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Biomedical subjects

Kazuo Kitamura

Publications and source records attributed to Kazuo Kitamura.

At least 19 recordsLinked to original sources
PubMed2006

Isolation and identification of proangiotensin-12, a possible component of the renin-angiotensin system.

The renin-angiotensin (RA) system plays an important role in regulating blood pressure and fluid balance. In the search for bioactive peptides with an antibody binding to the N-terminal portion of angiotensin II (Ang II), we isolated a new angiotensinogen-derived peptide from the rat small intestine. Consisting of 12 amino acids, this peptide was termed proangiotensin-12 based on its possible role of an Ang II precursor. Proangiotensin-12 constricted aortic strips and, when infused intravenously, raised blood pressure in rats, while both the vasoconstrictor and pressor response to proangiotensin-12 were abolished by captopril and by CV-11974, an Ang II type I receptor blocker. Proangiotensin-12 is abundant in a wide range of organs and tissues including the small intestine, spleen, kidneys, and liver of rats. The identification of proangiotensin-12 suggests a processing cascade of the RA system, different from the cleavage of angiotensinogen to Ang I by renin.

Amino Acid Sequence↗
PubMed2006

Soluble guanylate cyclase stimulation on cardiovascular remodeling in angiotensin II-induced hypertensive rats.

It is unknown whether long-term pharmacological stimulation of soluble guanylate cyclase (sGC), elevating intracellular cGMP levels, has a beneficial effect on hypertension. The purpose of this study is to investigate the effects of BAY41-2272, an orally available sGC stimulator, on cardiovascular remodeling in hypertensive rats. Eight-week-old male Wistar rats with hypertension induced by angiotensin II infused subcutaneously at 250 ng/kg per minute were treated orally with a low ([L] 2 mg/kg per day) or high ([H] 10 mg/kg per day) dose of BAY41-2272 for 14 days. BAY41-2272-H partially suppressed the rise in blood pressure and reduced the heart weight (4.20+/-0.34 versus 3.68+/-0.20 mg/g; P<0.01), whereas BAY41-2272-L had no effect. However, both doses decreased the angiotensin II-induced left ventricular accumulation of collagen in the perivascular area (L, -20%, P<0.05; H, -30%, P<0.01) and myocardial interstitium (L, -21%, P<0.05; H, -38%, P<0.01), reducing the number of activated fibroblasts surrounding coronary arteries (L, -74%; H, -79%; P<0.05). BAY41-2272 downregulated the angiotensin II-induced left ventricular gene expression of type 1 collagen (L, -41%, P<0.05; H, -49%, P<0.01) and transforming growth factor-beta1 (L, -49%, P<0.05; H, -65%, P<0.01). cGMP levels were elevated by BAY41-2272 not only in the left ventricle, but also in cultured cardiac fibroblasts, resulting in reduced thymidine incorporation into the cells. Thus, stimulation of sGC by BAY41-2272 attenuates fibrosis of the left ventricle in rats with angiotensin II-induced hypertension partly in a pressure-independent manner, suggesting an important role for sGC generating cGMP in inhibiting cardiovascular remodeling.

Angiotensin II↗
PubMed2006

Increased production of adrenomedullin in glomeruli from anti-glomerular basement membrane glomerulonephritis rats treated with methylprednisolone.

BACKGROUND/AIMS: Adrenomedullin (AM) has anti-proliferative and apoptotic effects on mesangial cells (MCs). Both effects play an important role in the progression of glomerulonephritis (GN). Glucocorticoids are widely used for the treatment of GN; however, the relationship between AM regulation in MCs or glomeruli and glucocorticoid treatment has not been clarified. METHODS: Using the cultured rat MCs, AM secretion induced by methylprednisolone (m-PSL), and MC proliferation and apoptosis caused by AM were examined. In addition, the role of AM receptor antagonist, AM(22-52), was also investigated. Then, we made an anti-glomerular basement membrane (GBM) GN rat model and compared the AM expression and production in each glomeruli obtained from the control or m-PSL-treated anti-GBM GN rats. RESULTS: In the cultured rat MCs, AM secretion was increased by m-PSL. MC proliferation was inhibited, while MC apoptosis was increased by AM. MC apoptosis was inhibited by the addition of AM(22-52). M-PSL therapy ameliorated the progression of anti-GBM GN rats. AM expression and production were increased in the glomeruli from m-PSL-treated rats compared to the controls. CONCLUSION: Considering the anti-proliferative and apoptotic effects of AM on MCs, increased AM in the glomeruli might participate in the improvement of glomerular lesions in anti-GBM GN rats treated with m-PSL.

