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Toshio Nishikimi

Publications and source records attributed to Toshio Nishikimi.

At least 19 recordsLinked to original sources
PubMed2006

Long-term administration of rho-kinase inhibitor ameliorates renal damage in malignant hypertensive rats.

We have shown recently that fasudil, a Rho-kinase inhibitor, has renoprotective effects in salt-sensitive hypertensive rats. We hypothesized that activation of Rho-kinase is involved in the pathogenesis of glomerulosclerosis in malignant hypertensive rats. To test this hypothesis, we studied the following 4 groups: control Wistar-Kyoto rats, untreated deoxycorticosterone-acetate salt spontaneously hypertensive rats (DOCA-SHR), low-dose fasudil-treated DOCA-SHR, and high-dose fasudil-treated DOCA-SHR. After 3 weeks of treatment, the effects of fasudil were examined. DOCA-SHR was characterized by increased blood pressure (BP); increased kidney weight; decreased renal function; increased proteinuria; abnormal histological findings; increased monocyte/macrophage infiltration; increased urinary 8-isoprostran levels; increased gene expression of collagen I, collagen III, transforming growth factor-beta, and reduced nicotinamide-adenine dinucleotide phosphate oxidase subunits (p40phox, p47phox, and p67phox); and decreased gene expression of endothelial NO synthase (eNOS) in the renal cortex as compared with Wistar-Kyoto rats. Long-term high-dose fasudil treatment significantly improved renal function and histological findings without changing BP, as compared with untreated DOCA-SHR. Interestingly, long-term fasudil treatment significantly decreased monocyte/macrophage infiltration and urinary 8-isoprostran excretion, in association with decreased mRNA levels of transforming growth factor-beta, collagen I, collagen III, and NADPH oxidase subunits (p40phox, p47phox, and p67phox), and increased mRNA levels of eNOS in the renal cortex. Long-term low-dose fasudil treatment tended to improve these variables slightly but did not affect most of them significantly. Our results suggest that long-term fasudil treatment provides renoprotective effects independent of BP-lowering activity. These renoprotective effects are associated with inhibition of extracellular matrix gene expression, monocyte/macrophage infiltration, oxidative stress, and upregulation of eNOS gene expression.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Molecular mechanisms and therapeutic strategies of chronic renal injury: renoprotective effect of rho-kinase inhibitor in hypertensive glomerulosclerosis.

Among the GTP-binding proteins, Rho is known to function as a molecular switch in various cellular functions. Among the Rho effectors, the cellular function and signal transduction of Rho-kinase have been extensively studied. However, information about its in vivo functions is still limited. With the recent development of a specific Rho-kinase inhibitor such as Y-27632 and fasudil, the understanding of the role of the Rho/Rho-kinase pathway in vitro and in vivo has advanced. However, to date, there have been few studies investigating the role of Rho-kinase in renal disease. Recent studies have shown that Rho-kinase inhibitor significantly attenuated the tubulointerstitial fibrosis in kidney induced by unilateral ureteral obstruction. However, there have been few studies investigating the role of the Rho/Rho-kinase pathway in hypertensive glomerular sclerosis. In this review, we described the role of the Rho/Rho-kinase pathway in the progression of renal glomerulosclerosis in several forms of hypertensive rats. Our results suggest that chronic inhibition of the Rho-kinase pathway may be a new therapeutic approach for hypertensive glomerulosclerosis. Our results also suggest that the mechanism of the renoprotective effect of Rho-kinase inhibitor is partly mediated via inhibition of extracellular matrix gene expression, monocytes/macrophages infiltration, oxidative stress, and upregulation of eNOS gene expression.

1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine↗
PubMed2006

Chronic effect of combined treatment with omapatrilat and adrenomedullin on the progression of heart failure in rats.

