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Roman MUFF, Walter BORN, Jan A. FISCHER
2003 Volume 26 Issue Suppl Pages
S3-S8
Published: 2003
Released on J-STAGE: August 01, 2005
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Co-expression of an initially orphan calcitonin receptor-like (CL)1 receptor with individual receptor-activity-modifying proteins (RAMP)1, -2 and -3 results in CL receptor/RAMP1, -2 and -3 proteins at the cell surface. The RAMP define the selectivity of the CL receptor for the vasodilatory peptides adrenomedullin (AM) and calcitonin gene-related peptide (CGRP). The selectivity for AM and CGRP agonists and antagonists of human, rat, porcine and bovine CL receptors, co-expressed with RAMP2 and -3, has been studied in different cell types. This revealed CL receptor/RAMP2 and CL receptor/RAMP3 as AM1 and AM2 receptor subtypes, respectively. The AM1 receptor crossreacts with CGRP at high and the AM2 receptor at lower concentrations. Here the pharmacological properties of the cloned AM receptors are compared to those revealed in tissues and cell lines. According to nomenclature recommendation of the IUPHAR (International Union of Pharmacology) subcommittee XXXII, the former CRLR is now the CL receptor (1). (Hypertens Res 2003; 26 (Suppl): S3-S8)
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Masayoshi SHICHIRI, Yukio HIRATA
2003 Volume 26 Issue Suppl Pages
S9-S14
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin, originally discovered in human pheochromocytoma, has been shown to have potent vasodilatory activity. However, like other vasoactive peptide hormones, its physiological roles have been found to extend far beyond the regulation of vascular tonus, and to include such functions as the regulation of cell proliferation and differentiation. There is a growing body of evidence that adrenomedullin exerts a wide range of effects on cell growth and apoptotic death, and that these effects are dependent on cell type and experimental conditions. Signaling pathways independent of cyclic AMP, such as protein tyrosine kinase(s) and mitogen-activated protein kinases, may play key roles in the regulation of mitogenesis and apoptosis by adrenomedullin. (Hypertens Res 2003; 26 (Suppl): S9-S14)
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Katsuro KIKUMOTO, Takeshi KATAFUCHI, Naoto MINAMINO
2003 Volume 26 Issue Suppl Pages
S15-S23
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin (AM), calcitonin gene-related peptide (CGRP), amylin (AMY) and calcitonin (CT) are members of the CGRP/CT superfamily of peptides. Among them, AM and CGRP are reported to share a core receptor, the calcitonin receptor-like receptor (CRLR), and the specificity of the CRLR is determined by the expression levels of receptor-activity-modifying proteins (RAMPs). In the case of AMY, co-expression of the calcitonin receptor (CTR) and RAMPs was recently reported to form its specific receptor. However, detailed analysis of the receptor specificity of the CRLR and CTR in the presence of RAMPs has so far been performed mainly in the human system. Thus, we cloned cDNAs encoding porcine CRLR, RAMP1, RAMP2 and RAMP3 precursors from a porcine lung and hypothalamus cDNA library, and determined their sequences. Then, porcine RAMPs, CRLR and CTR were expressed in COS-7 or porcine vascular smooth muscle cells, and the resulting receptor complexes were analyzed by the cyclic adenosine 3′,5′-monophosphate (cAMP) production assay. The specificity of CRLR was clearly determined by the expression of RAMPs; RAMP1 converted CRLR to CGRP receptor, while RAMP2 and RAMP3 converted it to AM receptor, but the affinity of CTR for AMY was not increased by the expression of any known RAMPs. In contrast to previous findings, porcine CTR and RAMP did not appear to form an AMY receptor having sufficient affinity and specificity for the physiological interaction. (Hypertens Res 2003; 26 (Suppl): S15-S23)
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Kenji KUWASAKO, Kazuo KITAMURA, Tomohiko UEMURA, Yasuko NAGOSHI, Johji ...
