Norio Inomata

Asubio Pharma Co., Ltd., Kōbe, Hyōgo, Japan

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Publications (17)49.65 Total impact

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    ABSTRACT: Ghrelin plays multiple physiological roles such as growth hormone secretion and exerting orexigenic actions; however, its physiological roles in the electrical activity of autonomic nerves remain unclear. Here, we investigated the effects of human ghrelin on several autonomic nerve activities in urethane-anesthetized rats using an electrophysiological method. Intravenous injection of ghrelin at 3 μg/kg significantly and transiently potentiated the efferent activity of the gastric vagus nerve; however, it did not affect the efferent activity of the hepatic vagus nerve. The activated response to ghrelin in the gastric efferent vagus nerve was not affected by the gastric afferent vagotomy, suggesting that this effect was not induced via the gastric afferent vagus nerve. Ghrelin did not affect the efferent activity of the brown adipose tissue, adrenal gland sympathetic nerve, and the renal sympathetic nerve. In addition, rectal temperature and the plasma concentrations of norepinephrine, corticosterone, and renin were also not changed by ghrelin. These findings demonstrate that ghrelin stimulates the gastric efferent vagus nerve in an organ-specific manner without affecting the gastric afferent vagus nerve and that ghrelin does not acutely affect the efferent basal activity of the sympathetic nerve in rats.
    Journal of Pharmacological Sciences 12/2013; · 2.15 Impact Factor
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    ABSTRACT: Ghrelin is a gastric peptide that regulates energy homeostasis. Angiotensin II (Ang II) is known to induce body weight loss and skeletal muscle catabolism through the ubiquitin-proteasome pathway. In this study, we investigated the effects of ghrelin on body weight and muscle catabolism in mice treated with Ang II. The continuous subcutaneous administration of Ang II to mice for 6 days resulted in cardiac hypertrophy and significant decreases in body weight gain, food intake, food efficiency, lean mass, and fat mass. In the gastrocnemius muscles of Ang II-treated mice, the levels of insulin-like growth factor 1 (IGF-1) were decreased, and the levels of mRNA expression of catabolic factors were increased. Although the repeated subcutaneous injections of ghrelin (1.0mg/kg, twice daily for 5 days) did not affect cardiac hypertrophy, they resulted in significant body weight gains and improved food efficiencies and tended to increase both lean and fat mass in Ang II-treated mice. Ghrelin also ameliorated the decreased IGF-1 levels and the increased mRNA expression levels of catabolic factors in the skeletal muscle. IGF-1 mRNA levels in the skeletal muscle significantly decreased 24h after Ang II infusion, and this was reversed by two subcutaneous injections of ghrelin. In C2C12-derived myocytes, the dexamethasone-induced mRNA expression of atrogin-1 was decreased by IGF-1 but not by ghrelin. In conclusion, we demonstrated that ghrelin improved body weight loss and skeletal muscle catabolism in mice treated with Ang II, possibly through the early restoration of IGF-1 mRNA in the skeletal muscle and the amelioration of nutritional status.
    Regulatory Peptides 06/2012; 178(1-3):21-8. · 2.06 Impact Factor
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    ABSTRACT: Ghrelin consists of 28 amino acid residues with an octanoyl modification at the third serine residue. Recently we have found that the C-terminal part of ghrelin protects the ester bond of 3-octanoyled serine from plasma esterases and plays the essential role to prolong the plasma half-life and to show its biological activity in vivo. In the present study, we researched whether the C-terminal part of ghrelin has a potential to prolong the plasma half-life of motilin, by comparing the pharmacokinetics of various chimeric peptides of ghrelin and motilin. Motilin is another gastro-intestinal peptide hormone related with ghrelin structurally, binding to the same family of G protein-coupled receptors. Chimeric peptides were designed to be composed of motilin(1-12) fragment, the active core binding to the motilin receptor, GPR38, and C-terminal part of ghrelin. The modification of motilin(1-12) fragment by C-terminal part of ghrelin hardly influenced its agonist activity to GPR38 and almost all these chimeric peptides showed more than two times longer plasma half-lives than motilin in rats. From the relationship between structures of chimeric peptides and their corresponding plasma half-lives, the mid-region of ghrelin rich in basic amino acids ((15)RKESKK(20)) was considered to be the most important in prolonging the plasma half-life of motilin. The deletion of these fragments or replacement of 17th glutamic acid with a neutral amino acid resulted in short plasma half-lives. In conclusion, our data suggested that the C-terminal part of ghrelin has a potential to improve the biokinetics of motilin probably by a metabolic stabilizing effect.
