Intravenous Infusion of Adrenomedullin and Increase in Regional Cerebral Blood Flow and Prevention of Ischemic Brain Injury after Middle Cerebral Artery Occlusion in Rats

Doğan, Aclan; Suzuki, Yoshio; Koketsu, Naoki; Osuka, Koji; Saito, Kiyoshi; Takayasu, Misako; Shibuya, Masabumi; Yoshida, Jun

doi:10.1097/00004647-199701000-00004

Cited by 103 publications

(53 citation statements)

References 19 publications

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“…A previous study by Dogan et al (31) showed that infusion of 1.0 μg/kg/min of rat AM alone for 2 hours (that is, the total dose of AM is 120 μg/kg BW) starting at 1 hour before the induction of D 1 7 ( 9 -1 0 ) 1 0 7 5 -1 0 8 Figure 5. Effects of human AM/AMBP-1 on morphologic photomicrography of the brain after stroke.…”

Section: Discussionmentioning

confidence: 99%

Peripheral Administration of Human Adrenomedullin and Its Binding Protein Attenuates Stroke-Induced Apoptosis and Brain Injury in Rats

Chaung

et al. 2011

Mol Med

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Stroke is a leading cause of death and the primary medical cause of acquired adult disability worldwide. The progressive brain injury after acute stroke is partly mediated by ischemia-elicited inflammatory responses. The vasoactive hormone adrenomedullin (AM), upregulated under various inflammatory conditions, counterbalances inflammatory responses. However, regulation of AM activity in ischemic stroke remains largely unknown. Recent studies have demonstrated the presence of a specific AM binding protein (that is, AMBP-1) in mammalian blood. AMBP-1 potentiates AM biological activities. Using a rat model of focal cerebral ischemia induced by permanent middle cerebral artery occlusion (MCAO), we found that plasma levels of AM increased significantly, whereas plasma levels of AMBP-1 decreased significantly after stroke. When given peripherally early after MCAO, exogenous human AM in combination with human AMBP-1 reduced brain infarct volume 24 and 72 h after MCAO, an effect not observed after the treatment by human AM or human AMBP-1 alone. Furthermore, treatment of human AM/AMBP-1 reduced neuron apoptosis and morphological damage, inhibited neutrophil infiltration in the brain and decreased serum levels of S100B and lactate. Thus, human AM/AMBP-1 has the ability to reduce stroke-induced brain injury in rats. AM/AMBP-1 can be developed as a novel therapeutic agent for patients with ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Peripheral Administration of Human Adrenomedullin and Its Binding Protein Attenuates Stroke-Induced Apoptosis and Brain Injury in Rats

Chaung

et al. 2011

Mol Med

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“…ADM causes relaxation of rat cerebral arterioles (Nishimura & Suzuki 1997) and has been shown to limit ischaemic brain injury following cerebral artery occlusion in rats (Dogan et al 1997). The site of production of most ADM is endothelial cells, and it seems highly probable that ADM acts in a paracrine manner on vascular smooth muscle cells (VSMCs) to increase local blood flow around areas of ischaemic tissue, where the presence of a non-desensitising receptor would ensure that the vasodilatory signal would not be lost or attenuated.…”

Section: Discussionmentioning

confidence: 99%

Desensitisation of calcitonin gene-related peptide responsiveness but not adrenomedullin responsiveness in vascular smooth muscle cells

Drake¹,

Lowe²,

Mirtella³

et al. 2000

Journal of Endocrinology

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Adrenomedullin (ADM) and calcitonin gene-related peptide (CGRP) are distantly related peptides. Both act through G protein-coupled receptors on vascular smooth muscle cells to increase intracellular cAMP concentrations, causing vasorelaxation. Recent evidence suggests that both peptides bind to a common heptahelical receptor, with specificity for each peptide being determined by a receptor activity modifying protein (RAMP). This hypothesis predicts that each peptide should desensitise the cellular response to subsequent stimulation by the other. We have studied the patterns of desensitisation of ADM/CGRP receptors in rat aortic vascular smooth muscle cells. Cells were incubated for 20 min in either serum free medium (SFM), alone (control) or in SFM containing vasoactive agonist (e.g. ADM 10 8 M, CGRP 10 7 M, angiotensin II 10 9 M or isoproterenol 10 6 M). Cells were then washed and incubated for a further 20 min in SFM containing a second agonist and 1 mM isobutyryl methyl xanthine. Cells were harvested and assayed for cAMP.Pre-exposure of cells to CGRP, isoproterenol, angiotensin II or ADM, decreased cAMP generation in response to subsequent stimulation with CGRP by 84% ( 5), 66% ( 18), 45% ( 5) and 60% ( 10) respectively (mean ..). Pre-incubation of cells with 100 nM H-89, a protein kinase A (PKA) inhibitor, abolished the desensitisation of CGRP by itself, implying that this desensitisation was mediated through PKA. In contrast, there was no attenuation of the cAMP response to stimulation with ADM by pre-exposure to ADM and all other agonists tested. Identical results were seen with or without PKA inhibition by H-89. These results indicate that the ADM receptor does not desensitise over this time period in RAVSMCs, in contrast to the CGRP receptor, which is desensitised by pre-exposure to CGRP and other vasoactive agonists. These data also suggest that ADM and CGRP act through separate receptors in these cells.

