Autoradiographic Studies on the Binding Sites of 125I-Adrenomedullin in Rat Tissues.

Hasegawa, Hiroshi; Mizuhira, Vinci; Notoya, Mitsuru; Inazawa, Kazuhiro; Mizojiri, Kenji; Kïtamura, Kazuo; Eto, Tanenao; Kangawa, Kenji

doi:10.1267/ahc.31.335

Cited by 17 publications

(9 citation statements)

References 16 publications

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“…In contrast, urinary AM may be derived from renal tubular cells rather than from plasma. An autoradiographic study using venous injection of 125 I-AM revealed intense 125 I-AM uptake in the proximal tubules, suggesting that most plasma AM filtered by the glomerulus is reabsorbed by the proximal tubular cells [73]. Thus, the decrease in urinary AM excretion in chronic renal failure may in part be explained by the decreased number of nephrons producing AM.…”

Section: -C Plasma and Urinary Am Levels In Renal Disease And Renalmentioning

confidence: 99%

Adrenomedullin in the Kidney-Renal Physiological and Pathophysiological Roles

Nishikimi

2007

CMC

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Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in human pheochromocytoma tissue. AM and AM gene expression are widely distributed in the cardiovascular system, including the kidney. The co-localization of AM and its receptor components such as calcitonin receptor-like receptor (CRLR), receptor activity modifying protein (RAMP)2 and RAMP3 in the kidney, heart, and vasculature suggests an important role for the peptide as a regulator of renal, cardiac, and vascular function. Indeed, in addition to its cardiovascular effects, AM has renal vasodilatory, natriuretic, and diuretic actions. Consistent with these observations, immunohistochemical studies revealed that AM is stained in the collecting duct, distal convoluted tubules, vessels, and glomerular mesangial cells, endothelial cells and podocytes. Plasma AM levels are increased in patients with renal impairment in proportion to the severity of the disease. Previously we and other investigators showed that two molecular forms of AM, AM-glycine, an inactive form, and AM-mature, an active form, circulate in human plasma. Urine also contains both forms of AM; however, the AM-mature/AM-glycine ratio is higher in urine than in plasma. Interestingly, plasma AM-glycine and AM-mature levels are increased in renal failure, whereas urinary AM-glycine and AM-mature are decreased in this condition. These results indicate that the origin of urinary AM is different from that of plasma AM. Experimental studies showed that the renal tissue AM-mature/AM-glycine ratio is higher than that in plasma and urine. In addition, renal tissue concentrations of AM are increased in severely hypertensive rats. Considering that AM has antiapoptotic, antifibrotic, and antiproliferative effects, the increase of AM in renal disease may be a protective mechanism. In fact, AM gene delivery or long-term AM infusion significantly improved glomerular sclerosis, interstitial fibrosis, and renal arteriosclerosis in several malignant hypertensive models. This review describes the biochemistry, physiology, and circulating levels of AM and also discusses what is known about the pathophysiological role of AM in renal disease.

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Section: -C Plasma and Urinary Am Levels In Renal Disease And Renalmentioning

confidence: 99%

Adrenomedullin in the Kidney-Renal Physiological and Pathophysiological Roles

Nishikimi

2007

CMC

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“…A previous study showed that AM is present in human urine and that AM levels are several times higher in urine than in plasma, suggesting that urinary AM is produced in the kidney. An autoradiographic study involving a venous injection of "#&I-AM revealed that intense "#&I-AM uptake was observed in the proximal tubules [30]. These findings indicate that plasma AM filtered by the glomerulus is almost totally re-absorbed by the proximal tubular cells.…”

Section: Figure 5 Relationships Between Urinary Excretion Of Sodium (mentioning

confidence: 84%

“…These findings are consistent with the hypothesis that AM-m is produced in the peripheral circulation and is extracted in the pulmonary circulation. Previously, an autoradiographic study showed that an intravenous injection of "#&I-AM was avidly taken up by the lung [30], suggesting that the lung has abundant binding sites for AM. In addition, AM binding sites and AM receptor mRNA were reported to be highly concentrated in the lung [31,32].…”

Section: Figure 5 Relationships Between Urinary Excretion Of Sodium (mentioning

confidence: 99%

Elevation of two molecular forms of adrenomedullin in plasma and urine in patients with acute myocardial infarction treated with early coronary angioplasty

