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I Kishimoto

Publications and source records attributed to I Kishimoto.

36 records · Page 2Linked to original sources
PubMed1996

The heart communicates with the kidney exclusively through the guanylyl cyclase-A receptor: acute handling of sodium and water in response to volume expansion.

Disruption of guanylyl cyclase-A (GC-A) results in mice displaying an elevated blood pressure, which is not altered by high or low dietary salt. However, atrial natriuretic peptide (ANP), a proposed ligand for GC-A, has been suggested as critical for the maintenance of normal blood pressure during high salt intake. In this report, we show that infusion of ANP results in substantial natriuresis and diuresis in wild-type mice but fails to cause significant changes in sodium excretion or urine output in GC-A-deficient mice. ANP, therefore, appears to signal through GC-A in the kidney. Other natriuretic/diuretic factors could be released from the heart. Therefore, acute volume expansion was used as a means to cause release of granules from the atrium of the heart. That granule release occurred was confirmed by measurements of plasma ANP concentrations, which were markedly elevated in both wild-type and GC-A-null mice. After volume expansion, urine output as well as urinary sodium and cyclic GMP excretion increased rapidly and markedly in wild-type mice, but the rapid increases were abolished in GC-A-deficient animals. These results strongly suggest that natriuretic/diuretic factors released from the heart function exclusively through GC-A.

Animals↗
PubMed1996

Regulation of secretion and clearance of C-type natriuretic peptide in the interaction of vascular endothelial cells and smooth muscle cells.

OBJECTIVE: To clarify the significance of C-type natriuretic peptide in the interaction between endothelial cells and vascular smooth muscle cells by investigating the endothelial production of C-type natriuretic peptide and the clearance mechanism of C-type natriuretic peptide using the endothelial cells-smooth muscle cells co-culture system. RESULTS: Secretion of C-type natriuretic peptide in the direct co-culture of endothelial cells with smooth muscle cells elicited as much as a 60-fold increase compared with endothelial cells alone. The accumulation of intracellular cyclic GMP in the co-culture was consequently increased and the elevation of cyclic GMP level in the co-culture was abolished by the anti-C-type natriuretic peptide monoclonal antibody. The elevated cyclic GMP production in the co-culture was abolished by the anti-transforming growth factor-beta neutralizing antibody. Candoxatrilat (10(-6)-10(-4) mol/l), a neutral endopeptidase inhibitor, dose-dependently increased the concentrations of C-type natriuretic peptide in the culture medium with endothelial cells alone, but not in the endothelial cells-smooth muscle cells co-culture. The transcript of neutral endopeptidase messenger RNA was detected in endothelial cells but not in smooth muscle cells by reverse transcriptase polymerase chain reaction. Treatment with C-atrial natriuretic factor4-23 (10(-9)-10(-6) mol/l), the specific ligand for the clearance receptor of the natriuretic peptides, resulted in dose-dependent augmentation of C-type natriuretic peptide concentration and concomitant intracellular cyclic GMP production in the endothelial cells-smooth muscle cells co-culture but not in endothelial cells alone. CONCLUSION: The present study demonstrated that direct interaction between endothelial cells and smooth muscle cells augments C-type natriuretic peptide secretion from endothelial cells through transforming growth factor-beta activation, and revealed that the enzymatic degradation is responsible for the steady state level of C-type natriuretic peptide in endothelial cells alone and that the receptor-mediated clearance mainly determines the augmented level of C-type natriuretic peptide in the interaction between endothelial cells and smooth muscle cells. The results taken together raise the possibility that endothelial C-type natriuretic peptide might play a role in regulation of vascular tone and remodelling.

Animals↗
PubMed1996

Regulation of endothelial production of C-type natriuretic peptide in coculture with vascular smooth muscle cells. Role of the vascular natriuretic peptide system in vascular growth inhibition.