2003 Volume 26 Issue Suppl Pages
S25-S31
Published: 2003
Released on J-STAGE: August 01, 2005
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When co-expressed with receptor activity-modifying protein (RAMP) 2, calcitonin receptor-like receptor (CRLR) functions as an adrenomedullin (AM) receptor (CRLR/RAMP2). In the present study, we examined the function of the cysteine (C) residues in the extracellular loops of human (h)CRLR (C212, C225 and C282) and in the extracellular domain of hRAMP2 (C68, C84, C99 and C131). Using site-directed mutagenesis, the cysteine residues were substituted, one at a time, with alanine (A). Co-expression in HEK293 cells of hRAMP2 with the hCRLR C212A or C282A mutant significantly reduced the 50% of effective concentration (EC50) for AM-evoked cyclic adenosine monophosphate (cAMP) production, despite full cell surface expression of the receptor heterodimer. Co-expression of the C225A mutant had no effect on [125I]AM binding or receptor signaling. These results suggest that the cysteine residues in the first (C212) and the second (C282) extracellular loops form a disulfide bond that is important for stabilizing the receptor in the correct conformation for ligand binding and activation. Cells expressing hCRLR with an hRAMP2 mutant (C68A, C84A, C99A or C131A) showed no specific AM binding or AM-stimulated cAMP accumulation. Though abundant in the intracellular compartment, these receptors were not detected at the cell surface, suggesting that all four cysteine residues are essential for efficient transport to the plasma membrane. Cysteine residues in the extracellular loops of hCRLR and in the extracellular domain of hRAMP2 thus appear to play distinct roles in the cell surface expression and function of the receptor heterodimer. (Hypertens Res 2003; 26 (Suppl): S25-S31)
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Kousuke MARUTSUKA, Kinta HATAKEYAMA, Yuichiro SATO, Atsushi YAMASHITA, ...
2003 Volume 26 Issue Suppl Pages
S33-S40
Published: 2003
Released on J-STAGE: August 01, 2005
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In this short review, we describe the distribution of adrenomedullin (AM)-immunoreactive cells in human tissues and their related biological properties, focusing on the blood coagulation and mucosal defense systems. AM is widely distributed in human tissues, especially in cardiovascular and endocrine tissues. Within vessels, AM has been immunohistochemically detected in vascular smooth muscle cells (SMCs) and endothelial cells (ECs). In atherosclerotic lesions, the peptide is present not only in these cells, but also in macrophages, and the most intense AM immunoreactivity is detected in macrophages located in shoulder lesions of atheromatous plaque, which are considered to be rupture-prone regions. AM inhibits tissue factor production, and augments the production and release of tissue factor pathway inhibitor from aortic ECs. AM also induces the release of antithrombin and urokinase-type plasminogen activator from ECs. Taken together, these antithrombotic properties of the peptide are expected to play an important role in the maintenance of blood circulation. Furthermore, AM immunoreactivity is observed in mucosal and glandular epithelia of the gastrointestinal, respiratory and reproductive systems. AM and the proadrenomedullin N-terminal 20 peptide (PAMP) show strong antibacterial activity against Escherichia coli. In addition, AM is also present in the auditory system. These lines of evidence suggest that AM and its related peptides not only play a role in vasodilatation, but also exhibit multiple biological activities in mammals. (Hypertens Res 2003; 26 (Suppl): S33-S40)
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Yin LI, Kazuhito TOTSUNE, Kazuhisa TAKEDA, Kazumichi FURUYAMA, Shigeki ...
2003 Volume 26 Issue Suppl Pages
S41-S44
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin (AM) is a potent vasodilator peptide which has an inhibitory action on insulin secretion. Resistin is a novel peptide specifically secreted from adipocytes, and implicated in insulin resistance. We studied the expression of AM and resistin in 3T3-L1 adipocytes and preadipocytes by Northern blot analysis and radioimmunoassay. Immunoreactive-AM was detected in the culture media of 3T3-L1 preadipocytes and adipocytes, with higher concentrations found in preadipocytes. Northern blot analysis showed that AM mRNA was expressed in 3T3-L1 preadipocytes but was undetectable in adipocytes. In contrast, resistin mRNA was expressed in 3T3-L1 adipocytes, whereas it was not detected in 3T3-L1 preadipocytes. The present study thus showed that AM expression was decreased, and resistin expression increased, during adipocyte-differentiation of 3T3-L1 cells. (Hypertens Res 2003; 26 (Suppl): S41-S44)
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Junichi YAMAGA, Seiichi HASHIDA, Kazuo KITAMURA, Mariko TOKASHIKI, Tos ...