    Peptides 02/2012; 33(2):279-84. · 2.52 Impact Factor
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    ABSTRACT: Ghrelin is an endogenous ligand for growth hormone secretagogue receptor 1a (GHS-R1a), and consists of 28 amino acid residues with octanoyl modification at Ser(3). The previous studies have revealed that N-terminal part of ghrelin including modified Ser(3) is the active core for the activation of GHS-R1a. On the other hand, the role of C-terminal (8-28) region in ghrelin has not been clarified yet. In the present study, we prepared human ghrelin, C-terminal truncated ghrelin derivatives and anamorelin, a small molecular GHS compound which supposedly mimics the N-terminal active core, and examined GHS-R1a agonist activity in vitro, pharmacokinetic (PK) profile and growth hormone (GH) releasing activity in rats. All compounds demonstrated potent GHS-R1a agonist activities in vitro. Although the lack of C-terminal two amino acids did not modify PK profile and GH releasing activity, the deletion of C-terminal 8 and 20 amino acids affected them, and ghrelin(1-7)-Lys-NH(2) exhibited very short plasma half-life and low GH releasing activity in vivo. In rat plasma, ghrelin(1-7)-Lys-NH(2) was degraded more rapidly than ghrelin, suggesting that C-terminal part of ghrelin protected octanoylation of Ser(3) from plasma esterases. Subdiaphragmatic vagotomy significantly attenuated GH response to ghrelin but not to anamorelin. These results suggest that the C-terminal part of ghrelin has an important role in the biological activity in vivo. We also found that ghrelin stimulated GH release mainly via a vagal nerve pathway but anamorelin augmented GH release possibly by directly acting on brain in rats.
    Peptides 02/2011; 32(5):1001-7. · 2.52 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2010; 30(37).
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    ABSTRACT: Cyclins and other cell-cycle regulators have been used in several studies to regenerate cardiomyocytes in ischaemic heart failure. However, proliferation of cardiomyocytes induced by nuclear-targeted cyclin D1 (D1NLS) stops after one or two rounds of cell cycles due in part to accumulation of p27Kip1, an inhibitor of cyclin-dependent kinase (CDK). Thus, expression of S-phase kinase-associated protein 2 (Skp2), a negative regulator of p27Kip1, significantly enhances the effect of D1NLS and CDK4 on cardiomyocyte proliferation in vitro. Here, we examined whether Skp2 can also improve cardiomyocyte regeneration and post-ischaemic cardiac performance in vivo. Wistar rats underwent ischaemia/reperfusion injury by ligation of the coronary artery followed by injection of adenovirus vectors for D1NLS and CDK4 with or without Skp2. Enhanced proliferation of cardiomyocytes in the presence of Skp2 was demonstrated by increased expression of Ki67, a marker of proliferating cells (1.95% vs. 4.00%), and mitotic phosphorylated histone H3 (0.24% vs. 0.58%). Compared with rats that received only D1NLS and CDK4, expression of Skp2 improved left ventricular function as measured by the maximum and minimum rates of change in left ventricular pressure, the left ventricle end-diastolic pressure, left ventricle end-diastolic volume index, and the lung/body weight ratio. Expression of Skp2 enhanced the effect of D1NLS and CDK4 on the proliferation of cardiomyocytes and further contributed to improved post-ischaemic cardiac function. Skp2 might be a versatile tool to improve the effect of cyclins on post-ischaemic regeneration of cardiomyocytes in vivo.
