hypertrophy and hyperreninemia, features characteristic of human Bartter's syndrome. We, therefore, explored the possibility that Bartter's syndrome may involve an AT1 abnormality. Using a pair of AT1-specific oligonucleotide primers and two different DNA polymerases (Taq and Pfu), we amplified the approximately 1 kb AT1 coding region of genomic DNA isolated from leukocytes of five patients with Bartter's syndrome by PCR and analyzed the sequence of the product. While the sequence of all clones from four patients were identical to that already reported for the normal human AT1 DNA sequence, 50% of the clones from one patient with Bartter's syndrome were found to have A-->G transition at nucleotide 931 which causes an amino acid substitution (arg-->gly) on the carboxy-terminal cytosolic tail of AT1. This mutation was not found in DNA from 50 normal controls which were screened by restriction enzyme digestion pattern of the PCR products of this region. As PCR-amplified AT1 DNA clones from four other individuals with Bartter's syndrome did not display any abnormality in the coding region, the possibility exists that Bartter's syndrome consists of multiple disease entities, where an AT1 gene abnormality represents a specific subgroup of the syndrome and/or some abnormality includes mutations outside of the coding region.
Animals↗
Alpha- and beta-cell function in obese Zucker (fa/fa) rats: a study with the isolated perfused pancreas.
1. The effects of various stimuli, including changes in glucose concentration, arginine, tyramine and noradrenaline, on insulin and glucagon secretion were investigated using isolated perfused pancreata of obese and lean male Zucker rats at 12 months of age. 2. In Zucker fatty rats, the insulin secretion rate was significantly (P < 0.01) higher than that of lean rats at all glucose concentrations tested (8.3, 16.7 and 1.4 mmol/l). However, the integrated insulin secretory response to raising the glucose concentration from 8.3 to 16.7 mmol/l was almost absent in these rats. The glucagon secretion rates were significantly lower at 8.3 and 1.4 mmol/l glucose (P < 0.001 for both), and in responses to 10 micrograms/ml tyramine and 0.1 mumol/l noradrenaline (P < 0.05 for both), in Zucker fatty rats. Integrated insulin and glucagon responses to 10 mmol/l arginine were identical in the two groups. 3. Histopathological and immunochemical studies revealed hyperplasia of beta-cells and scattered alpha-cells in the enlarged islets of Zucker fatty rats. 4. These results suggest that, in Zucker fatty rats, the decreased glucagon secretion in the isolated perfused pancreas is attributable to changes in the environment of alpha-cells and/or the inhibitory effects of hypersecreted insulin.
Animals↗
Effects of vasopressin V1 and V2 receptor antagonists on progressive renal failure in rats.
1. The relationship between vasopressin and the progression of renal failure has been proposed, but not intensively investigated because of a lack of orally available, selective vasopressin antagonists. 2. The effects of novel, orally available vasopressin V1 and V2 receptor antagonists on several indices of the progression of chronic renal failure, i.e. blood pressure, urinary protein excretion, sodium balance and renal histopathology, were investigated by using Wistar rats with adriamycin-induced nephropathy accelerated by deoxycorticosterone acetate-salt hypertension. Groups 2 and 3 were treated with V1 and V2 antagonists, respectively, while the untreated group 1 served as the control. To block the effects of vasopressin efficaciously, V1 and V2 antagonists were simultaneously administered (group 4). 3. At week 6, 2 weeks after the beginning of administration of deoxycorticosterone acetate-salt and vasopressin antagonists after the second injection of adriamycin, V1 and V2 antagonists given either alone or in combination significantly reduced the systolic blood pressure as compared with the control, and urine volume was increased in groups 3 and 4. The proteinuria was also decreased at week 10 in groups 2, 3 and 4. Differences in sodium excretion between all groups were not significant. Histopathological alterations in the kidneys of group 4 were significantly ameliorated. 4. These results suggest that a combination of V1 and V2 antagonists can have therapeutic effects in certain types of chronic renal failure.
Animals↗
Recent research on hypertension.
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Antihypertensive Agents↗
The efficacy of monatepil, a new calcium antagonist, in the treatment of essential hypertension.