2003 Volume 26 Issue Suppl Pages
S45-S53
Published: 2003
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The mature form of the vasodilator peptide adrenomedullin (AM-m) is synthesized from a glycine-extended precursor (AM-Gly) by enzymatic amidation. We have developed a highly sensitive enzyme immunoassay (Immune Complex Transfer Enzyme Immunoassay; ICTEIA) that enables us to measure levels of AM-Gly in plasma and tissue directly. The detection limit of this assay is 1 amol/assay, and the intra- and inter-assay precision are 4.5-14.1% and 9.9-20.5%, respectively. Dilution curves for plasma samples showed good linearity, and the analytical recovery was 107-116.6%. Using ICTEIA, we determined that the plasma concentration of immunoreactive AM-Gly is substantially higher than that of AM-m (5.22±2.56 vs. 1.21±0.79 fmol/ml). In contrast, levels of AM-Gly were much lower than those of AM-m in the lung, heart, kidney, adrenal gland and liver. We also evaluated AM-Gly and AM-m levels in rats in a morbid state induced by intraperitoneal administration of lipopolysaccharide (LPS). In most tissues, levels of AM-m and AM-Gly were both increased by LPS; however, AM-Gly/AM-m ratios were not significantly affected, which suggests that AM-Gly is rapidly converted to AM-m in tissue. (Hypertens Res 2003; 26 (Suppl): S45-S53)
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Alfredo MARTÍNEZ, Rubén PÍO, Peter F. ZIPFEL, Fra ...
2003 Volume 26 Issue Suppl Pages
S55-S59
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin (AM) is a multifunctional peptide involved in roles as varied as blood pressure regulation, growth, neurotransmission, and inflammation control, among others. We previously identified complement factor H as a serum binding protein for AM and showed that factor H regulates AM functions and vice versa. Here we searched for the specific binding sites for AM by using recombinant fragments of factor H and a non-radioactive binding assay with fluorescein-tagged AM. By this methodology, two specific binding sites for AM were found in factor H. One of them shows a high affinity for AM and is located at the carboxy terminal end of factor H, comprising short consensus repeats (SCR) 15-20. Smaller fragments of this region did not bind to AM efficiently, suggesting that the high affinity binding site of factor H requires a complex three-dimensional structure to recognize AM. Another binding site with lower affinity for AM was found in the middle of the factor H molecule, at SCR 8-11. Antibodies against factor H prevented AM binding altogether, but the main binding partner of factor H, C3b, did not, indicating that C3b and AM bind to different regions of factor H. These structure-function data support previous biochemical observations. Our understanding of the binding between AM and factor H may help in the development of new treatments for diseases in which these molecules play active roles. (Hypertens Res 2003; 26 (Suppl): S55-S59)
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Béla KIS, Csongor S. ÁBRAHÁM, Mária A. DEL ...
