Biomedical subjects

N Hama

Publications and source records attributed to N Hama.

At least 37 records · Page 2Linked to original sources

PubMed1996

C-type natriuretic peptide in chronic renal failure and its action in humans.

We have previously reported that C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is produced in vascular endothelial cells and acts as an endothelium-derived relaxing peptide. To clarify the clinical significance of CNP in renal disorders, we examined the plasma level of CNP in patients with various cardiovascular diseases, including chronic renal failure (CRF) patients who were under hemodialysis therapy. We also investigated biological effects of intravenously-administered CNP (0.43 nmol/kg) by bolus injection from the peripheral vein in healthy volunteers and measured systemic hemodynamic variables, plasma levels of CNP, atrial natriuretic peptide (ANP), brain natriuretic peptide (BNP), cGMP, aldosterone and also urine volume, urinary excretions of sodium, potassium, chloride and cGMP. The plasma CNP levels in healthy humans (N = 13) was 1.4 +/- 0.6 fmol/ml. In CRF patients, the plasma CNP significantly increased up to 3.0 +/- 1.1 fmol/ml. The administration of CNP elicited significant increase of plasma cGMP level (from 4.77 +/- 1.25 to 8.33 +/- 1.59 pmol/ml 15 min after the administration) and of urinary cGMP excretion (from 30.7 +/- 4.3 to 74.9 +/- 13.4 nmol/30 min). Intravenously-administered CNP exerted significant diuretic (% increase: +117 +/- 85.0), natriuretic, kalliuretic and chloriuretic actions with the increase of endogenous creatinine clearance. CNP also elicited significant hypotensive actions (delta BPs/delta BPd: -4.3 +/- 1.3/-4.1 +/- 1.0 mm Hg) with the concomitant increase of heart rate (+7.6 +/- 2.6 bpm). Plasma aldosterone concentration significantly decreased from 45.4 +/- 2.3 to 35.4 +/- 4.9 pg/ml 30 minutes after the administration. Taken together, these results suggest a role for CNP in human renal function.

Adult↗

PubMed1995

Rapid ventricular induction of brain natriuretic peptide gene expression in experimental acute myocardial infarction.

BACKGROUND: We have demonstrated that brain natriuretic peptide (BNP) is a cardiac hormone predominantly synthesized in and secreted from the ventricle. We have also reported that, compared with atrial natriuretic peptide (ANP), the plasma concentration of BNP is increased to a greater degree in patients with congestive heart failure and more rapidly in patients with acute myocardial infarction (AMI). METHODS AND RESULTS: To investigate ventricular gene expression of BNP in AMI, we analyzed plasma and ventricular BNP concentrations along with ventricular BNP mRNA in rats with AMI produced by coronary artery ligation. The BNP concentration in the left ventricle increased about 2-fold as early as 12 hours postinfarction and 5-fold 1 day postinfarction compared with sham-operated rats, whereas left ventricular ANP concentration remained unchanged within 1 day. The tissue concentration of BNP increased in the noninfarcted region as well as in the infarcted region. The surviving myocytes in and around the necrotic tissues in the infarcted region were intensely stained with the anti-BNP antiserum, indicating augmented production in the remaining myocytes in the infarcts. The BNP concentration in the right ventricle also increased about 10-fold 12 hours postinfarction, whereas the ANP concentration remained unchanged within 12 hours. Northern blot analysis revealed that BNP mRNA expression was augmented 3-fold in the left ventricle as early as 4 hours postinfarction. In contrast, ANP mRNA expression was unchanged. Reflecting the rapid induction of ventricular BNP production, the plasma BNP concentration rose to about 100 pg/mL 12 hours postinfarction (sham-operated rats, < 70 pg/mL). CONCLUSIONS: These results demonstrate the rapid induction of ventricular BNP gene expression in rats with AMI compared with ANP and suggest that BNP gene expression in the ventricle is regulated distinctively from ANP gene expression against acute ventricular overload. They also suggest that the BNP gene can be one of the acutely responsive cardiac genes for the ventricular overload and suggest a possible pathophysiological role of BNP distinct from ANP in AMI.