A multicenter, open-label trial in Japan examined the efficacy, safety, and optimal dose of monatepil (AJ-2615) as monotherapy and in combination therapy with angiotensin-converting enzyme (ACE) inhibitors or beta-blockers. Patients with essential hypertension who had never been treated or had been refractory to conventional antihypertensive agents were enrolled in the trial. During a 4-week control period patients assigned to monotherapy received placebo and those assigned to combination therapy received an ACE inhibitor or beta-blocker and placebo. Patients with systolic blood pressure (BP) > or = 160 mm Hg and diastolic BP > or = 95 mm Hg at the end of the control period were enrolled in the study. The initial dose of monatepil was 30 mg/day in monotherapy and 15 mg/day in combination therapy; the daily dose was titrated to 60 mg/day according to the antihypertensive response. The treatment period was 8 to 12 weeks. Blood pressure decreased from 168 +/- 8/100 +/- 6 to 142 +/- 9/85 +/- 7 mm Hg (SD) with monatepil monotherapy, from 171 +/- 11/102 +/- 6 to 141 +/- 9/84 +/- 6 mm Hg in combination with ACE inhibitors, and from 175 +/- 13/102 +/- 7 to 153 +/- 21/91 +/- 9 mm Hg in combination with beta-blockers (P < .001). When patients in whom mean BP decreased by > or = 13 mm Hg were defined as responders, the response rate was 80.4%, 78.1%, and 51.6% in the respective groups.(ABSTRACT TRUNCATED AT 250 WORDS)
Adrenergic beta-Antagonists↗
Effects of oral AVP receptor antagonists OPC-21268 and OPC-31260 on congestive heart failure in conscious dogs.
Rapid right ventricular pacing could induce congestive heart failure in conscious dogs with significant increase in plasma concentration of arginine vasopressin (AVP) (from 1.2 +/- 0.2 to 3.4 +/- 0.6 pg/ml). In this experimental model of heart failure, oral administration of the selective AVP V1 receptor antagonist OPC-21268 significantly increased cardiac output and improved renal function without significant changes in serum electrolytes and hormones. Oral administration of the selective AVP V2 receptor antagonist OPC-31260 induced marked water diuresis, which resulted in significant increases in serum sodium concentration, plasma renin activity, and plasma concentration of AVP, although it did not produce hemodynamic improvement. Combined administration of OPC-21268 and OPC-31260 showed supra-additive hemodynamic responses as well as additive renal and metabolic responses, i.e., it showed prolonged decrease in mean arterial pressure and profound increase in cardiac output. These results suggest that AVP plays a significant role in elevation of vascular tone through V1 receptors and plays a major role in retaining free water through V2 receptors in this model of heart failure. Furthermore, combined administration of V1 and V2 receptor antagonists could induce not only metabolic and hormonal responses but also more beneficial hemodynamic responses than those observed following treatment with V1 receptor antagonist alone.
Animals↗
Chronic and selective vasopressin blockade in spontaneously hypertensive rats.
Chronic effects of orally available, nonpeptide vasopressin V1 and V2 receptor antagonists on conscious spontaneously hypertensive rats (SHR) were investigated. SHR and Wistar rats were divided into four groups, groups S-1 to S-4 and W-1 to W-4, respectively. Groups S-1 and W-1 were untreated as control. Groups S-2 and W-2 were treated with V1 antagonist, groups S-3 and W-3 received V2 antagonist, and groups S-4 and W-4 were treated with both of V1 and V2 antagonists. V1 and/or V2 antagonists did not affect degree of blood pressure of W-2, W-3, and W-4 rats, and V1 antagonist, alone or combined with V2 antagonist, slightly reduced increases in blood pressure of S-2 and S-4 rats without significance. However, V2 antagonist induced significantly massive and hyposmolar urine in W-3 rats compared with that in S-3 rats. In conclusion, in SHR, circulating vasopressin contributes to increases in blood pressure via either V1 or V2 receptors less than expected from previous studies with antibodies or peptide antagonists.
Animals↗
Effects of N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) on insulin and glucagon secretion in isolated perfused rat pancreas.