Recently, we have demonstrated that C-type natriuretic peptide (CNP) is produced in vascular endothelial cells (ECs). In the present study, we investigated the interaction of ECs and vascular smooth muscle cells (SMCs) for endothelial production of CNP and its action on vascular growth, using the EC/SMC coculture system. The concentration of CNP-like immunoreactivity in the medium was increased 60-fold within 48 hours in the EC/SMC coculture with direct contact compared with that in EC alone. Northern blot analysis revealed the augmented expression of CNP mRNA in the EC/SMC coculture. The accumulation of intracellular cGMP in the coculture was concomitantly increased, and this response was blocked by anti-CNP monoclonal antibody and HS-142-1, a nonpeptide atrial natriuretic peptide receptor antagonist. The concentration of biologically active transforming growth factor-beta (TGF-beta) in the culture medium of the coculture with direct contact of ECs and SMCs was elevated to the level to stimulate endothelial production of CNP. Actually, the neutralizing antibody against TGF-beta abrogated the cGMP accumulation in the coculture. These results show that endothelial production of CNP in the EC/SMC coculture is at least in part regulated by TGF-beta. Furthermore, the conditioned medium from ECs stimulated by TGF-beta was demonstrated to have a growth-inhibitory effect on SMCs, which was abolished by anti-CNP monoclonal antibody and HS-142-1. The treatment with anti-CNP monoclonal antibody and HS-142-1 also significantly increased the cell number of the EC/SMC coculture. The present study reveals the pathophysiological significance of endothelial CNP as a paracrine/autocrine vascular regulator for vascular growth in the interaction of ECs and SMCs.

Animals↗
PubMed1995

Salt-resistant hypertension in mice lacking the guanylyl cyclase-A receptor for atrial natriuretic peptide.

Around half of all humans with essential hypertension are resistant to salt (blood pressure does not change by more than 5 mm Hg when salt intake is high), and although various inbred strains of rats display salt-insensitive elevated blood pressure, a gene defect to account for the phenotype has not been described. Atrial natriuretic peptide (ANP) is released from the heart in response to atrial stretch and is thought to mediate its natriuretic and vaso-relaxant effects through the guanylyl cyclase-A receptor (GC-A). Here we report that disruption of the GC-A gene results in chronic elevations of blood pressure in mice on a normal salt diet. Unexpectedly, the blood pressure remains elevated and unchanged in response to either minimal or high salt diets. Aldosterone and ANP concentrations are not affected by the genotype. Therefore, mutations in the GC-A gene could explain some salt-resistant forms of essential hypertension and, coupled with previous work, further suggest that the GC-A signaling pathway dominates at the level of peripheral resistance, where it can operate independently of ANP.

Adrenal Glands↗
PubMed1995

Altered gene expression of natriuretic peptide receptor subtypes in the kidney of stroke-prone spontaneously hypertensive rats.

1. To elucidate the physiological and pathophysiological role of the natriuretic peptide system in the progression of hypertensive renal disease, we examined the gene expression of natriuretic peptide receptor subtypes, guanylate cyclase-A (GC-A), guanylate cyclase-B (GC-B) and clearance receptor (C receptor), in the kidney of stroke-prone spontaneously hypertensive rats (SHRSP) at 8 and 20 weeks of age, and compared them with their gene expression in age-matched Wistar-Kyoto (WKY) rats. 2. Northern blot analyses revealed that messages for three natriuretic peptide receptor subtypes were expressed in the kidney, and their expressions were higher in the glomeruli than in the whole kidney in each strain. 3. In 20 week old rats with established hypertension, the glomerular concentration of GC-A mRNA was significantly higher in SHRSP than in WKY. The concentrations of GC-B and C receptor mRNA in the glomeruli tended to increase and decrease, respectively, but they were not statistically significant in SHRSP. 4. In 8 week old rats, the glomerular concentrations of GC-A, GC-B and C receptor mRNA were not significantly different between SHRSP and WKY. 5. This study demonstrates that in the progression of hypertension, the expression of GC-A, which mediates biological actions of natriuretic peptides, is enhanced in the kidney of SHRSP compared to that of WKY. Together with the augmented secretion of the ligands previously revealed, altered expression of natriuretic peptide receptor subtypes in SHRSP may have a deterrent role in the development of hypertension and its renal complications.