BACKGROUND: We and other investigators have reported that short- and long-term treatment with adrenomedullin has beneficial effects in heart failure. This study examined the effects of long-term treatment with a vasopeptidase inhibitor plus adrenomedullin in a model of heart failure in rats and assessed potential mechanisms of action. METHODS: Dahl salt-sensitive rats aged 11 weeks were randomly divided into three groups: an omapatrilat group, an omapatrilat plus adrenomedullin group, and an untreated group. The effects of these treatments were evaluated after 7 weeks of treatment. RESULTS: Omapatrilat monotherapy significantly improved left ventricular weight (LVW), blood pressure (BP), and central hemodynamics as compared with the untreated group. Omapatrilat decreased the gene expression levels of adrenomedullin and atrial natriuretic peptide (ANP) in the left ventricle. In addition, omapatrilat decreased mRNA levels of transforming growth factor-beta (TGF-beta), collagen I, collagen III, plasminogen activator inhibitor-1 (PAI-1), and intercellular adhesion molecule-1 (ICAM-1) in the left ventricle, and omapatrilat decreased perifibrosis score and myocyte area histologically. Omapatrilat plus adrenomedullin further improved LVW, central hemodynamics, and mRNA expression of TGF-beta, collagen I, collagen III, PAI-1, and ICAM-1 without changing BP. Omapatrilat plus adrenomedullin further reduced mRNA levels of ANP and adrenomedullin without altering levels of ANP or adrenomedullin in plasma. Interestingly, omapatrilat slightly decreased mRNA levels of subunits of NADPH oxidase, whereas omapatrilat plus adrenomedullin further decreased these variables. CONCLUSIONS: Our results suggest that combined treatment with adrenomedullin and omapatrilat may be a new strategy for the management of heart failure, acting partly by inhibition of the extracellular matrix gene, adhesion molecule, antifibrinolysis, and oxidative stress production.

Adrenomedullin↗
PubMed2005

Activation of AMP-activated protein kinase enhances angiotensin ii-induced proliferation in cardiac fibroblasts.

AMP-activated kinase (AMPK) is a highly conserved heterotrimeric kinase that functions as a metabolic regulator of cellular enzymes involved in carbohydrate and fat metabolism, which regulate ATP conservation and synthesis. Here, we investigated whether AMPK signaling has a role in the regulation of angiotensin II (Ang II)-induced proliferation in rat cardiac fibroblasts. Aminoimidazole-4-carboxamide-1-beta-ribofuranoside (AICAR) activated AMPK in rat cardiac fibroblasts and increased Ang II-induced extracellular signal-regulated kinase 1/2 phosphorylation and activity. AICAR also increased Ang II-induced c-fos mRNA expression in the cells. [3H]-thymidine and [3H]-proline incorporation by cardiac fibroblasts treated with Ang II was enhanced when the cells were pretreated with AICAR. Inhibition of AMPK by small interfering RNA for AMPKalpha1 suppressed Ang II-induced extracellular signal-regulated kinase activity, c-fos mRNA expression, and cell proliferation. Treatment of rats with AICAR (1 mg/g body weight per day) for 1 week significantly enhanced Ang II-induced hypertrophy of the myocardium. Our findings indicate that AMPK works as a stimulator of the Ang II-induced proliferative pathway in cardiac fibroblasts. Inhibition of AMPK signaling might serve as a new therapeutic target of remodeling of the hypertrophic myocardium.

AMP-Activated Protein Kinases↗
PubMed2005

The role of natriuretic peptides in cardioprotection.

Atrial natriuretic peptide (ANP) and brain (B-type) natriuretic peptide (BNP) are circulating hormones of cardiac origin that play an important role in the regulation of intravascular blood volume and vascular tone. The plasma concentrations of ANP and BNP are elevated in heart failure, and they are considered to compensate for heart failure because of their diuretic, natriuretic, and vasodilating actions and inhibitory effects on renin and aldosterone secretion. Evidence is also accumulating from recent work that ANP and BNP exert their cardioprotective functions not only as circulating hormones but also as local autocrine and/or paracrine factors. In studies using cultured neonatal myocytes and fibroblasts, exogenous administration of both ANP and ANP antagonists demonstrated that ANP has antihypertrophic and antifibrotic functions. Corroborating these in vitro results, mice lacking natriuretic receptor-A (NPR-A), the receptor for ANP and BNP, develop cardiac hypertrophy and fibrosis independent of their blood pressure. Recent studies also suggest that the intracardiac natriuretic peptides/cGMP system plays a counter-regulatory role against the intracardiac renin-angiotensin-aldosterone system and TGF-beta mediated pathway. In a clinical setting, human recombinant ANP and BNP may be used for a therapy of heart failure; however, further evaluation is required in the future.

Animals↗
PubMed2005

Up-regulated synthesis of mature-type adrenomedullin in coronary circulation immediately after reperfusion in patients with anterior acute myocardial infarction.