N-[(trans-4-isopropylcyclohexyl)-carbonyl]-D-phenylalanine (A-4166) has a structure which differs from those of other known blood glucose-lowering agents including sulfonylureas. It has been shown that oral administration of A-4166 exerts blood glucose-lowering effects in animal in vivo studies. In the present study, we investigated the effects of A-4166 on insulin and glucagon secretion at several glucose concentrations using isolated perfused rat pancreas preparations. Both 3.0 and 30 mumol/l A-4166 significantly stimulated insulin secretion as compared with basal levels at glucose concentrations of 8.0 and 11.0 mmol (p < 0.01 and p < 0.05, respectively). In contrast, glucagon secretion was not affected by administration of A-4166 up to 30 mumol/l at these glucose concentrations. At a glucose concentration of 5.6 mmol/l, neither 0.3 nor 3.0 mumol/l A-4166 produced significant changes in insulin and glucagon secretion. However, A-4166 at 30 mumol/l significantly stimulated insulin secretion and inhibited glucagon secretion as compared with basal levels (p < 0.01 and p < 0.01, respectively). We conclude that A-4166 at 3.0 and 30 mumol/l directly stimulates insulin secretion but has little effect on glucagon secretion in isolated perfused rat pancreas at glucose concentrations of 8.0 and 11.0 mmol/l. these results, taken together with previously published data, suggest that oral administration of A-4166 could be a useful strategy for stimulating endogenous insulin secretion in non-insulin-dependent diabetic patients.
Animals↗
Glucocorticoid increases angiotensin II type 1 receptor and its gene expression.
Recently, we demonstrated that glucocorticoid potentiates inositol triphosphate production evoked by angiotensin II in vascular smooth muscle cells. To clarify this mechanism, we investigated the effects of dexamethasone on the modulation of angiotensin II type 1 receptor and on postreceptor mechanisms in vascular smooth muscle cells. The number of angiotensin II type 1 receptors began to increase after 12 hours' incubation with dexamethasone. After 48 hours, the Bmax value reached 27 +/- 3 fmol/mg protein in dexamethasone-treated cells and 15 +/- 3 fmol/mg protein in control cells. However, binding affinity did not change. A glucocorticoid antagonist, RU 38486, completely blocked these effects of dexamethasone. Also, to elucidate the effects of dexamethasone on postreceptor mechanisms, GTP analogue-induced inositol trisphosphate production in permeabilized cells was examined. Pretreatment with 1 mumol/L dexamethasone for 48 hours did not affect these inositol trisphosphate productions. Moreover, dexamethasone had no effect on the level of Gq alpha protein. Furthermore, steady-state levels of angiotensin II type 1 receptor messenger RNA were increased 2.2 +/- 0.3-fold after 30 minutes' exposure to 1 mumol/L dexamethasone and 7.8 +/- 0.4-fold after 24 hours. We conclude that glucocorticoid induced expression of the angiotensin II type 1 receptor gene and resulted in an increase in the number of angiotensin II type 1 receptors through the glucocorticoid-specific receptor, without significant effect on postreceptor systems in vascular smooth muscle cells.
Angiotensin II↗
Nitric oxide increases renal blood flow by interacting with the sympathetic nervous system.
To investigate whether changes in renal blood flow induced by nondepressor doses of L-arginine, the precursor of nitric oxide, are mediated by a sympathetic neural mechanism, we examined the following in conscious rabbits: (1) the effects of intravenous infusion of L- or D-arginine (15 to 200 mumol/kg per minute) on renal blood flow and renal sympathetic nerve activity with or without intravenous infusion of a nonpressor dose of NG-monomethyl-L-arginine (L-NMMA), a nitric oxide synthase inhibitor, and (2) the effects of L-arginine on renal blood flow after renal denervation with or without L-NMMA pretreatment. In renal innervated rabbits, L-arginine (100 and 200 mumol/kg per minute) increased renal blood flow by 9 +/- 2 and 16 +/- 3 mL/min (P < .05, respectively) and decreased renal sympathetic nerve activity by 12 +/- 4% and 19 +/- 3% of control (P < .05, respectively). In contrast, no changes occurred in any variable during D-arginine infusion. L-NMMA attenuated the renal blood flow and renal sympathetic nerve activity responses to L-arginine (P < .05). In renal denervated rabbits, L-NMMA also attenuated the renal blood flow responses to L-arginine (P < .05) and abolished them (P < .05) compared with those in renal innervated rabbits. All renal blood flow responses to L-arginine were accompanied by parallel changes in plasma L-citrulline concentration.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Effects of antihypertensive agents on baroreceptor function in early hypertensive rats.