    Cardiovascular Research 08/2008; 80(2):181-90. · 5.81 Impact Factor
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    ABSTRACT: We investigated participation of monocyte chemoattractant protein-1 (MCP-1) in tubulointerstitial fibrosis and correlation between MCP-1 and proteinuria in Wistar-Kyoto (WKY) rats with glomerulonephritis induced by anti-glomerular basement membrane (anti-GBM) antibody. WKY rats showed marked proteinuria and severe glomerular crescent formation at 7 days post antibody injection. At 28 days, tubulointerstitial fibrotic lesions were observed, followed by sustained heavy proteinuria and severe tubulointerstitial fibrosis at 56 days. Histological examination revealed that the overlapped immunoreactivities of MCP-1, rat albumin, and p65NF-kappaB were detected in the same tubular segments of nephritic kidney, and a significant positive correlation was observed between proteinuria and MCP-1 expression in the tubulointerstitial fibrosis. ED-1- and CD8-positive cells were also abundant, and there was a good correlation between monocyte/macrophage recruitment and MCP-1 expression in the tubulointerstitial area. These results suggest that MCP-1 participates in the progression of tubulointerstitial fibrosis, through massive albuminuria, which is accompanied by marked monocyte/macrophage recruitment.
    Journal of Clinical Immunology 08/2007; 27(4):409-29. · 3.38 Impact Factor
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    ABSTRACT: N-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP), which is hydrolyzed by angiotensin-converting enzyme, is a natural regulator of hematopoiesis. Here it is shown that Ac-SDKP inhibits TGF-beta action in mesangial cells. Because TGF-beta is thought to play a pivotal role in the development and progression of glomerulonephritis, the therapeutic effects of Ac-SDKP on an established model of renal dysfunction and histologic alteration in Wistar-Kyoto rats with anti-glomerular basement membrane nephritis was examined. Fourteen days after the induction of anti-glomerular basement membrane nephritis, the rats were treated subcutaneously with Ac-SDKP at a dose of 1 mg/kg per d for 4 wk. Treatment with Ac-SDKP significantly improved proteinuria and renal dysfunction, including increased plasma blood urea nitrogen and creatinine levels and decreased creatinine clearance. Histologic examination showed severe glomerulosclerosis and interstitial fibrosis in the vehicle-treated rats, whereas these histologic injuries were significantly ameliorated in rats that were treated with Ac-SDKP. The histologic improvements were accompanied by the suppression of gene and protein expression of fibronectin, interstitial collagen, and TGF-beta1 in the nephritic kidney. Furthermore, treatment with Ac-SDKP resulted in the inhibition of Smad2 phosphorylation, an increase in Smad7 expression in the kidney, and reduction of macrophage accumulation into the glomeruli and tubulointerstitium in nephritic rats. In conclusion, Ac-SDKP significantly ameliorated the progression of renal dysfunction and fibrosis even after the establishment of nephritis. The inhibitory effect of Ac-SDKP was mediated in part by the inhibition of TGF-beta/Smad signal transduction and the inflammatory response. These findings suggest that Ac-SDKP treatment may be a novel and useful therapeutic strategy for the treatment of progressive renal diseases.
    Journal of the American Society of Nephrology 04/2006; 17(3):674-85. · 8.99 Impact Factor
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    ABSTRACT: Peptide YY (PYY), an anorectic peptide, is secreted postprandially from the distal gastrointestinal tract. PYY(3-36), the major form of circulating PYY, binds to the hypothalamic neuropeptide Y Y2 receptor (Y2-R) with a high-affinity, reducing food intake in rodents and humans. Additional gastrointestinal hormones involved in feeding, including cholecystokinin, glucagon-like peptide 1, and ghrelin, transmit satiety or hunger signals to the brain via the vagal afferent nerve and/or the blood stream. Here we determined the role of the afferent vagus nerve in PYY function. Abdominal vagotomy abolished the anorectic effect of PYY(3-36) in rats. Peripheral administration of PYY(3-36) induced Fos expression in the arcuate nucleus of sham-operated rats but not vagotomized rats. We showed that Y2-R is synthesized in the rat nodose ganglion and transported to the vagal afferent terminals. PYY(3-36) stimulated firing of the gastric vagal afferent nerve when administered iv. Considering that Y2-R is present in the vagal afferent fibers, PYY(3-36) could directly alter the firing rate of the vagal afferent nerve via Y2-R. We also investigated the effect of ascending fibers from the nucleus of the solitary tract on the transmission of PYY(3-36)-mediated satiety signals. In rats, bilateral midbrain transections rostral to the nucleus of the solitary tract also abolished PYY(3-36)-induced reductions in feeding. This study indicates that peripheral PYY(3-36) may transmit satiety signals to the brain in part via the vagal afferent pathway.