OBJECTIVE: Levels of adrenomedullin (AM), a potent vasodilatory peptide, have been shown to increase in the early stage of acute myocardial infarction (AMI). The purpose of this study was to determine whether coronary sinus-aortic step-up of mature forms of AM is accelerated in patients with AMI after reperfusion. METHODS: The subjects were 29 consecutive patients with a first episode of anterior AMI and 10 normal controls. All patients with AMI underwent balloon reperfusion therapy within 24 h after symptom onset. Plasma levels of two molecular forms of AM (an active, mature form [AM-m] and an intermediate, inactive glycine-extended form [AM-Gly]) in the aorta and coronary sinus (CS) were measured by specific immunoradiometric assay after reperfusion. RESULTS: Plasma levels of AM-m and AM-Gly in the aorta and CS were higher in AMI patients than in controls. CS-aortic step-up of AM-m, which is an index of myocardial production of AM-m, was significantly greater in AMI patients than in controls (1.7 +/- 1.4 vs. 0.4 +/- 0.3 pmol/L, P < 0.01). However, there was no significant difference in CS-aortic step-up of AM-Gly (P = 0.30). AMI patients with left ventricular dysfunction (n = 10) had a significantly higher CS-aortic AM-m step-up than AMI patients without left ventricular dysfunction (n = 19). AM-m in the aorta and CS negatively correlated with the left ventricular ejection fraction (r = -0.50, r = -0.48, P < 0.01). CONCLUSIONS: Myocardial synthesis of AM-m is accelerated in patients with reperfused AMI, especially in patients with critical left ventricular dysfunction. Increased myocardial synthesis of active AM may protect against cardiac dysfunction, myocardial remodeling, or both after the onset of AMI.

Adrenomedullin↗
PubMed2005

Chronic administration of adrenomedullin attenuates the hypertension and increases renal nitric oxide synthase in Dahl salt-sensitive rats.

Adrenomedullin reduces systemic blood pressure and increases urinary sodium excretion partly through the release of nitric oxide. We hypothesized that chronic adrenomedullin infusion ameliorates salt-sensitive hypertension and increases the expression of renal nitric oxide synthase (NOS) in Dahl salt-sensitive (DS) rats, because the reduced renal NOS expression promotes salt sensitivity. DS rats and Dahl salt-resistant (DR) rats were fed a high sodium diet (8.0% NaCl) for 3 weeks. The high sodium diet resulted in an increase in blood pressure and a reduction of urinary sodium excretion in association with increased renal adrenomedullin concentrations and decreased expression of renal neuronal NOS (nNOS) and renal medullary endothelial NOS (eNOS) in DS rats compared with DR rats. Chronic adrenomedullin infusion partly inhibited the increase of blood pressure and proteinuria in association with a restoration of renal nNOS and medullary eNOS expression in DS rats under the high sodium diet. The immunohistochemical analysis revealed that the restored renal nNOS expression induced by chronic adrenomedullin infusion may reflect the restoration of nNOS expression in the macula densa and inner medullary collecting duct. These results suggest that adrenomedullin infusion has beneficial effects on this hypertension probably in part through restored renal NOS expression in DS rats.

Adrenomedullin↗
PubMed2005

Upregulation of intracardiac adrenomedullin and its receptor system in rats with volume overload-induced cardiac hypertrophy.

Specific adrenomedullin receptors have been identified as calcitonin receptor-like receptor (CRLR)/receptor activity-modifying proteins (RAMP2 and RAMP3) complexes. Although we have demonstrated that adrenomedullin is increased in volume overload-induced cardiac hypertrophy, it remains unknown whether the adrenomedullin receptor is altered or not. This study sought to investigate the significance of intracardiac adrenomedullin and its receptor system in volume overload-induced cardiac hypertrophy. Left ventricular adrenomedullin levels were higher in aortocaval shunt (ACS) rats than in controls (+58%). The left ventricular gene expressions of adrenomedullin, CRLR, RAMP2 and RAMP3 were increased (+27%, +76%, +108% and +131%, respectively) and the left ventricular collagen gene expressions were also increased (type I: +138%, type III: +87%). The left ventricular adrenomedullin level correlated with the gene expression of type III collagen (R=0.42). These results suggest that intracardiac adrenomedullin and its receptor system are upregulated and may participate in the regulation of cardiac remodeling in volume overload-induced cardiac hypertrophy.

Adrenomedullin↗
PubMed2005

Increased susceptibility to heart failure in response to volume overload in mice lacking natriuretic peptide receptor-A gene.