Animals↗

PubMed1995

Glucocorticoid-mediated regulation of protein phosphorylation in primary human T cells. Evidence for induction of phosphatase activity.

Glucocorticoid hormones (GC) have profound effects on the development and homeostasis of the immune system. In this communication we present evidence that GC regulate Ca(2+)-mediated pathways of T cell activation by a mechanism that involves abrogation of the autophosphorylation of the multifunctional Ca2+/calmodulin kinase (CaM kinase II) and induction of protein phosphatase activity. Primary human T cells were stimulated with the combination of ionomycin and phorbol ester in the presence or absence of dexamethasone (Dex) (10(-6)-10(-12) M). Stimulation of T cells resulted in a rapid activation of CaM kinase II and protein kinase C (PKC) activity as determined by the phosphorylation of synthetic peptide substrates recognized by these enzymes. Dex inhibited the activity of CaM kinase II but not PKC activity in a dose-dependent fashion (minimum effective dose 10(-10) M). Stimulation of 32P-labeled T cells induced a rapid increase in the phosphorylation level of CaM kinase II which was inhibited by Dex. The inhibitory effect of Dex on this enzyme was fully reversed in the presence of the phosphatase inhibitor okadaic acid (250 nM) or RU 486, a glucocorticoid antagonist. These results suggest that GC inhibit the activation of CaM kinase during T cell activation through a mechanism that involves both the GC receptor and protein phosphatases 2A and/or 1. Inhibition of protein phosphorylation through the induction of protein phosphatase activity may represent a novel mechanism for the diverse effects of GC on eukaryotic cells.

Amino Acid Sequence↗

PubMed1995

Calcium/calmodulin-dependent protein kinase II downregulates both calcineurin and protein kinase C-mediated pathways for cytokine gene transcription in human T cells.

Engagement of the T cell receptor for antigen activates phospholipase C resulting in an increase in intracellular free calcium concentration ([Ca2+]i) and activation of protein kinase C (PKC). Increased [Ca2+]i activates Ca2+/calmodulin-dependent kinases including the multifunctional Ca2+/calmodulin-dependent protein kinase II (CaM-K II), as well as calcineurin, a type 2B protein phosphatase. Recent studies have identified calcineurin as a key enzyme for interleukin (IL)-2 and IL-4 promoter activation. However, the role of CaM-K II remains unknown. We have used mutants of these kinases and phosphatases (gamma B*CaM-K and delta CaM-AI, respectively) to explore their relative role in cytokine gene transcription and their interactions with PKC-dependent signaling systems. gamma B*CaM-K and delta CaM-AI, known to exhibit constitutive Ca(2+)-independent activity, were cotransfected (alone or in combination) in Jurkat T cells with a plasmid containing the intact IL-2 promoter driving the expression of the chloramphenicol acetyltransferase reporter gene. Cotransfection of gamma B*CaM-K with the IL-2 promoter construct downregulated its transcription in response to stimulation with ionomycin and phorbol myristate acetate (PMA). The inhibitory effect of CaM-K II on IL-2 promoter was associated with decreased transcription of its AP-1 and NF-AT transactivating pathways. Under the same conditions, delta CaM-AI superinduced IL-2 promoter activity (approximately twofold increase). When both mutants were used in combination, gamma B*CaM-K inhibited the induction of the IL-2 promoter by delta CaM-AI. Similar results were obtained when a construct containing the IL-4 promoter also was used. gamma B*CaM-K also downregulated the activation of AP-1 in response to transfection with a constitutively active mutant of PKC or stimulation with PMA. These results suggest that CaM-K II may exert negative influences on cytokine gene transcription in human T cells, and provide preliminary evidence for negative cross-talk with the calcineurin- and PKC-dependent signaling systems.

Calcineurin↗

PubMed1995

Massive pericardial effusion in scleroderma: a review of five cases.