    Endocrinology 06/2005; 146(5):2369-75. · 4.72 Impact Factor
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    ABSTRACT: As an extension of our previous investigation, a series of 7-aminoalkylpyrrolo[2,3-c]azepine derivatives was synthesized and evaluated as alpha1-adrenergic- and serotonin 2 (5-HT2)-receptor antagonists, with the aim of finding a novel potent antihypertensive agent with both activities. Among the compounds obtained in this study, (E)-1-ethyl-7-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-4-hy droxyimino-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-on e (16d) displayed potent alpha1-adrenoceptor blocking activity (pA2=7.83+/-0.20) and 5-HT2-receptor blocking activity (pA2=9.47+/-0.17) in isolated guinea pig arteries. At 3 mg/kg oral administration, compound 16d exhibited antihypertensive activity more potent than that of doxazosin in deoxycorticosterone acetate (DOCA)-salt hypertensive dogs. Furthermore, this compound reduced the rate of mouse acute pulmonary thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or more, and its effect lasted for at least 6 h at 3 mg/kg.
    CHEMICAL & PHARMACEUTICAL BULLETIN 09/2000; 48(8):1129-37. · 1.56 Impact Factor
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    ABSTRACT: Antiarrhythmic effects and cardiovascular effects of pilsicainide hydrochloride were compared with those of disopyramide in a canine model of coronary ligation-induced ventricular arrhythmias and anesthetized dogs. Pilsicainide (1.25, 2.5 and 5 mg/kg) and disopyramide (2.5 and 5 mg/kg) decreased the arrhythmic ratio ¿(ventricular arrhythmias/total heart rate) x 100¿ dose-dependently. Pilsicainide at 2.5 and 5 mg/kg and disopyramide at 5 mg/kg suppressed ventricular arrhythmias more than 50%. The effective dose of pilsicainide was lower than that of disopyramide, but the effective plasma concentration of pilsicainide was between 3 and 8 micrograms/ml, which was almost the same as that of disopyramide. In anesthetized dogs, both drugs decreased LV dP/dt max in almost the same concentration-dependent manner. PQ-interval was prolonged by pilsicainide, but not by disopyramide. QRS and QTc were prolonged by both drugs in a concentration-dependent manner. However, the prolongation of QTc by disopyramide was provoked at lower plasma concentrations than by pilsicainide. Because the excessive prolongation of QTc lead to the lethal arrhythmias such as torsades de pointes, pilsicainide may be useful as an injectable antiarrhythmic agent superior to disopyramide.
    Folia Pharmacologica Japonica 06/2000; 115(5):295-308.
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    ABSTRACT: A series of 5-aminoalkylpyrrolo[3,2-c]azepine derivatives was synthesized and their serotonin 2 (5-HT2) receptor antagonist and antiplatelet aggregation activities were evaluated. 5-HT2 receptor antagonist activity was largely determined by the nature of the substituent at the 8-position as well as the aminoalkyl group at the 5-position of the pyrrolo[3,2-c]azepine ring. Compound 18a, 5-[3-[4-(4-fluorophenyl)piperazin-1-yl]propyl]-8-hydroxy-1-methyl- 1,4,5,6,7,8-hexahydropyrrolo[3,2-c]azepin-4-one, was recognized as having potent 5-HT2 receptor antagonist activity with weak alpha1 adrenoceptor blocking activity and no significant D2 receptor binding affinity, while the corresponding isomeric pyrrolo[3,4-c]azepine derivative (22) displayed only weak 5-HT2 receptor antagonist activity. After racemic 18a was resolved directly via diastereomeric salt formation, each enantiomer was evaluated precisely. The 5-HT2 receptor antagonist activity of 18a was found to reside primarily in (-)-18a (which was about 14-fold more potent than (+)-18a in isolated guinea pig arteries). Consequently, (S)-(-)-18a (SUN C5174) displayed the overall best profile with potent 5-HT2 receptor antagonist activity (pA2=8.98+/-0.06) and high selectivity versus other receptors. SUN C5174 showed a marked inhibitory effect on the platelet aggregation induced by serotonin in combination with collagen and adenosine diphosphate (ADP) in canine or human platelet-rich plasma (IC50=6.5 to 16 nM). Moreover, this compound significantly inhibited the mortality rate in mouse acute pulmonary thromboembolytic death induced by collagen and serotonin at oral doses of 0.3 mg/kg or higher. SUN C5174 is currently undergoing clinical evaluation.