OBJECT: Contribution of the natriuretic peptide system to the development of heart failure (HF) in vivo was examined using mice lacking or having decreased natriuretic peptide receptor-A (NPRA), a guanylyl cyclase-linked receptor. METHODS: Volume-overloaded HF was produced by aortocaval fistula in mice with wild-type (+/+), heterozygous (+/-), and homozygous null mutants (-/-) of the NPRA gene. Severity of HF was assessed 4 weeks after operation on the basis of organ weight, hemodynamics, echocardiographic indices, urinary variables, neurohumoral factors, and myocardial gene expression. RESULTS: There were no significant differences in lung weight, kidney weight, left ventricular end-diastolic pressure (LVEDP), left ventricular systolic function, or urinary variables among the three sham-operated groups; however, sham-operated (-/-) mice had higher blood pressure and individual cardiac chamber weights than did (+/+) mice. In contrast, (-/-) mice with aortocaval fistula had higher LVEDP, left and right ventricular weights, lung weight, and left ventricular dimension, as well as lower fractional shortening and urinary sodium and cyclic guanosine monophosphate (cGMP) excretion than did (+/+) mice with aortocaval fistula. In addition, ventricular mRNA expression of natriuretic peptides and beta-myosin heavy chain increased markedly only in (-/-) mice. Plasma atrial natriuretic peptide, renin, and aldosterone, but not cGMP, showed greater responses to aortocaval fistula in (-/-) mice than in (+/+) mice. Both sham-operated and aortocaval fistula NPRA (+/-) mice almost consistently showed a phenotype intermediate between those of NPRA (-/-) and NPRA (+/+) mice. CONCLUSION: These results provide genetic evidence that NPRA signaling protects against HF induced by volume overload in mice.

Aldosterone↗
PubMed2005

Response of adrenomedullin system to cytokine in cardiac fibroblasts-role of adrenomedullin as an antifibrotic factor.

OBJECTIVE: The adrenomedullin system acts as an autocrine or paracrine factor (or both) in the development of cardiac hypertrophy and in the regulation of cardiac function. However, several aspects of the local action of adrenomedullin remain unclear. We studied the effects of interleukin 1-beta (IL-1beta) on the adrenomedullin system in cardiac fibroblasts and also examined the pathophysiological significance of such effects. METHODS: We cultured rat neonatal cardiac fibroblasts with or without IL-1beta and measured (1) two molecular forms of adrenomedullin in culture medium by specific immunoradiometric assay; (2) gene expression of adrenomedullin, calcitonin receptor like receptor (CRLR), receptor activity modifying protein2 (RAMP2), and RAMP3, components of the adrenomedullin receptor, by Northern blot analysis or RT-PCR analysis; (3) intracellular cAMP levels in response to exogenously administered adrenomedullin; and (4) (3)H-proline incorporation with and without a specific adrenomedullin antisense oligodeoxynucleotide. RESULTS: (1) IL-1beta time-dependently increased the levels of two molecular forms of adrenomedullin, adrenomedullin-mature and adrenomedullin-glycine (P<0.01). In contrast to known levels in plasma (about 10%), adrenomedullin-mature was a major molecular form in the culture medium of cardiac fibroblasts and myocytes (65-80%). (2) IL-1beta significantly increased gene expression of adrenomedullin and its receptor components (adrenomedullin: +46%, CRLR: +460%, RAMP2: +32%, RAMP3: +350%, all P<0.01). (3) Preincubated IL-1beta elevated the intracellular cAMP response to exogenous adrenomedullin administered at a concentration of 10(-7) M (+26%, P<0.05). (4) Adrenomedullin antisense oligodeoxynucleotide treatment significantly lowered adrenomedullin-mature levels in culture medium (-50%). Adrenomedullin nonsense oligodeoxynucleotide treatment did not change (3)H-proline incorporation or mRNA levels of collagen I and III, whereas adrenomedullin antisense oligodeoxynucleotide treatment significantly increased (3)H-proline incorporation and mRNA levels of collagen I and III in IL-1beta-treated cardiac fibroblasts. CONCLUSION: These results provide evidence that the adrenomedullin system acts as an autocrine antifibrotic factor in the regulation of collagen synthesis in cardiac fibroblasts exposed to higher cytokine levels. This may beneficially modulate the pathophysiology of certain cardiac diseases.

Adrenomedullin↗
PubMed2005

Alteration of renal adrenomedullin and its receptor system in the severely hypertensive rat: effect of diuretic.