Medical records of five patients with scleroderma (SSc), each of whom had pericardial effusion with an estimated volume of more than 200 ml, were reviewed to study the clinical and immunological significance of massive pericardial effusion in SSc. Diffuse SSc (4/5), with a wide area of pigmentation (4/5), flexion contracture (4/5), oesophageal hypomotility (5/5), pulmonary fibrosis (4/5) and autoantibodies to topoisomerase I (3/5) were the common features in this group. High protein, lactate dehydrogenase and low white blood cell count were the characteristics of pericardial fluid. None of the patients had signs of acute pericarditis. Four of the five cases died within 9 months of the diagnosis of pericarditis; two with renal failure, one with cardiac tamponade and another with sudden death. The pericarditis in diffuse SSc, especially in cases with anti-topoisomerase I, may be characterized by a chronic form of pericarditis with poor prognosis, often complicated by renal failure.

Adult↗

PubMed1995

[A case of mixed connective tissue disease associated with gastric cancer and cancer of the uterine cervix].

We report here a very rare case of MCTD complicating double cancer. A 43-year-old woman with suspected MCTD was admitted because of high fever and lymphadenopathy. The laboratory findings indicated high titers of speckled ANA, anti-RNP, DNA and Scl-70, but anti-Sm. SS-A and SS-B was not detected. Chest CT and Spirogram revealed lung fibrosis, restrictive ventilatory impairment, and decreased diffusion capacity. Biopsy specimen by gastric fiberscope s screening indicated II c advanced type of poorly differentiated adenocarcinoma. After subtotal gastrectomy, she had high fever, pleuritis, leukopenia, butterfly erythema and hypoxemia, which were improved by 30 mg/day of oral prednisolone. One year after from the last operation, she had contact bleeding, and squamous cell carcinoma of the uterine cervix was diagnosed. She had Raynaud's phenomenon 6 months after from hysterectomy.

Adenocarcinoma↗

PubMed1995

[A case of Sjögren's syndrome and systemic lupus erythematosus complicated with necrotizing angiitis of the gallbladder].

A 71 year-old man with Sjogren's syndrome and systemic lupus erythematosus was admitted to our hospital because of abdominal pain and fever. Laboratory investigation showed an ESR of 76 mm/hr, elevation of CRP and marked leukocytosis. Abdominal ultrasound and CT scan showed enlargement of the gallbladder and intravesicular sludge without stones. With a clinical diagnosis of acute cholecystitis and pan-peritonitis, the surgical procedures including cholecystectomy were performed. Histological examination of the gallbladder showed a presence of necrotizing angiitis of small arteries. The postoperative course was uneventful with daily administration of 10 mg of prednisolone.

Acute Disease↗

PubMed1994

Detection of C-type natriuretic peptide in human circulation and marked increase of plasma CNP level in septic shock patients.

We have previously reported that C-type natriuretic peptide (CNP), the third member of natriuretic family, was produced in vascular endothelial cells and hypothesized that CNP might be a local regulator of vascular tone and/or growth from endothelial cells. In order to clarify the pathophysiological significance of CNP in humans, we examined the presence of CNP in human circulation and determined plasma levels of CNP in patients with various cardiovascular disorders. The plasma level of CNP in healthy persons was 1.4 +/- 0.6 fmol/ml (n = 13). The plasma level of CNP was markedly increased in patients with septic shock (13.2 +/- 10.1 fmol/ml, n = 11), while there was no alteration in patients with congestive heart failure or hypertension. There was two-fold increase of the plasma CNP level in patients with chronic renal failure. These results indicate that CNP, which can be considered as an endothelium-derived relaxing peptide, is detectable in human circulation and suggest the pathophysiological significance of endothelial CNP in humans.

Aged↗

PubMed1994

Natriuretic peptide-potentiating actions of neutral endopeptidase inhibition in rats with experimental heart failure.