    CHEMICAL & PHARMACEUTICAL BULLETIN 06/2000; 48(5):623-35. · 1.56 Impact Factor
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    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2000; 31(52).
  • [Show abstract] [Hide abstract]
    ABSTRACT: ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.
    ChemInform 01/2000; 31(43).
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    ABSTRACT: A series of 1-aminoalkyl-pyrrolo[2,3-c]azepin-8-one derivatives was synthesized and evaluated as alpha 1 adrenergic and serotonin 2 (5-HT2) receptor antagonists, with the aim of finding a novel antihypertensive agent potently exhibiting both activities. Some compounds with a 4-[4-(4-fluorobenzoyl)piperidino]butyl group at the 1-position exhibited both activities, and varied significantly in terms of the substituents at the 4-position of the pyrroloazepine ring. Among the compounds obtained in this study, (E)-1-[4-[4-(4-fluorobenzoyl)piperidino]-butyl]-4-hydroxyimino-7- methyl-1,4,5,6,7,8-hexahydropyrrolo[2,3-c]azepin-8-one (15a, SUN9221) displayed potent alpha 1-adrenergic antagonistic activity (pA2 = 8.89 +/- 0.21) and 5-HT2 antagonistic activity (pA2 = 8.74 +/- 0.22) in isolated guinea pig arteries. This compound exhibited antihypertensive activity and a duration of action equivalent to orally administered prazosin or doxazosin, 3 mg/kg, in conscious spontaneously hypertensive rats, as well as potent antiplatelet aggregation activity.
    CHEMICAL & PHARMACEUTICAL BULLETIN 03/1999; 47(2):246-56. · 1.56 Impact Factor
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    ABSTRACT: Angiotensin (Ang) II has two major receptor isoforms, AT1 and AT2. Currently, AT1 antagonists are undergoing clinical trials in patients with cardiovascular diseases. Treatment with AT1 antagonists causes elevation of plasma Ang II which selectively binds to AT2 and exerts as yet undefined effects. Cardiac AT2 level is low in adult hearts, whereas its distribution ratio is increased during cardiac remodeling and its action is enhanced by application of AT1 antagonists. Although in AT2 knock-out mice sensitivity to the pressor action of Ang II was increased, underlying mechanisms remain undefined. Here, we report the unexpected finding that cardiac-specific overexpression of the AT2 gene using alpha-myosin heavy chain promoter resulted in decreased sensitivity to AT1-mediated pressor and chronotropic actions. AT2 protein undetectable in the hearts of wild-type mice was overexpressed in atria and ventricles of the AT2 transgenic (TG) mice and the proportions of AT2 relative to AT1 were 41% in atria and 45% in ventricles. No obvious morphological change was observed in the myocardium and there was no significant difference in cardiac development or heart to body weight ratio between wild-type and TG mice. Infusion of Ang II to AT2 TG mice caused a significantly attenuated increase in blood pressure response and the change was completely blocked by pretreatment with AT2 antagonist. This decreased sensitivity to Ang II-induced pressor action was mainly due to the AT2-mediated strong negative chronotropic effect and exerted by circulating Ang II in a physiological range that did not stimulate catecholamine release. Isolated hearts of AT2 transgenic mice perfused using a Langendorff apparatus also showed decreased chronotropic responses to Ang II with no effects on left ventricular dp/dt max values, and Ang II-induced activity of mitogen-activated protein kinase was inhibited in left ventricles in the transgenic mice. Although transient outward K+ current recorded in cardiomyocytes from AT2 TG mice was not influenced by AT2 activation, this study suggested that overexpression of AT2 decreases the sensitivity of pacemaker cells to Ang II. Our results demonstrate that stimulation of cardia AT2 exerts a novel antipressor action by inhibiting AT1-mediated chronotropic effects, and that application of AT1 antagonists to patients with cardiovascular diseases has beneficial pharmacotherapeutic effects of stimulating cardiac AT2.
    Journal of Clinical Investigation 03/1998; 101(3):527-35. · 12.81 Impact Factor
  • Journal of Cardiac Failure - J CARD FAIL. 01/1998; 4(3):92-92.