2003 Volume 26 Issue Suppl Pages
S61-S70
Published: 2003
Released on J-STAGE: August 01, 2005
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Since the discovery that adrenomedullin gene expression is 20- to 40-fold higher in endothelial cells than even in the adrenal medulla, this peptide has been regarded as an important secretory product of the vascular endothelium, together with nitric oxide, eicosanoids, endothelin-1, and other vasoactive metabolites. Cerebral endothelial cells secrete an exceptionally large amount of adrenomedullin, and the adrenomedullin concentration is about 50% higher in the cerebral circulation than in the peripheral vasculature. The adrenomedullin production of cerebral endothelial cells is induced by astrocyte-derived factors. Adrenomedullin causes vasodilation in the cerebral circulation, may participate in the maintenance of the resting cerebral blood flow, and may be protective against ischemic brain injury. Recent data from our laboratory indicate that adrenomedullin, as an endothelium-derived autocrine/paracrine hormone, plays an important role in the regulation of specific blood-brain barrier properties. Adrenomedullin is suggested to be one of the physiological links between astrocyte-derived factors, cyclic adenosine 3′,5′-monophosphate (cAMP), and the induction and maintenance of the blood-brain barrier. Moreover, the role of adrenomedullin in the differentiation and proliferation of endothelial cells and in angiogenesis suggests a more complex function for adrenomedullin in the cerebral circulation and in the development of the blood-brain barrier. (Hypertens Res 2003; 26 (Suppl): S61-S70)
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Hideyuki KOBAYASHI, Toshihiko YANAGITA, Hiroki YOKOO, Akihiko WADA
2003 Volume 26 Issue Suppl Pages
S71-S78
Published: 2003
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Adrenomedullin (AM) and peptides of the proadrenomedullin N-terminal 20 peptide (PAMP20) family are multifunctional peptides abundantly expressed in the adrenal medulla. These peptides are released by regulated exocytosis along with catecholamines upon stimulation of adrenal chromaffin cells. They are also released gradually during culture, and this release is stimulated by a 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent pathway. The expression and release of AM increase under hypoxia in chromaffin cells. The expression of AM in pheochromocytoma PC12 cells is reduced during neuronal differentiation with nerve growth factor. On the other hand, PAMP20 and PAMP12 suppress catecholamine release and synthesis by interfering with nicotinic cholinergic receptors. AM increases blood flow in the adrenal gland, and causes a gradual release of catecholamine, but does not modify regulated exocytosis upon the stimulation of cells. Current data indicate that the expression of these peptides is regulated by intracellular signaling pathways, and changes under various physiological and pathological conditions. AM and PAMP20 family peptides have distinct physiological functions. PAMP20 and PAMP12 are endogenous peptides that modulate chromaffin cell function in an autocrine manner, whereas AM may mainly regulate vascular cell function in a paracrine manner. (Hypertens Res 2003; 26 (Suppl): S71-S78)
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Hiroaki NISHIMATSU, Yasunobu HIRATA, Takayuki SHINDO, Hiroki KURIHARA, ...
2003 Volume 26 Issue Suppl Pages
S79-S84
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin (AM) is a potent vascular wall-derived vasorelaxing peptide which induces the release of nitric oxide (NO). To explore the role of endogenous AM in vascular function, we examined the effects of acetylcholine (ACh), AM, and AM receptor antagonists [AM (22-52), and calcitonin gene-related peptide (CGRP) (8-37)] on the isometric tension of aortic rings isolated from AM transgenic (TG) and knockout (KO) mice and wild type littermates (WT). ACh and AM caused a dose-dependent reduction of the isometric tension of aortic rings, but the degree of vasodilatation was smaller in TG than in KO or WT (%Δtension [10-6 mol/l ACh]: KO -69±10%, WT -39±8%, TG -29±1%, p <0.01). On the other hand, NG-nitro-L- arginine methyl ester, an NO synthase inhibitor, induced greater vasoconstriction in TG (%Δtension 10-5 mol/l: KO +78±16%, WT +99±27%, TG +184±20%, p <0.01), whereas E-4021, a cyclic guanosine monophosphate (cGMP)-specific phosphodiesterase inhibitor, caused greater vasodilation in TG mice. Both AM antagonists increased tension in TG to a greater extent than in KO or WT mice (%Δtension [10-6 mol/l CGRP (8-37)]: KO +24±5%, WT +51±6%, TG +75±7%, p <0.01). Endothelial denudation of the aorta diminished the vasoconstriction caused by the AM antagonists. In conclusion, the amounts of AM expressed in the aortic endothelium influenced baseline NO release. AM antagonists increased vascular tone in WT as well as in TG, suggesting that endogenous AM plays a physiological role in the regulation of aortic tone. (Hypertens Res 2003; 26 (Suppl): S79-S84)
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Gian Paolo ROSSI, Maria Teresa CONCONI, Ludwik K. MALENDOWICZ, Gastone ...