Adrenomedullin↗
PubMed2006

Adrenomedullin in mast cells of abdominal aortic aneurysm.

OBJECTIVES: Produced by vascular walls, adrenomedullin (AM) exerts antifibrotic actions in the process of cardiovascular remodeling. The purpose of this study was to examine the pathophysiological role of AM in the development of human abdominal aortic aneurysm (AAA). METHODS AND RESULTS: Immunohistochemical analyses revealed that vascular smooth muscle cells in the media were positive for AM in the early stage of atherosclerotic aorta. Intense immunoreactivity was observed in mast cells of the outer media and adventitia of AAA, and the number of mast cells was greater (p < 0.01) in AAA than in atherosclerotic aorta without any aneurysmal change. To determine the role of AM in mast cells, we examined cultured human mast cell leukemia line-1 (HMC-1) and fibroblasts isolated from AAA patients. Cultured HMC-1 cells were found to express preproAM gene and release AM peptide into the cultured media. When assessed by collagenase-sensitive [3H]proline incorporation and procollagen type I C-peptide secretion, collagen synthesis in co-culture of HMC-1 and the fibroblasts was reduced by 10(-6) mol/L synthetic AM, while conversely, it increased following blockade of the action of endogenous AM with 10 microg/mL anti-AM monoclonal antibody. CONCLUSION: The present study suggests an anti-fibrotic role for AM released from mast cells, providing new insight into the biological actions of mast cell-derived AM in the development of AAA.

Adrenomedullin↗
PubMed2006

Functions of the cytoplasmic tails of the human receptor activity-modifying protein components of calcitonin gene-related peptide and adrenomedullin receptors.

Receptor activity-modifying proteins (RAMPs) enable calcitonin receptor-like receptor (CRLR) to function as a calcitonin gene-related peptide receptor (CRLR/RAMP1) or an adrenomedullin (AM) receptor (CRLR/RAMP2 or -3). Here we investigated the functions of the cytoplasmic C-terminal tails (C-tails) of human RAMP1, -2, and -3 (hRAMP1, -2, and -3) by cotransfecting their C-terminal deletion or progressive truncation mutants into HEK-293 cells stably expressing hCRLR. Deletion of the C-tail from hRAMP1 had little effect on the surface expression, function, or intracellular trafficking of the mutant heterodimers. By contrast, deletion of the C-tail from hRAMP2 disrupted transport of hCRLR to the cell surface, resulting in significant reductions in (125)I-hAM binding and evoked cAMP accumulation. The transfection efficiency for the hRAMP2 mutant was comparable with that for wild-type hRAMP2; moreover, immunocytochemical analysis showed that the mutant hRAMP2 remained within the endoplasmic reticulum. FACS analysis revealed that deleting the C-tail from hRAMP3 markedly enhances AM-evoked internalization of the mutant heterodimers, although there was no change in agonist affinity. Truncating the C-tails by removing the six C-terminal amino acids of hRAMP2 and -3 or exchanging their C-tails with one another had no effect on surface expression, agonist affinity, or internalization of hCRLR, which suggests that the highly conserved Ser-Lys sequence within hRAMP C-tails is involved in cellular trafficking of the two AM receptors. Notably, deleting the respective C-tails from hRAMPs had no effect on lysosomal sorting of hCRLR. Thus, the respective C-tails of hRAMP2 and -3 differentially affect hCRLR surface delivery and internalization.

Amino Acid Sequence↗
PubMed2006

[Bone and bone related biochemical examinations. Hormone and hormone related substances. Calcitonin gene-related peptide (CGRP)].

Calcitonin gene-related peptide (CGRP) is secreted from osteoclasts and several cancer cells, as well as from sensory nerve endings innervating blood vessels and bones. A potent vasodilator, CGRP powerfully counteracts hypertensive responses and protects organs from blood pressure-related damage, though it also can precipitate migraine attacks, bronchoconstriction and hypersensitive colon. Because plasma CGRP concentrations are very low, even in patients, it is thought that CGRP functions as local modulator rather than as a circulating hormone. Nevertheless, it is useful to measure plasma CGRP when evaluating the severity of target diseases (e.g., heart failure and sepsis) and when screening or following up patients with neuroendocrine tumors (e.g., medullary thyroid carcinoma). That said, one should understand the biochemical characteristics of CGRP prior to blood sampling, and should use highly sensitive assays that detect only the active form of the molecule.