We developed a rat model of heart failure induced by myocardial infarction (MI) which preserves responsiveness to exogenously administered natriuretic peptide, and investigated the potentiating action of neutral endopeptidase (NEP) inhibition on the renal response to endogenous natriuretic peptide in MI rats, comparing with that in the established cardiac-failing model with arterio-venous fistula (AVF). The endogenous plasma concentration of alpha-rat atrial natriuretic peptide (alpha-rANP) in the MI rat was 6.4-fold higher than that in the normal rat, and intravenous infusion of phosphoramidon (165 nmol/min/kg), an NEP inhibitor, induced larger increases in circulating alpha-rANP levels and natriuresis in MI rats than in normal controls. The maximal natriuretic effect of phosphoramidon (165 nmol/min/kg) was equal to that of exogenously administered alpha-rANP (100 pmol/min/kg) in MI rats, whereas plasma alpha-rANP concentration under NEP inhibition was much lower than that after administration of alpha-rANP. The endogenous alpha-rANP levels in AVF rats were as high as those in MI rats. However, the natriuretic effect of phosphoramidon was less in AVF rats than in MI rats, which was consistent with the decreased natriuretic activity observed with administration of exogenous to alpha-rANP in the AVF rat. These results indicate that the natriuretic effect of NEP inhibition is dependent on elevated endogenous alpha-rANP levels in cardiac-failing rats, but cannot be accounted for simply in terms of the increase in circulating alpha-rANP levels. Endogenous natriuretic peptide-mediated natriuresis under NEP inhibition also appears to correlate with the responsiveness to the exogenously administered peptide.

Animals↗

PubMed1994

Clearance mechanisms of atrial and brain natriuretic peptides in rats.

To assess clearance mechanisms of atrial and brain natriuretic peptides in the circulation, we examined the effects of a neutral endopeptidase (NEP) inhibitor and a clearance receptor ligand on plasma concentrations of the peptides in normal rats. Plasma concentrations of endogenous alpha-rat atrial natriuretic peptide (alpha-rANP) were not significantly elevated by intravenous infusion of a NEP inhibitor, phosphoramidon, but were elevated threefold by intravenous infusion of a clearance receptor ligand, des(Gln18-Gly22)-rANP(4-23)-NH2 [C-ANF(4-23)]. On the other hand, the clearance of alpha-rANP given intravenously at the pharmacological dose, 600 pmol/min/kg for 2 min, was decreased to one-third by the administration of phosphoramidon, although the administration of C-ANF(4-23) did not significantly decrease the clearance. The clearance of rat brain natriuretic peptide (rBNP) given at 600 pmol/min/kg for 2 min was approximately 38% lower than that of alpha-rANP. The effect of phosphoramidon on the clearance of rBNP was not significant and was similar to that of C-ANF(4-23). These results suggest that clearance receptor is involved in the clearance of the physiological levels of alpha-rANP and that NEP plays a major role in the clearance of a pharmacological dose of alpha-rANP, at which clearance receptors are thought to be saturated, and also indicate a pharmacokinetic difference between alpha-rANP and rBNP.

Amino Acid Sequence↗

PubMed1994

A monoclonal antibody to C-type natriuretic peptide--preparation and application to radioimmunoassay and neutralization experiment.

C-type natriuretic peptide (CNP), the third member of natriuretic peptides, has recently been discovered from the porcine brain. Using a polyclonal antiserum to CNP, we demonstrated that CNP-like immunoreactivity (CNP-LI) is present mainly in the central nervous system. Recently, however, we have discovered the production and secretion of CNP in vascular endothelial cells. These observations suggested that CNP may act not only as a neuropeptide but also as a local regulator of vascular tone or growth. In order to further clarify the pathophysiological significance of CNP, we aimed at the preparation of a monoclonal antibody to CNP. A monoclonal antibody to CNP, KY-CNP-I, has been produced. This monoclonal antibody belongs to the immunoglobulin G1 subclass and has high affinity for CNP. Using this monoclonal antibody, we established a specific radioimmunoassay (RIA) for CNP. The RIA detected CNP-LI in rat brain extracts and culture media conditioned with bovine endothelial cells. In addition, the pretreatment of cultured aortic smooth muscle cells with KY-CNP-I attenuated cyclic GMP production induced by CNP in vitro. The preadministration of KY-CNP-I to rats also attenuated plasma cyclic GMP increase after intravenous injection of CNP in vivo. These results indicate that this monoclonal antibody is a useful tool to clarify the pathophysiological role of CNP as a neuropeptide and as a local vascular regulator.