Animals↗
PubMed1995

Endothelin-induced activation of mitogen-activated protein kinases in glomerular mesangial cells from normotensive and stroke-prone spontaneously hypertensive rats.

1. Kinase assay in myelin basic protein (MBP) containing polyacrylamide gels revealed that endothelin-1 (ET-1) and ET-3 increased MBP kinase activities in glomerular mesangial cells (MC) from Wistar-Kyoto (WKY) rats and spontaneously hypertensive rat (SHRSP). ET-1 stimulated MBP kinase activities more potently than ET-3. 2. Immunoprecipitation with anti-41-kDa MAPK antiserum showed that the MBP kinases activated by ET-1 correspond to 43- and 41-kDa MAPK. 3. Since Phorbol 12-myristate 13-acetate, a direct activator of protein kinase C, also activated MAPK, protein kinase C was suggested to mediate ET-induced activation of MAPK. 4. These results suggest that MAPK may mediate the ET actions in glomerular mesangial cells from normotensive rats as well as spontaneously hypertensive rats. Since ET is produced by vascular endothelial cells of the kidney and glomerular mesangial cells, the ET signalling pathway may have some physiological and pathophysiological significance in vivo glomerulus.

Animals↗
PubMed1995

Rapid transcriptional activation and early mRNA turnover of brain natriuretic peptide in cardiocyte hypertrophy. Evidence for brain natriuretic peptide as an "emergency" cardiac hormone against ventricular overload.

We previously demonstrated that brain natriuretic peptide (BNP) is a cardiac hormone mainly produced in the ventricle, while the major production site of atrial natriuretic peptide (ANP) is the atrium. To assess the pathophysiological role of BNP in ventricular overload, we have examined the gene expression of BNP, In comparison with that of ANP, in a model of cardiac hypertrophy using cultured neonatal rat ventricular cardiocytes. During cardiocyte hypertrophy evoked by endothelin-1, Phenylephrine, or PMA, the steady state level of BNP mRNA increased as rapidly as the "immediate-early" induction of the c-fos gene expression, and reached a maximal level within 1 h. Actinomycin D, a transcriptional inhibitor, completely diminished the response, while the translational blocked with cycloheximide did not inhibit it. In contrast, ANP mRNA began to increase 3 h after the stimulation, and accumulated during cardiocyte hypertrophy. The BNP secretion from ventricular cardiocytes was also stimulated, more rapidly than the ANP secretion. Furthermore, the turnover of BNP mRNA was significantly faster than that of ANP mRNA, being consistent with the existence of AUUUA motif in the 3'-untranslated region of BNP mRNA. These results demonstrate that the gene expression of BNP is distinctly regulated from that of ANP at transcriptional and posttranscriptional levels, and indicate that the characteristics of the BNP gene expression are suitable for its possible role as an " emergency" cardiac hormone against ventricular overload.

Animals↗
PubMed1994

Natriuretic peptide clearance receptor is transcriptionally down-regulated by beta 2-adrenergic stimulation in vascular smooth muscle cells.