Adult↗
PubMed2005

Overexpression of proadrenomedullin N-terminal 20 peptide blunts blood pressure rise and attenuates myocardial hypertrophy and fibrosis in hypertensive rats.

We developed a transgenic (Tg) rat model that overexpresses human proadrenomedullin N-terminal 20 peptide (PAMP) only and then compared the effects of unilateral nephrectomy followed by a high salt diet for five weeks in Tg and wild-type rats. We found that systolic blood pressure was significantly lower in Tg UNX rats and cardiac hypertrophy and myocardial fibrosis was also attenuated in Tg rats. Evaluation of gene expression showed suppression of cardiac local renin-angiotensin system (RAS) in Tg rat. These results suggest that in addition to reducing blood pressure, PAMP suppresses cardiac hypertrophy through negative regulation of the local cardiac RAS.

Adrenomedullin↗
PubMed2005

Adrenomedullin: a protective factor for blood vessels.

Adrenomedullin (AM) is a vasodilator peptide having a wide range of biological actions such as reduction of oxidative stress and inhibition of endothelial cell apoptosis. The AM gene is expressed in vascular walls, and AM was found to be secreted from cultured vascular endothelial cells, smooth muscle cells, and adventitial fibroblasts. Plasma AM levels in patients with arteriosclerotic vascular diseases are elevated in possible association with the severity of the disease. When administered over a relatively short period, AM dilates blood vessels via an endothelium-dependent or independent mechanism. Experiments in vitro have shown that AM exerts multiple actions on cultured vascular cells, which are mostly protective or inhibitory against vascular damage and progression of arteriosclerosis. Either prolonged infusion or overexpression of AM suppressed intimal thickening, fatty streak formation, and perivascular hyperplasia in rodent models for vascular remodeling or atherosclerosis. Intimal thickening induced by periarterial cuff was more severe in AM gene-knockout mice than their littermates, suggesting a protective role for endogenous AM. Moreover, AM has recently been suggested to possess angiogenetic properties. Collectively, a body of evidence suggests that AM participates in the mechanism against progression of vascular damage and remodeling, thereby alleviating the ischemia of tissues and organs.

Adrenomedullin↗
PubMed2005

Beyond vasodilation: the antioxidant effect of adrenomedullin in Dahl salt-sensitive rat aorta.

We have investigated the antioxidant effect of adrenomedullin (AM) on endothelial function in the Dahl salt-sensitive (DS) rat hypertension model. Dahl salt-resistant (DR) and DS rats were fed an 8% NaCl diet. In addition, the DS rats were subcutaneously infused with either saline or recombinant human AM for 4 weeks. Although systolic blood pressures measured weekly in AM- and saline-infused rats did not significantly differ, aortic O2*- levels were significantly (P<0.01) higher in the latter. Likewise, both endothelial nitric oxide synthase (eNOS) mRNA and protein were significantly higher in saline-infused DS rats. Infusion of AM reduced both O2*- and eNOS expression to levels comparable to those seen in DR rats. AM infusion also upregulated the gene expression of guanosine-5'-triphosphate cyclohydrolase I and downregulated the expression of p22(phox), suggesting that AM increased the NOS coupling and bioavailability of NO. AM possesses significant antioxidant properties that improve endothelial function.

Adrenomedullin↗
PubMed2005

Effect of adrenomedullin administration on acetic acid-induced colitis in rats.

Adrenomedullin (AM) administered intracolonically ameliorated the severity of acetic acid-induced colonic ulceration in rats. Ulcers were induced by subserosal injection of acetic acid into the colon. AM-treated group was administered 0.25-1.0 microg of AM in 0.5 ml of saline intracolonically once a day; the control group received only saline. AM administration dose-dependently and significantly reduced the size of the ulcerative lesions, the associated edema, and the infiltration of the affected area by inflammatory cells. AM also reduced tissue levels of interleukin-6, but not interferon-gamma. AM reduces the severity of acetic acid-induced colitis in rats, probably by inhibiting the production and/or release of Th-2 cell-derived factors such as interleukin-6.