Animals↗

PubMed1993

Central action of C-type natriuretic peptide on vasopressin secretion in conscious rats.

The effect of intracerebroventricular injection of C-type natriuretic peptide (CNP) on arginine vasopressin (AVP) secretion was studied in conscious rats, and was compared to that of atrial natriuretic peptide (ANP). The AVP secretion induced by central injection of 0.1 nmol angiotensin II was significantly suppressed by the pretreatment with 1 nmol CNP. ANP at a dose of 0.1 nmol elicited almost equivalent suppressive action to 1 nmol CNP. Considering that CNP is a specific ligand for ANP-B receptor, while ANP is that for ANP-A receptor, the result demonstrates that CNP possesses the similar central action to ANP, and suggests that the distribution of ANP-A and ANP-B receptors and/or their affinity towards each natriuretic peptide are different in the central nervous system.

Angiotensin II↗

PubMed1993

C-type natriuretic peptide (CNP) is the major natriuretic peptide in human cerebrospinal fluid.

In order to investigate whether C-type natriuretic peptide (CNP) is present in human cerebrospinal fluid (CSF), we measured CNP-like immunoreactivity (-LI) in human CSF by specific radioimmunoassay (RIA) for CNP. We also measured atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) concentrations in human CSF. ANP-LI, BNP-LI, and CNP-LI concentrations of CSF collected from fifteen patients without neurological disorders were 0.20 +/- 0.13, 0.27 +/- 0.10, and 2.13 +/- 0.27 fmol/ml (mean +/- S.D.), respectively. In fifteen patients with neurological disorders, ANP-LI, BNP-LI, and CNP-LI concentrations in CSF were 0.21 +/- 0.18, 0.33 +/- 0.19, and 2.09 +/- 0.82 fmol/ml, respectively. Although ANP-LI and BNP-LI concentrations in plasma were much higher than those in CSF, CNP-LI was undetectable in plasma (less than 0.2 fmol/ml). These results demonstrate that three natriuretic peptides are present in CSF and that CNP is the major natriuretic peptide in human CSF. These results suggest that CNP in CSF is originated from and play important roles in the central nervous system.

Adult↗

PubMed1993

Nonlinear mixed effect modeling of the pharmacodynamics of natriuretic peptides in rats.

Natriuretic peptides have not only natriuretic/diuretic but also hypotensive activities, and the decreased renal perfusion caused by the excessive hypotension is known to attenuate the diuretic actions. The present study was designed to examine the relationship between the dosing (intravenous constant infusion) rates and the diuretic actions of alpha-rat atrial natriuretic peptide (alpha-rANP) and rat brain natriuretic peptide (rBNP) in rats, and population (nonlinear mixed effect model) analysis was applied to these complicated diuretic actions. The intrinsic diuretic activities of alpha-rANP and rBNP could be analyzed, and the effects of blood pressure, heart rate, and also inhibition of degradation enzyme on the diuresis of natriuretic peptides were estimated simultaneously. The population analysis was useful for analyzing such pharmacodynamic data for which the individual analysis could not be applied easily.

Animals↗

PubMed1993

Cytokine-induced C-type natriuretic peptide (CNP) secretion from vascular endothelial cells--evidence for CNP as a novel autocrine/paracrine regulator from endothelial cells.

We previously demonstrated that C-type natriuretic peptide (CNP), originally isolated from the porcine brain, is produced by endothelial cells and proposed that CNP can exert local control over vascular tone and growth as a local regulator from endothelial cells. Since cytokines play pivotal roles in the control of vascular tone and structure, we have examined effects of various cytokines on CNP secretion from endothelial cells using the specific radioimmunoassay for CNP. While interleukin (IL)-2 had no significant effect on CNP secretion, IL-1 alpha, IL-1 beta and tumor necrosis factor (TNF)-alpha stimulated CNP secretion in a time- and dose-dependent manner. Among them, TNF-alpha, one of the key mediators for inflammation and vascular remodeling, induced more than two orders of magnitude increase in CNP secretion. In addition, lipopolysaccharide (LPS) potently stimulated CNP secretion. These results indicate that IL-1, TNF-alpha and LPS, the endotoxin itself, can regulate local vascular tone and growth through the activation of CNP secretion from endothelial cells. Therefore, CNP could be of clinical relevance as an autocrine/paracrine regulator from endothelial cells for systemic and local cytokine-associated disorders, such as endotoxin shock and atherosclerosis.