2003 Volume 26 Issue Suppl Pages
S85-S92
Published: 2003
Released on J-STAGE: August 01, 2005
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The expression of components of the adrenomedullin (AM) system (AM and its receptors) has been detected in mammalian adrenal zona glomerulosa (ZG) cells, and evidence has been provided that AM is able to inhibit agonist-stimulated aldosterone secretion from and to enhance the proliferative activity of ZG cells. However, there has been no evidence that the endogenous AM system acts as a physiological regulator of ZG function. Hence, we investigated whether the suppression of AM gene transcription by a specific antisense oligodeoxynucleotide (ODN) is able to alter the secretion and growth of rat ZG cells cultured in vitro. ZG cell cultures were examined 0, 2, 4, 6 and 8 days after treatment with scrambled sense (S)-ODN (control cultures) and AM antisense (A)-ODN. Control cultures, as well as freshly dispersed ZG cells and ODN-untreated cultures, expressed AM as mRNA and protein. A-ODN treatment suppressed AM expression within 4 days and the suppression lasted until day 6. Confluent control cultures displayed basal and angiotensin-II (Ang-II), K+- and adrenocorticotropic hormone (ACTH)-stimulated aldosterone secretions similar to those of ODN-untreated cultures. A-ODN treatment magnified the aldosterone response to Ang-II and K+ at days 4 and 6 (but not at day 8), without affecting the basal or ACTH-stimulated secretion. As compared to ODN-untreated and control cultures, non-confluent A-ODN-treated ones showed a 40% elongation in the duplication time, a significant decrease in the proliferation index, and a marked rise in apoptotic index from day 4 to day 8. In conclusion, our study validates the use of A-ODN to block the endogenous AM system, showing that suppression of AM-synthesis requires at least 2 days to become appreciable and persists for at least 6 days. Moreover, it provides the first evidence that endogenous AM plays a physiological role in cultured rat ZG cells, by exerting a buffering action on their acute secretory response to Ang-II and K+ and by maintaining normal basal proliferative and apoptotic activities. (Hypertens Res 2003; 26 (Suppl): S85-S92)
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Kazutoshi MIYASHITA, Hiroshi ITOH, Naoki SAWADA, Yasutomo FUKUNAGA, Ma ...
2003 Volume 26 Issue Suppl Pages
S93-S98
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin (AM) is a vasoactive hormone which exerts its action through cyclic adenosine monophosphate(cAMP) /cAMP-dependent protein kinase (PKA) cascade and intracellular Ca2+ mobilization. Recently, evidence has accumulated that AM plays a critical role in the regulation of vascular tone, remodeling and morphogenesis. And although numerous reports have examined the action of AM on cultured vascular cells, the results have not been consistent and have depended on the experimental conditions used. Accordingly, the purpose of this study was to clarify the effect of AM on the proliferation and migration of cultured endothelial cells. Our results revealed that AM promoted the growth and migration of endothelial cells (ECs). AM significantly promoted the proliferation of human umbilical vein endothelial cells (HUVECs) (56.0±8.7% over the controls at 10-9 mol/l) and this stimulative effect was inhibited by two AM antagonists, AM(22-52) and calcitonin gene-related peptide (CGRP) (8-37). The number of HUVECs migrated to the lower surface of the transwell apparatus was also increased dose-dependently in the AM group (30.4±4.2% over the controls at 10-7 mol/l), and this increase was suppressed by the two AM antagonists and by two PKA antagonists, adenosine 3′,5′-cyclic monophosphorothioate Rp-isomer and myristoylated protein kinase A inhibitor amide 14-22. The promoting action of AM on endothelial migration was also suppressed by LY294002, an inhibitor for phosphatidylinositol 3-kinase, but not by NG-nitro-L-arginine-methyl ester (L-NAME), an antagonist for nitric oxide synthase (NOS). These results indicate that AM promotes proliferation and migration of ECs via a cAMP/PKA dependent pathway and lend support to the idea that AM exerts beneficial effects on vascular regeneration and might be used as a novel therapeutic strategy for patients with vascular disease. (Hypertens Res 2003; 26 (Suppl): S93-S98)