Three natriuretic peptide receptors (the ANP-A, ANP-B, and clearance (C) receptors) have been reported. The regulation of these receptors by catecholamines was examined in cultured rat vascular smooth muscle cells. Treatment with norepinephrine decreased the maximum 125I-ANP binding. The competitive binding assay with des[Gln18,Ser19,Gly20,Leu21, Gly22]ANP-(4-23)-NH2 (C-ANF-4-23), a specific ligand for the C receptor, revealed that the decrease in the 125I-ANP binding by norepinephrine was caused by the down-regulation of the C receptor. Isoproterenol also down-regulated the C receptor in a time- and dose-dependent manner. The catecholamine-induced down-regulation of the C receptor was antagonized by a beta 2-selective adrenergic antagonist, ICI 118,551 but not by an alpha 1-, alpha 2-, or beta 1-adrenergic antagonist. Forskolin, NaF and, 8-bromo-cyclic AMP also decreased the C receptor density. The isoproterenol-induced decrease in the C receptor level was further confirmed by affinity cross-linking and Western blot analysis. Northern blot analysis revealed that isoproterenol and 8-bromo-cyclic AMP decreased the steady-state level of C receptor mRNA. By contrast, neither the ANP-A receptor nor the ANP-B receptor mRNA level was affected by 8-bromo-cyclic AMP. The nuclear run-on assay showed that the transcriptional rate of the C receptor gene was decreased by isoproterenol, whereas those of the ANP-A and ANP-B receptor genes were unchanged. Isoproterenol attenuated the clearance of exogenously added ANP and augmented the ANP-stimulated intracellular cyclic GMP production to the same extent as the selective occupancy of the C receptor with C-ANF-(4-23), suggesting that the isoproterenol-induced enhancement of responsiveness to ANP could result not from the sensitization of the ANP-A or ANP-B receptor but from the down-regulation of the C receptor, which leads to the attenuated clearance of ANP. These findings suggest that the beta 2-adrenergic receptor stimulation down-regulates the C receptor through the decrease in the transcriptional rate of the C receptor gene and that the activation of the sympathetic nervous system augments the biological responsiveness to natriuretic peptides by attenuating their metabolic clearance in vascular walls.

8-Bromo Cyclic Adenosine Monophosphate↗
PubMed1994

Polyarthritis associated with hepatitis C virus infection.

Two cases of polyarthritis associated with hepatitis C infection are reported. In Patient 1, stiffness and polyarthritis occurred during the acute stage of hepatitis. The arthritic symptoms lasted for 4 months. A transient polyarthritis recurred 4 yr later. The persistent presence of anti-hepatitis C viral antibodies was noted. Hepatitis C viral RNA (HCV RNA) was identified in the serum using the polymerase chain reaction proving that the patient was a carrier. In Patient 2, polyarthritis occurred associated with chronic hepatitis C liver disease. Synovial biopsy showed infiltration of mononuclear cells. HCV RNA was demonstrated in both serum and SF. These cases suggest an aetiologic association between arthritis and hepatitis C antigenaemia.

Adult↗
PubMed1994

Molecular cloning of hamster brain and atrial natriuretic peptide cDNAs. Cardiomyopathic hamsters are useful models for brain and atrial natriuretic peptides.

Brain and atrial natriuretic peptides (BNP and ANP) are cardiac hormones with diuretic, natriuretic, and vasodilatory activities. Cardiomyopathic hamsters are widely used animal models of heart failure. Due to the structural divergence of BNP among species, examination on pathophysiological roles of BNP using cardiomyopathic hamsters is so far impossible. We therefore isolated hamster BNP and ANP cDNAs, and investigated synthesis and secretion of these peptides in normal and cardiomyopathic hamsters. The COOH-terminal 32-residue peptide of cloned hamster preproBNP with 122 amino acids, preceded by a single arginine residue, supposedly represents hamster BNP showing < 50% homology to rat BNP. Alpha-hamster ANP, 28-residue peptide, is identical to alpha-rat ANP. In hamsters, BNP and ANP occur mainly in the ventricle and the atrium, respectively. The 32-wk-old hypertrophic cardiomyopathic BIO14.6 strain exhibited ventricular hypertrophy. The 32-wk-old dilated cardiomyopathic BIO53.58 strain remained at the stage without apparent heart failure. In BIO14.6 and BIO53.58 strains at this age, ventricular BNP and ANP gene expressions are augmented, and the plasma BNP concentration is elevated to 136 and 108 fmol/ml, respectively, three times greater than the elevated plasma ANP concentration, which well mimics changes of the plasma BNP and ANP concentrations in human heart failure. Cardiomyopathic hamsters, therefore, are useful models to investigate the implication of BNP in human cardiovascular diseases.

Amino Acid Sequence↗
PubMed1993

Downregulation of C-receptor by natriuretic peptides via ANP-B receptor in vascular smooth muscle cells.