Animals↗

PubMed1993

Rheumatoid arthritis in a patient with pseudoxanthoma elasticum.

Pseudoxanthoma elasticum (PXE) is a rare, inherited disorder of the connective tissue. Possible association of autoimmune thyroiditis and PXE has been suggested, but reports of other autoimmune diseases complicating PXE are rare. We report a case of rheumatoid arthritis (RA) in a patient with PXE. Since the frequency of PXE is likely to be underdiagnosed, further studies to elucidate the true incidence and significance of the association of RA and PXE will be needed.

Adult↗

PubMed1992

Characterization of autoantibodies that recognize U4/U6 small ribonucleoprotein particles in serum from a patient with primary Sjögren's syndrome.

We identified autoantibodies that recognize the U4/U6 snRNPs in a serum from a 63-year-old Japanese patient (TT) with primary Sjögren's syndrome. This patient's serum immunoprecipitated U4 and U6 sn-RNAs exclusively from 32P-labeled HeLa cell extracts and a newly identified 120-kDa protein along with the Sm core proteins (B'/B, D, E, F, and G) from [35S] methionine-labeled HeLa cell extracts. Immunoblotting demonstrated that only the 120-kDa protein was recognized by this unique serum. In glycerol density gradient centrifugation, the 120-kDa protein reactive with TT serum cosedimented with U4 and U6 snRNAs, suggesting that the 120-kDa protein is a unique component of the U4/U6 snRNP particle. In the same study, the U4/U6 snRNP precipitated by TT serum sedimented only in the lower density, whereas anti-Sm antibodies precipitated U4/U6 snRNAs in a broad range of the gradient. This result suggests the presence of at least two molecular forms of the U4/U6 snRNP particles; larger particles, probably the U4/U5/U6 snRNP complex, and free particles. Thus, the U4/U6 snRNP recognized by TT serum includes the U4 and U6 snRNAs, with Sm core proteins, and the novel 120-kDa protein, and appears to be a free particle not associated with larger complexes.

Autoantibodies↗

PubMed1992

Endothelial production of C-type natriuretic peptide and its marked augmentation by transforming growth factor-beta. Possible existence of "vascular natriuretic peptide system".

C-type natriuretic peptide (CNP), the third member of the natriuretic peptide family, is thus far known to be distributed mainly in the central nervous system and is considered to act as a neuropeptide, in contrast to atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), which act as cardiac hormones. Recently, we and others have demonstrated that the ANP-B receptor, which is selectively activated by CNP, is localized not only in the central nervous system but in peripheral tissues, including blood vessels. This finding has made us speculate regarding the peripheral production of CNP. In the present study, cultured endothelial cells were examined for CNP production by RIA and Northern blot analysis. CNP-like immunoreactivity was detected in the conditioned media of endothelial cells. Northern blot analysis detected CNPmRNA with a size of 1.2 kb. In addition, transforming growth factor (TGF)-beta, one of the key growth factors for vascular remodeling, markedly stimulated the expression of CNPmRNA and induced a tremendous increase in CNP secretion. We could also detect CNP transcript in the bovine thoracic aorta using the reverse transcription-polymerase chain reaction method. The present study demonstrates the endothelial production of CNP and suggests that a member of the natriuretic peptide family may act as a local regulator in vascular walls. Since evidence for the pathophysiological importance of the vascular renin-angiotensin system has been accumulating and the natriuretic peptide system is known to be antagonistic to the renin-angiotensin system, the possible existence of "vascular natriuretic peptide system" may prove to be of physiological and clinical relevance.

Animals↗