Acetic Acid↗
PubMed2005

Adrenomedullin release in the rat mesenteric resistance artery.

Adrenomedullin (AM) is a potent vasodilator peptide whose major source is the vascular wall. In the present study, the mechanism of release of AM was investigated in the rat mesenteric resistance artery. The isolated mesenteric vascular bed was perfused with Krebs solution at a constant flow rate (5 ml/min) and AM in the perfusate was measured by a highly sensitive enzyme immunoassay (Immunoenzymometric assay; IEMA) method. In preparations without endothelium, spontaneous release of AM was detected in the perfusate (68.7+/-5.8 fmol/ml, n=45). Periarterial nerve stimulation (PNS, 4 and 8 Hz) caused 11.4+/-3.9% (4 Hz) and 9.1+/-3.5% (8 Hz) decreases in the spontaneous release of AM. Removal of Ca2+ from the medium did not affect the spontaneous AM release, but abolished the PNS-induced inhibition of spontaneous AM release. Perfusion of 10nM calcitonin gene-related peptide (CGRP) or 0.1 microM capsaicin (inducer of CGRP release) inhibited significantly the spontaneous AM release. PNS (8 Hz)-induced inhibition of spontaneous AM release was antagonized by CGRP(8-37) (CGRP receptor antagonist). These results suggest that AM is mainly released from vascular smooth muscle cells of the rat mesenteric artery and endogenous or exogenous CGRP inhibits AM release.

Adrenomedullin↗
PubMed2005

Antifibrotic effect of adrenomedullin on coronary adventitia in angiotensin II-induced hypertensive rats.

OBJECTIVE: The extracellular matrix (ECM) determines the structural integrity of the heart and vasculature, participating in cardiovascular remodeling. We previously reported that adrenomedullin (AM) inhibited cellular proliferation and protein synthesis of cardiac fibroblasts; however, the precise mechanisms of AM actions as an antifibrotic factor remain unknown. The purpose of this study was to examine the biological actions of AM against the profibrotic factor angiotensin II (Ang II) in coronary adventitia. METHODS AND RESULTS: Rats with hypertension induced by Ang II infusion were administered 0.06 mug/kg/min recombinant human AM subcutaneously for 14 days. The AM infusion significantly (p<0.05) reduced the Ang II-induced increase of coronary adventitial fibroblasts expressing Ki-67 and alpha-smooth muscle actin (alpha-SMA) in the left ventricle, by 65%, and 62%, respectively, without affecting systolic blood pressure, left ventricle/body weight, or cross-sectional area of myocardial fibers. Collagen deposition of coronary arteries was reduced by the AM infusion (-24%, p<0.01), and these effects of AM were accompanied by significant reductions in gene expression of type 1 collagen (-49%, p<0.05) and transforming growth factor-beta1 (TGF-beta1) (-55%, p<0.01). In cultured cardiac fibroblasts, 10(-7) mol/L AM exerted an inhibitory effect on TGF-beta1-induced alpha-SMA expression (p<0.01) that was mimicked by 8-bromo-cAMP and attenuated by the protein kinase A inhibitor H-89. CONCLUSION: AM decreased Ang II-induced collagen deposition surrounding the coronary arteries, inhibiting myofibroblast differentiation and expressions of ECM-related genes in rats. The present findings further support the biological action of AM as an antifibrotic factor in vascular remodeling.

Actins↗
PubMed2005

Bistability of cerebellar Purkinje cells modulated by sensory stimulation.

A persistent change in neuronal activity after brief stimuli is a common feature of many neuronal microcircuits. This persistent activity can be sustained by ongoing reverberant network activity or by the intrinsic biophysical properties of individual cells. Here we demonstrate that rat and guinea pig cerebellar Purkinje cells in vivo show bistability of membrane potential and spike output on the time scale of seconds. The transition between membrane potential states can be bidirectionally triggered by the same brief current pulses. We also show that sensory activation of the climbing fiber input can switch Purkinje cells between the two states. The intrinsic nature of Purkinje cell bistability and its control by sensory input can be explained by a simple biophysical model. Purkinje cell bistability may have a key role in the short-term processing and storage of sensory information in the cerebellar cortex.

Action Potentials↗
PubMed2005

Adrenomedullin alleviates not only neointimal formation but also perivascular hyperplasia following arterial injury in rats.