The natriuretic peptide system comprises at least three ligands, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), and C-type natriuretic peptide (CNP) and three receptors, the ANP-A receptor, the ANP-B receptor, and the clearance (C) receptor. In the present study, the regulation of natriuretic peptide receptors by their ligands was investigated in cultured rat vascular smooth muscle cells (SMC). The treatment of vascular SMC with ANP, BNP, or CNP decreased the C-receptor density significantly, and the rank order of potency for this downregulation was CNP > ANP > BNP. This rank order was the same as that for guanosine 3',5'-cyclic monophosphate (cGMP) production by ANP, BNP, or CNP in vascular SMC and also the same as that for the ligand selectivity of the ANP-B receptor rather than the C-receptor. The incubation of vascular SMC with 8-bromoguanosine 3',5'-cyclic monophosphate significantly decreased the C-receptor density and its mRNA expression. These results suggest that the down-regulation of the C-receptor by natriuretic peptides is induced not by the binding of natriuretic peptides to the C-receptor but by the activation of the ANP-B receptor-cGMP pathway.

Animals↗
PubMed1993

Lymphomatous polyarthritis in patients with peripheral T-cell lymphoma.

Direct involvement of the joints is a rare complication of malignant lymphoma and lymphoma cells in synovium or synovial fluid have been characterized in only a very few cases. We report two cases of CD4-positive, HTLV-I-negative peripheral T-cell lymphomas that manifested polyarthritis infiltrated with lymphoma cells which we further characterized. Patient 1, with a prior 7-year history of cutaneous T-cell lymphoma (mycosis fungoides) and polyarthralgia, developed pain and swelling in the right knee joint and right femoral region. Patient 2 was initially diagnosed with immunoblastic lymphadenopathy, later rediagnosed as the prodromal stage of T zone lymphoma. Seven years later she developed skin eruptions, cervical lymph node swelling, polyarthritis, and pleural effusion. Synovial fluid analysis in both cases showed predominant CD3+ or cytoplasmic CD3+, CD4+, and CD8- atypical lymphoid cell infiltration. In both cases the T-cell receptor beta and gamma chains were rearranged in the synovial fluid mononuclear cells. Analysis of these two cases and a review of the literature suggest that lymphoma cell infiltration of synovium occurs preferentially in patients with CD4+ peripheral T-cell lymphoma.

Adult↗
PubMed1992

Identification and endothelin-induced activation of multiple extracellular signal-regulated kinases in aortic smooth muscle cells.

In order to explore intracellular signaling pathways of the mitogenic action of endothelin (ET), we examined the effect of ET on activities of extracellular signal-regulated kinases (ERKs) in rat aortic smooth muscle cells (SMCs). Treatment of rat aortic SMCs with ET-1 increased kinase activities toward myelin basic protein (MBP). Both 43- and 41-kDa proteins were activated when kinase assays were done in MBP-containing polyacrylamide gels after SDS-PAGE. These proteins were identified as ERK1 and ERK2 with immunoprecipitation and immunoblotting using antipeptide antibodies, respectively. These results indicate that ERKs mediate signal transduction by ET.

Amino Acid Sequence↗
PubMed1992

Phenotype-related alteration in expression of natriuretic peptide receptors in aortic smooth muscle cells.

To elucidate the physiological and pathophysiological roles of the natriuretic peptide family in vascular smooth muscle cells, in which the natriuretic peptide family is implicated in growth inhibition as well as vasorelaxation, we have examined the phenotype-related expression of three kinds of natriuretic peptide receptors in rat aortic smooth muscle cells. The expression of natriuretic peptide receptors at the mRNA level was studied by Northern blot hybridization, and the expression at the protein level was determined by the cGMP production method and receptor binding assay. In intact aortic media, atrial natriuretic peptide (ANP)-A receptor mRNA and ANP-B receptor mRNA were detected, and the potency of cGMP production by ANP was at least two orders of magnitude stronger than that by C-type natriuretic peptide. Clearance receptor mRNA was undetectable, and only a small amount of the clearance receptor was detected by the binding assay in intact aortic media. By contrast, in cultured aortic smooth muscle cells at the first, fifth, and 17th passages, the ANP-B receptor mRNA level markedly increased; meanwhile, the expression of the ANP-A receptor mRNA became undetectable. C-type natriuretic peptide was one order of magnitude more potent than ANP in cGMP production in cultured aortic smooth muscle cells. The clearance receptor density and its mRNA level increased tremendously in these cultured cells. These results demonstrate that the marked phenotype-related alteration occurs in the expression of natriuretic peptide receptors in rat aortic smooth muscle cells.