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Hiroyuki OKUMURA, Noritoshi NAGAYA, Kenji KANGAWA
2003 Volume 26 Issue Suppl Pages
S99-S104
Published: 2003
Released on J-STAGE: August 01, 2005
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Recent studies have demonstrated that the activation of protein kinase Akt attenuates myocardial ischemia/reperfusion injury. However, it remains unknown whether adrenomedullin (AM), which is also a potent Akt activator, has cardioprotective effects after ischemia/reperfusion. In the present study, Sprague-Dawley rats were exposed to a 30-min period of ischemia induced by ligation of the left coronary artery followed by 24-h reperfusion. They were randomized to receive intravenous administration of AM (0.05 μg/kg/min) or saline for 60 min after coronary ligation. We examined the hemodynamics and myocardial apoptosis 24 h after ischemia/reperfusion. Echocardiographic measurements were performed 4 weeks after ischemia/reperfusion. Myocardial infarct size was also measured histologically. AM significantly reduced left ventricular (LV) end-diastolic pressure (17±2 to 8±2 mmHg, p <0.05) and the number of apoptotic nuclei in myocytes (387±39 to 147±72 per field, p <0.05). AM significantly increased LV dP/dtmax (4,803±228 to 5,672±199 mmHg/s, p <0.05). AM significantly increased LV fractional shortening (23±2 vs. 28±2%, p <0.05), and significantly reduced LV diastolic dimension (7.4±0.1 to 6.9±0.1 mm, p <0.05) and myocardial infarct size (33±2 to 20±2%, p <0.01) 4 weeks after ischemia/reperfusion. In conclusion, AM infusion during ischemia/reperfusion attenuated the development of LV remodeling and myocardial fibrosis in rats. Based on these results, the cardioprotective effects of AM may be attributed at least partly to its anti-apoptotic effect. (Hypertens Res 2003; 26 (Suppl): S99-S104)
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Hiroki KURIHARA, Takayuki SHINDO, Yoshio OH-HASHI, Yukiko KURIHARA, To ...
2003 Volume 26 Issue Suppl Pages
S105-S108
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin (AM) and calcitonin gene-related peptide (CGRP) share common structural characteristics and receptors and belong to the same peptide family. Both peptides show a diverse set of biological effects including vasodilation. Recent establishment of gene-knockout mice has revealed the physiological importance of these two peptides. AM-/- mice demonstrated defective vascular formation during embryogenesis and did not survive beyond midgestation. AM+/- heterozygous mice showed high blood pressure and susceptibility to tissue injury. On the other hand, αCGRP-/- mice demonstrated elevated peripheral vascular resistance and high blood pressure caused by increased peripheral sympathetic activity. Thus, AM and CGRP have distinct physiological roles. AM is indispensable for normal embryonic development, regulation of blood pressure and tissue protection against injury, whereas αCGRP contributes to the regulation of cardiovascular function through inhibitory modulation of sympathetic nervous activity. (Hypertens Res 2003; 26 (Suppl): S105-S108)
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Tatsuo SHIMOSAWA, Hiromitsu MATSUI, Guangqun XING, Kanami ITAKURA, Kat ...