Producing components of the extracellular matrix, the vascular adventitia has been recognized as an important modulator of the vascular remodeling process, which determines the vessel architecture. In this study, we examined the effect of the vasodilator peptide adrenomedullin on vascular remodeling induced by balloon injury of rat carotid arteries. Endothelial denudation with wall stretch by ballooning not only induced neointimal formation accompanied with a reduced ratio of the lumen to vessel area, but also increased the fibroblast number and collagen deposition in the adventitial layer. When compared with the saline infusion, intravenous adrenomedullin infusion at 200 ng/h for 14 days suppressed the neointimal formation (-33%, P=0.033), reversing the ratio of lumen to vessel ratio (P=0.030), without affecting systolic blood pressure. Moreover, the adrenomedullin infusion decreased the number of adventitial fibroblasts (-41%, P<0.001) and the collagen deposition (-36%, P=0.006) in the adventitial layer of the injured artery. In conclusion, the intravenous adrenomedullin infusion effectively attenuates vascular remodeling following the arterial injury via suppression of hyperplasia in the intima and adventitia, suggesting a potential of adrenomedullin as a therapeutic tool against vascular remodeling.

Adrenomedullin↗
PubMed2005

Atrial and brain natriuretic peptides as markers of cardiac load and volume retention in primary aldosteronism.

BACKGROUND: Atrial and brain natriuretic peptides (ANP and BNP, respectively) are cardiac hormones with natriuretic and vasodilator actions. The present study was carried out to determine the natriuretic peptide that is closely related to cardiac load and volume retention in patients with primary aldosteronism (PA). METHODS: We examined 11 patients with PA due to aldosterone-producing adrenal adenoma before and after surgical resection. Plasma levels of ANP and BNP were measured by specific immunoradiometric assays, and total blood volume was determined by a plasma tracer method with (131)I-human albumin. RESULTS: Plasma levels of ANP and BNP were elevated in the PA patients compared with normotensive control subjects (P < .01), and the elevated ANP and BNP levels were reduced (P < .01) after adenoma resection. When analyzed with the pre- and postoperative data, a significant relationship was observed between mean blood pressure and plasma levels of ANP (r = 0.64, P < .01) and BNP (r = 0.58, P < .01). The BNP was significantly correlated with the SV1 + RV5 voltage (r = 0.65, P < .01) and with total blood volume (r = 0.57, P < .01), but this was not the case for ANP. CONCLUSION: The present results suggest that the plasma level of BNP is more closely related to cardiac load or volume status than ANP is, in patients with PA due to adrenal adenoma.

Adenoma↗
PubMed2005

Long-term anti-hypertensive therapy with benidipine improves arterial stiffness over blood pressure lowering.

Pulse wave velocity (PWV) reflects arterial stiffness and is an independent predictor of cardiovascular mortality and morbidity. However, because it is closely related to blood pressure (BP), PWV is an imperfect measure for evaluating the effects of anti-hypertensive drugs on arterial wall properties. To clarify the effect of benidipine on arterial properties, we first derived the regression line between BP and PWV changes in a short-term experiment. Using this line, we evaluated the long-term effect of benidipine on PWV changes. In the short-term experiment, 29 participants were intravenously administered nicardipine for 90 min. Maximum decreases of brachial-ankle PWV (baPWV) were plotted against the corresponding decreases in BP. In the long-term experiment, 9 hypertensive patients were treated with benidipine for 1 year, during which BP and baPWV were monitored. After 1 year, benidipine was suspended for 2 weeks, and BP and baPWV were reevaluated. In the short-term experiment, PWV was dependent on BP only, and the equation of the regression line was deltaPWV (cm/s) =10.114 x deltaMBP (mmHg) (r=0.913) or deltaPWV (%) =0.719 x deltaMBP (%) (r=0.926). In the long-term therapy, benidipine treatment achieved stable BP control within 3 months; the real PWV decreases (r-PWV) were almost identical to the PWV decrease estimated (e-PWV) from BP lowering at 3 months. However, r-PWV exceeded e-PWV after 6 months. Relative BP and PWV improvements compared to the control were maintained 2 weeks after suspension of benidipine. In conclusion, long-term benidipine administration improves arterial wall properties beyond what can be accounted for by changes in BP.

Adult↗
PubMed2005

[Adrenomedullin].

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Adrenomedullin↗