Actins↗
PubMed1991

Isolation and characterization of porcine endothelin-like peptide.

Two endogenous molecules possessing an endothelin-like sequence with an apparent molecular weight of 7 kDa were isolated from serum-free culture medium of porcine aortic endothelial cells, using a specific radioimmunoassay. N-terminal sequences of two molecules were identical to each other and were Ser-Leu-Lys-Asp-Leu-Phe-Pro-Ala-Lys-Ala-Ala-Asp-Arg-Arg-Asp-Arg-X-Gln-X- Ala-X- Gln-Lys-Asp, which corresponds to the sequence [94-117] of preproendothelin-1. This finding indicates that these two molecules may be closely related peptides such as the oxidized form or disulfide analogues and also suggests that the endogenous peptide possessing an endothelin-like sequence is generated by proteolytic cleavage at paired basic amino acids Arg92-Arg93. Further studies on the structure and function of new endogenous peptides possessing an endothelin-like sequence are ongoing in our laboratory.

Amino Acid Sequence↗
PubMed1989

Blood oxygen tension-related change of theophylline clearance in experimental hypoxemia.

The effects of arterial blood oxygen tension on the pharmacokinetics of theophylline were investigated using an experimental acute hypoxemia model in rats. Conscious rats were exposed to hypoxic gas composed of 8% O2-92% N2. After blood gas tensions and blood pH were stabilized, rats received 5 mg/kg i.v. theophylline, and urine and blood samples were collected. The steady-state volume of distribution, unbound free fraction and hematocrit were unaffected by hypoxemia. Total body clearance was significantly changed (P less than .01) from 0.156 +/- 0.020 l/kg/hr in control to 0.0556 +/- 0.0067 l/kg/hr in hypoxemic rats due to the reduction of both hepatic and renal clearances. In another constant rate i.v. infusion study, the plateau plasma concentration of theophylline was elevated steeply as soon as animals had inspired hypoxic gas, and the elevated concentrations went down after returning to room air. The present results suggested that the variation of arterial oxygen tension is one possible mechanism for a rapid and large intraindividual variability in theophylline clearance in acutely ill patients with chronic obstructive pulmonary disease.

Animals↗
PubMed1986

Effect of medium-chain glycerides (MGK) on the intestinal absorption and the hepatobiliary transport of bromthymol blue.

The effect of medium chain glyceride (MGK) emulsion on the intestinal absorption and the biliary excretion of bromthymol blue (BTB) was investigated in rats. Extensive tissue accumulation of BTB was reduced when BTB was administered with MGK emulsion formulation. HCO-100, an emulsifier, was also important for the decrease in the tissue accumulation of BTB. The ratios of absorption percent to tissue accumulation percent and to free fraction, not contained in the droplet of emulsion, in MGK emulsion were much greater than that of the control. Pretreatment with BTB-free emulsion reduced BTB absorption under the control, although tissue accumulation was not affected. The absorption appeared to decrease with increase in the time of pretreatment. The effect of leaving treatment after pretreatment on the absorption of BTB was also investigated. With the increase in leaving time after pretreatment, reduced absorption tended to resume to the level of control. The change in monocaprylate content from 54 to 60% in MGK made a difference in BTB absorption and it was suggested that monocaprylate content in MGK was one of the significant factors of MGK emulsion on drug absorption. Bile recovery study was simultaneously carried out with an in situ recirculation experiment. The recovery of BTB into bile tended to decrease. The ratio of recovery percent of BTB into bile to the absorption percent of BTB also decreased extensively, which is possibly another effect of MGK on drug disposition.

Animals↗