To investigate the effects of antihypertensive treatment with four currently used agents (trichlormethiazide, atenolol, nicardipine, and enalapril) on the arterial baroreceptor function at the early phase of hypertension, we administered the agents to spontaneously hypertensive rats and Wistar-Kyoto rats from 8 to 10 weeks of age and examined the aortic nerve activity function. In untreated spontaneously hypertensive rats, the relation between the arterial pressure and aortic nerve activity was shifted to the right, that is, to a higher pressure level (threshold pressure, 90 +/- 3 versus 76 +/- 1 mm Hg, P < .05), and the maximum gain which was obtained by logistic function analysis was depressed (1.55 +/- 0.08% versus 2.18 +/- 0.13% maximum/mm Hg, P < .01) as compared with untreated Wistar-Kyoto rats. An equivalent decrease in arterial pressure with each of the four agents (-20 +/- 1 mm Hg, P < .01) produced a leftward shift of the arterial pressure-aortic nerve activity relation to a similar extent (threshold pressure, 77 +/- 1 mm Hg, P < .05) in spontaneously hypertensive rats. In addition, treatment with the four agents equally augmented the maximum gain in spontaneously hypertensive rats (2.13 +/- 0.09% maximum/mm Hg, P < .05). The antihypertensive agents affected neither the blood pressure nor the aortic nerve activity in Wistar-Kyoto rats. These findings suggest that antihypertensive treatment with the four classes of agents equally enhances the arterial baroreceptor function through blood pressure reduction but not through specific depressor mechanisms at the early stage of hypertension.
Animals↗
Multiple factors contribute to acetylcholine-induced renal afferent arteriolar vasodilation during myogenic and norepinephrine- and KCl-induced vasoconstriction. Studies in the isolated perfused hydronephrotic kidney.
Acetylcholine (ACh) elicits vasodilation by releasing a number of endothelium-derived relaxing factors (EDRFs). We used the isolated perfused hydronephrotic rat kidney to examine the characteristics of ACh-induced vasodilation of renal afferent arterioles during different types of underlying vasoconstriction. Basal arteriolar tone was increased by either elevating perfusion pressure to 180 mm Hg (myogenic), administering 0.3 mumol/L norepinephrine (NE), or elevating medium potassium concentration to 30 mmol/L (KCl). ACh (10 mumol/L) completely reversed myogenic and NE-induced vasoconstriction and reversed KCl-induced vasoconstriction by 80 +/- 5%. However, whereas ACh produced a sustained vasodilation during KCl- and NE-induced vasoconstriction, only a transient reversal of myogenic vasoconstriction was observed, and myogenic tone recovered within 5 to 10 minutes. ACh-induced vasodilation of arterioles preconstricted with KCl was markedly inhibited by either indomethacin (100 mumol/L) or nitro-L-arginine (100 mumol/L) and was completely abolished by pretreatment with both inhibitors. In contrast, indomethacin and nitro-L-arginine had no effect on the transient response to ACh observed during pressure-induced vasoconstriction. In vessels preconstricted with NE, nitro-L-arginine converted the normally sustained response to ACh to a transient vasodilation, which was refractory to both nitric oxide synthase and cyclooxygenase inhibition. Since this component was not observed during KCl-induced vasoconstriction, it may reflect the actions of an, as yet unidentified, endothelium-derived hyperpolarizing factor (EDHF). Our findings thus suggest that prostanoids, nitric oxide, and EDHF all contribute to ACh-induced renal afferent arteriolar vasodilation and that the relative contributions of these individual EDRFs depends on the nature of the underlying renal vascular tone.
Acetylcholine↗
Pressure promotes DNA synthesis in rat cultured vascular smooth muscle cells.
High blood pressure is one of the major risk factors for atherosclerosis. In this study, we examined the effects of pressure on cell proliferation and DNA synthesis in cultured rat vascular smooth muscle cells. Pressure without shear stress and stretch promotes cell proliferation and DNA synthesis in a pressure-dependent manner. Pressure-induced DNA synthesis was inhibited significantly by the phospholipase C (PLC) inhibitor 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate, the protein kinase C inhibitor H-7, 1-(5-isoquinolinylsulfonyl)-2-methyl-piperazine, staurosporine, and the tyrosine kinase inhibitor ([3,4,5-trihydroxyphenyl]methylene)propanedinitrile. To clarify whether activation of PLC and calcium mobilization are involved in pressure-induced DNA synthesis, production of 1,4,5-inositol trisphosphate (IP3) and intracellular Ca2+ was measured. Pure pressure increased IP3 and intracellular Ca2+ in a pressure-dependent manner. The increases in both IP3 and intracellular Ca2+ were inhibited significantly by 2-nitro-4-carboxyphenyl-N,N-diphenylcarbamate. This study demonstrates a novel cellular mechanism whereby pressure regulates DNA synthesis in vascular smooth muscle cells, possibly via activation of PLC and protein kinase C.
Animals↗