2003 Volume 26 Issue Suppl Pages
S109-S112
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin (AM), a vasodilatory peptide, has recently been shown to have multipotent properties. Among its other pharmacological actions, AM has been hypothesized to protect organs from hypertension, hypoxia, or infection. In vitro studies have shown that AM has an inhibitory effect on vascular smooth muscle cell proliferation and oxidative stress, but that it enhances nitric oxide (NO) production, which in turn is thought to protect against organ damage. Recent advances in genetic engineering have made it possible to investigate the chronic effects of AM in vivo. Applying genetic engineering, it is revealed that adrenomedullin was shown to protect liver, kidney, vasculature, and heart from septic shock, ischemia and hypertension. However, speculation as to the mechanism of its organ-protective effect varies from report to report. Possible mechanisms include preservation of blood flow, interaction with NO and/or oxidative stress. And although there continue to be technical limitations to the use of these genetically modified models, their application in further investigations should help to clarify the potential efficacy of AM as a new therapeutic agent. (Hypertens Res 2003; 26 (Suppl): S109-S112)
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Johji KATO, Toshihiro TSURUDA, Kazuo KITAMURA, Tanenao ETO
2003 Volume 26 Issue Suppl Pages
S113-S119
Published: 2003
Released on J-STAGE: August 01, 2005
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Adrenomedullin (AM), a potent vasodilator peptide originally isolated from pheochromocytoma, is expressed in cardiovascular tissues such as those of the cardiac atria and ventricles. Cell culture experiments have shown that AM peptide is synthesized and secreted from cardiac myocytes and fibroblasts of neonatal rats. Humoral factors, such as angiotensin II (Ang II) and endothelin-1 (ET-1), and mechanical stress due to pressure and volume overload to the heart have been shown to be involved in AM expression of the myocardium in both in vitro and in vivo studies. The effects of AM on cardiomyocytes and cardiac fibroblasts have been examined in in vitro studies, with the result that AM was shown to exert inhibitory actions on myocyte hypertrophy and on proliferation and collagen production of cardiac fibroblasts in an autocrine or paracrine manner. In rats, experimental therapeutic intervention consisting of transfer of the AM gene or of recombinant AM appears to partly inhibit the progression of cardiac hypertrophy and remodeling. It has been shown that the calcitonin receptor-like receptor (CRLR) and receptor-activity-modifying protein (RAMP) act together to function as AM receptors, although in this regard there are a number of issues, including the cellular mechanism of AM actions, that remain to be addressed. In addition, the role of proadrenomedullin N-terminal 20 peptide (PAMP), which is derived from preproAM, is another topic for future experiments. Collectively, the research data accumulating in this area suggest that AM plays a role as an autocrine or paracrine hormone in the cardiac ventricles, and that AM might be utilized as a therapeutic tool in the treatment of hypertensive or ischemic heart disease. (Hypertens Res 2003; 26 (Suppl): S113-S119)
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Toshio NISHIKIMI, Fumiki YOSHIHARA, Yosuke MORI, Kenji KANGAWA, Hiroak ...
2003 Volume 26 Issue Suppl Pages
S121-S127
Published: 2003
Released on J-STAGE: August 01, 2005
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Many neurohumoral factors participate in the pathophysiology of heart failure, and adrenomedullin (AM) may be involved in their derangement. This work reviews the accumulating evidence in support of a compensatory role of AM in heart failure, and describes the possible mechanisms of this role. It has been established that plasma AM levels are increased in patients with heart failure in proportion to the severity of the disease. Furthermore, recent studies suggest that plasma AM level is an independent prognostic indicator of heart failure. Thus, AM may be not only a biochemical marker for evaluating the severity of heart failure, but also a prognostic indicator of this syndrome. In patients with heart failure, AM production is increased not only in the plasma, but also in the heart. AM secretion from the failing human heart is also increased, but this increase is small and responds slowly to the stimulus. This phenomenon may be explained by the fact that AM is secreted via a constitutive pathway and that AM is an autocrine and/or a paracrine factor in the heart. An experiment using cultured myocytes suggested that cytokines and mechanical stress are important stimuli for AM production in the heart. Regarding the action of AM in the heart, recent studies have suggested that AM exerts an inotropic action both in vitro and in vivo. AM also attenuates cardiac hypertrophy in myocytes and inhibits proliferation and collagen production in cardiac fibroblasts. These results suggest that AM may be an antifibrotic, antihypertrophic, and positive inotropic factor in the failing and hypertrophied heart. Because AM has many cardiorenal actions, AM administration may be useful for the treatment of heart failure. Indeed, acute administration of AM has been shown to improve the hemodynamics, renal function, and hormonal parameters in patients with heart failure. Moreover, recent studies have shown that AM gene therapy or long-term AM infusion significantly improved cardiac hypertrophy and fibrosis, and prolonged the survival time in an animal model of hypertension and heart failure. In conclusion, these findings suggest that AM plays a compensatory role in the pathophysiology of heart failure and that administration of AM may be a new and promising approach for the treatment of patients with this syndrome. (Hypertens Res 2003; 26 (Suppl): S121-S127)
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Toshihiko ISHIMITSU, Kohju TSUKADA, Junichi MINAMI, Hidehiko ONO, Hiro ...