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“…Adrenomedullin has been identified in a variety of tissues, including the CNS, and adrenomedullin-like immunoreactivity has been also described in human cerebrospinal fluid (9). More recently, it has been reported that adrenomedullin also exerts vasodilator activity in the cerebral circulation (10,11) and that this peptide is involved in the regulation of systemic and local blood flow during neonatal cardiovascular adaptation (12, 13) and during birth stress (14). In human fetuses, there is evidence that adrenomedullin participates in cerebral fetal hemodynamic modifications (15).…”

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confidence: 99%

Circulating Adrenomedullin Is Increased in Preterm Newborns Developing Intraventricular Hemorrhage

Gazzolo¹,

Marinoni²,

Giovannini³

et al. 2001

Pediatr Res

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Adrenomedullin is a novel vasoactive peptide that participates in cerebral blood flow regulation and circulates in human plasma. To verify whether plasma adrenomedullin is able to identify preterm newborns at risk of intraventricular hemorrhage (IVH), we performed a case-control study. Plasma samples collected within 6 h after birth in 24 preterm newborns who developed IVH, as diagnosed at 72 h, were assessed for adrenomedullin and compared with those obtained from 48 preterm newborns, matched for gestational age, who did not develop IVH. Cerebral ultrasound and Doppler velocimetry waveform patterns in the middle cerebral artery were also recorded at the time of blood sampling. Adrenomedullin blood concentrations and middle cerebral artery pulsatility index values were significantly higher in infants developing IVH (20.1 Ϯ 4.5 fmol/mL and 1.71 Ϯ 0.21 fmol/mL, respectively) than in controls (7.5 Ϯ 3.0 fmol/mL and 1.49 Ϯ 0.19 fmol/mL, respectively). Adrenomedullin blood concentrations correlated with middle cerebral artery pulsatility index (r ϭ Ϫ0.77, p Ͻ 0.01) and with the grade of IVH extension (r ϭ 0.83, p Ͻ 0.01). This study suggests that adrenomedullin blood concentration might be a promising tool for identifying preterm infants at risk of IVH immediately after birth, when imaging assessment and clinical symptoms of hemorrhage are still silent. Abbreviations: IVH, intraventricular hemorrhage CGRP, calcitonin gene-related peptide FHR, fetal heart rate MCA PI, middle cerebral artery pulsatility index NICU, neonatal intensive care unit RDS, respiratory distress syndrome PvO 2 , venous oxygen partial pressure PvCO 2 , venous carbon dioxide partial pressure IVH is the most common variety of cerebral hemorrhage, affecting about 15 to 20% of preterm infants, which continues to represent one of the major problems in the NICU (1). Perinatal asphyxia constitutes a risk in preterm infants by altering cerebral blood flow regulatory mechanisms (e.g.; hemodynamic, neurogenic, and metabolic mechanisms) and causing loss of cerebral vascular autoregulation. Hypotension, cerebral ischemia, and reperfusion are the main events involved in vascular autoregulation (2-4). Severe and prolonged hypoxia or ischemia result in cell death and tissue damage. Reperfusion could be critical because organ damage, particularly of the brain, may be amplified during this period. An exaggerated release of vasoactive agents, acting in autocrineparacrine manner, could be responsible for reperfusion injury (5), which, in turn, leads to IVH.Adrenomedullin is a 52-amino acid, newly discovered vasoactive peptide first isolated from pheochromocytoma, that shares some homology with CGRP (6). Cultured vascular endothelial cells and smooth muscle cells produce adrenomedullin (7), which elicits its vasodilator activity through an increase in intracellular cAMP (8). Adrenomedullin has been identified in a variety of tissues, including the CNS, and adrenomedullin-like immunoreactivity has been also described in human cerebrospinal fluid (9). More recently, i...

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Intravenous Infusion of Adrenomedullin and Increase in Regional Cerebral Blood Flow and Prevention of Ischemic Brain Injury after Middle Cerebral Artery Occlusion in Rats

Cited by 103 publications

References 19 publications

Peripheral Administration of Human Adrenomedullin and Its Binding Protein Attenuates Stroke-Induced Apoptosis and Brain Injury in Rats

Peripheral Administration of Human Adrenomedullin and Its Binding Protein Attenuates Stroke-Induced Apoptosis and Brain Injury in Rats

Desensitisation of calcitonin gene-related peptide responsiveness but not adrenomedullin responsiveness in vascular smooth muscle cells

Circulating Adrenomedullin Is Increased in Preterm Newborns Developing Intraventricular Hemorrhage

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