OBJECTIVE: We investigated the pathophysiological role of the renal adrenomedullin (AM) system, including the ligand, receptor, and amidating activity, in severe hypertensive rats. METHOD: We studied three groups: control Wistar Kyoto rats (WKY), spontaneously hypertensive stroke-prone rats (SHR-SP), and diuretic-treated SHR-SP. We measured AM-mature, active form, and AM-total (active form+inactive form) in plasma and renal tissues, and mRNA levels of AM and AM receptor system components such as calcitonin receptor-like receptor (CRLR), receptor activity-modifying protein (RAMP) 2, and RAMP3 in renal tissues. RESULTS: SHR-SP had higher blood pressure, plasma neurohumoral factors, and lower renal function than WKY. SHR-SP had higher AM-mature and AM-total levels in plasma and renal tissues than WKY. Although the plasma AM-mature/AM-total ratio was similar in the two groups, AM-mature/AM-total ratio in renal tissues was higher in SHR-SP than in WKY. In addition, mRNA levels of AM in the renal cortex and medulla and the mRNA levels of CRLR, RAMP2, and RAMP3 in the renal cortex were higher in SHR-SP than in WKY. Chronic diuretic treatment decreased blood pressure and improved kidney function and neurohumoral factors, with reductions in plasma and renal AM system. CONCLUSION: Upregulation of circulating and renal AM system may modulate pathophysiology in SHR-SP.

Adrenomedullin↗
PubMed2005

Renoprotective effect of long-term combined treatment with adrenomedullin and omapatrilat in hypertensive rats.

BACKGROUND: Previous studies demonstrated that adrenomedullin (AM) is metabolized by neutral endopeptidases and that the renal effect of AM is augmented by the inhibition of neutral endopeptidases. We have recently shown that the long-term administration of AM has renoprotective effects. OBJECT: This study assessed the chronic renoprotective effects of AM combined with a vasopeptidase inhibitor in hypertensive rats and attempted to elucidate the mechanism involved. METHODS: We studied the following four groups: control Dahl salt-resistant (DR) rats, untreated Dahl salt-sensitive (DS) rats, omapatrilat (35 mg/kg per day)-treated DS rats; and human AM (500 ng/h) plus omapatrilat-treated DS rats. After 7 weeks' treatment, blood pressure, renal function, neurohumoral factors, gene expression levels, and histological findings were examined. RESULTS: DS rats were characterized by increased blood pressure, decreased renal function, abnormal histological findings, and increased gene expression of collagen I and III, transforming growth factor beta (TGF-beta), and NADPH oxidase subunits (p40phox, p47phox, and gp91phox) in the renal cortex compared with DR rats. Compared with DS rats, omapatrilat significantly decreased systolic blood pressure (-26 mmHg), improved renal function, histological findings, and messenger RNA expression levels of collagen I, collagen III, and TGF-beta. Combined treatment with omapatrilat and AM further improved renal function, histological findings, and mRNA expression levels of collagen I, collagen III, and TGF-beta, without a further reduction in blood pressure. Only combined treatment decreased mRNA levels of p40phox, p47phox, and gp91phox. There were no differences in plasma AM or atrial natriuretic peptide levels among three DS groups. CONCLUSION: Our results suggest that combined treatment with omapatrilat and AM provides additional renoprotective effects independent of blood pressure-lowering activity partly via inhibition of gene expressions of oxidative stress and extracellular matrix.

Adrenomedullin↗
PubMed2005

Cardiac adrenomedullin: its role in cardiac hypertrophy and heart failure.

Co-localization of adrenomedullin (AM) and its receptor components such as calcitonin receptor like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in peripheral tissues, including the heart, kidney, and vasculature, suggests an important role for the peptide as a regulator of cardiovascular function. Indeed, we previously reported that AM gene expression and / or immunoreactivity are increased in the ventricles of cardiac hypertrophy and heart failure. Recently, we also found that not only levels of AM peptide and AM gene expression, but also mRNA levels of CRLR, RAMP2 and RAMP3 are increased in cardiac hypertrophy and failing heart. Cardiac myocytes and fibroblast produce and secrete two molecular forms of AM and express CRLR, RAMP2 and RAMP3, and AM is known to have inhibitory effect of collagen synthesis and antiproliferative effect in cardiac fibroblasts. Stimulation by IL-1beta significantly increased gene expression of AM and its receptor components in cardiac fibroblasts. Preincubated IL-1beta elevated the intracellular cAMP response to exogenous administered AM. AM antisense oligodeoxynucleotide treatment significantly lowered AM levels in cultured medium. IL-1beta significantly increased (3)H-proline incorporation and AM antisense oligodeoxynucleotide treatment further increased (3)H-proline incorporation. Collectively, these results support a protective role for increased AM in the cardiac hypertrophy and heart failure. Then, we tested the effects of acute administration of AM in experimental and human heart failure, because AM has hemodynamic effects including vasodilation, increases in cardiac contractility, cardiac output, diuresis, and natriuresis. We observed profound and sustained cardiovascular, hormonal and renal effects. These effects may incorporate many of the therapeutic goals of heart failure management.

Adrenomedullin↗