2003 Volume 26 Issue Suppl Pages
S129-S134
Published: 2003
Released on J-STAGE: August 01, 2005
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The studies concerning the structure and variations of the human adrenomedullin (AM) gene are reviewed, and their relations to the gene function and genetic predisposition to cardiovascular diseases are discussed. The genomic human AM gene is composed of four exons, and the whole nucleotide sequence corresponding to mature AM resides in the fourth exon. In chromosomal sublocalization, the AM gene is located in the distal portion of the short arm of chromosome 11 (11p15.1-3). Analysis of the promoter region of the AM gene has revealed that two transcription factors, nuclear factor for interleukin-6 expression (NF-IL6) and activator protein 2 (AP-2), participate in the regulation of AM gene expression. It is surmised that NF-IL6 mediates inflammatory stimuli and AP-2 mediates signals of phospholipase C and protein kinase C activation. In addition to these factors, hypoxia induces AM gene expression via the hypoxia inducible factor-1 (HIF-1) binding site. The 3′-end of the AM gene is flanked by a microsatellite marker of cytosine adenine (CA) repeats. In Japanese, there are four types of alleles with different CA-repeat numbers: 11, 13, 14 and 19. It is suggested that existence of the 19-repeat allele is associated with genetic predispositions to develop essential hypertension and diabetic nephropathy. (Hypertens Res 2003; 26 (Suppl): S129-S134)
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M. Gary NICHOLLS, Christopher J. CHARLES, John G. LAINCHBURY, Lynley K ...
2003 Volume 26 Issue Suppl Pages
S135-S140
Published: 2003
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Patients with heart failure have frequently been reported to show elevated levels of plasma adrenomedullin. These levels generally correlate with severity of hemodynamic dysfunction and also with neurohormonal indices which are activated according to the severity of heart failure. Furthermore, adrenomedullin gene expression in the heart and kidney is increased in experimental and clinical heart failure. A small number of studies have examined the responses to infusion of adrenomedullin in experimental and clinical heart failure. These studies have generally shown that infusion of adrenomedullin has beneficial hemodynamic effects and promotes maintenance or improvement in renal function, although most of these trials were of short duration. The available data suggest that adrenomedullin in the heart, kidney and plasma is increased in heart failure, possibly to counter the activation or actions of vasoconstricting and sodium-retaining hormone systems. An improved understanding of the role of adrenomedullin in heart failure might lead to the development of therapeutic agents acting through adrenomedullin receptors. (Hypertens Res 2003; 26 (Suppl): S135-S140)
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Noritoshi NAGAYA, Kunio MIYATAKE, Shingo KYOTANI, Toshio NISHIKIMI, No ...
2003 Volume 26 Issue Suppl Pages
S141-S146
Published: 2003
Released on J-STAGE: August 01, 2005
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This study sought to investigate pulmonary vasodilator responses to intrapulmonary and intravenous infusion of adrenomedullin (AM) in patients with pulmonary hypertension. In 10 patients with pulmonary hypertension, blood flow velocity in a segmental pulmonary artery was measured using a Doppler flow wire during intrapulmonary infusion of AM, acetylcholine (ACh), and adenosine triphosphate (ATP). The hemodynamic effects of intravenously administered AM (0.05 μg/kg/min) were examined in another 5 patients with primary pulmonary hypertension. Intrapulmonary infusion of AM, ACh or ATP caused a significant dose-dependent increase in blood flow velocity in a segmental pulmonary artery, respectively. The increase in flow velocity with AM at 10-8 mol/l (41±6% of the baseline value) was comparable to that with ACh at 10-4 mol/l (39±11%) and that with ATP at 10-5 mol/l (36±14%), suggesting a strong pulmonary vasodilator activity of AM. Intravenous infusion of AM produced a 41% increase in cardiac index (p <0.05) and a 30% decrease in pulmonary vascular resistance (p <0.05) with a 3% reduction in mean pulmonary arterial pressure (p =NS). These results suggest that, on a molar basis, AM may have much more potent pulmonary vasodilator activity than ACh and ATP, and thus may have beneficial hemodynamic effects in patients with pulmonary hypertension. (Hypertens Res 2003; 26 (Suppl): S141-S146)
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