Asakawa¹,

Nishikimi²,

Suzuki³

et al. 2001

Clinical Science

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Adrenomedullin (AM) has vasodilatory, diuretic and natriuretic actions. Two molecular forms of AM circulate in human plasma: an active, mature form of AM (AM-m) and an intermediate, inactive, glycine-extended form of AM (AM-Gly). In the present study we investigated the pathophysiological significance of the two molecular forms of AM in plasma and urine in patients with acute myocardial infarction. We serially measured venous and arterial plasma levels and urinary excretion of AM-m, AM-Gly and total AM (Am-T; =AM-m+AM-Gly) over 2 weeks using our recently developed immunoradiometric assay in 26 consecutive patients with acute myocardial infarction and in age-matched normal controls, and studied the relationships between AM levels and clinical parameters. Plasma AM-m, AM-Gly and AM-T levels were increased on admission in patients with acute myocardial infarction compared with age-matched normal controls. Levels of AM-m, AM-Gly and AM-T in plasma reached a peak 24 h after the onset of symptoms. Plasma AM-m, AM-Gly and AM-T levels were significantly correlated with plasma levels of brain natriuretic peptide and pulmonary arterial pressure. Plasma AM-Gly levels in the vein were similar to those in the artery, whereas plasma AM-m levels were significantly lower in the artery than in the vein. Urinary excretion of AM-m, AM-Gly and AM-T was also increased on admission, and reached a peak at 12 h after the onset of symptoms. Urinary excretion of AM-m and AM-Gly was significantly correlated with urinary sodium excretion. The AM-m/AM-T ratio was significantly higher in the urine than in the vein or artery. AM-m levels were significantly correlated with AM-Gly levels in both the urine and plasma; however, there were no significant correlations between plasma and urinary AM levels. The results suggest that levels of both molecular forms of AM are increased in the urine as well as in the plasma in the acute phase of myocardial infarction. Since AM exerts potent cardiovascular and renal effects, increased concentrations of AM in plasma and urine in the acute phase of myocardial infarction may be involved in the defence mechanism against further elevations of peripheral and pulmonary vascular resistance and oliguria in acute myocardial infarction.

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“…The origin of AM in plasma and urine may be different: it has been suggested that the origin of AM in plasma is the vasculature. In contrast, urinary AM may be derived from renal tubular cells rather than from plasma because an autoradiographic study using venous injection of 125 I -AM revealed intense 125 I -AM uptake in the proximal tubules, suggesting that most plasma AM filtered by the glomerulus is reabsorbed by the proximal tubular cells [120]. Thus, the decrease in urinary AM excretion in chronic renal failure may in part be explained by the decreased number of nephrons producing AM.…”

Section: B Circulating Am Levels In Hypertensionmentioning

confidence: 99%

Adrenomedullin in Hypertension

Nishikimi¹,

Matsuoka

2005

CHYR

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Adrenomedullin (AM) is a potent vasodilatory peptide originally discovered in human pheochromocytoma tissue. The gene expression of AM is widely distributed in the cardiovascular system and many physiological actions of AM on cardiovascular system have been reported. Previous studies demonstrated that the plasma AM level is increased in patients with hypertension and further increased in patients with organ damage. We and other groups recently showed that two molecular forms of AM, AM-glycine, an inactive form, and AM-mature, an active form, circulate in human plasma and that the major molecular form in plasma is AM-glycine. Recent studies using AM antagonist or AM knockout mice confirmed the role of AM in the regulation of blood pressure. Indeed, administration of AM is beneficial in patients with hypertension, renal disease, and heart failure. In addition, recent studies revealed that AM and its receptor components such as calcitonin receptor like receptor (CRLR), receptor activity modifying protein (RAMP) 2, and RAMP3 are colocalized in peripheral tissues, including the heart, kidney, and vasculature, suggesting a role of AM as a regulator of local function. In fact, tissue AM levels and the gene expression levels of AM and its receptor are altered in hypertension. We recently showed that cardiac tissue AM levels and the gene expression levels of AM, CRLR, RAMP2, and RAMP3 are increased in left ventricular hypertrophy and further increased in hypertensive heart failure. These findings imply that increased expression of the AM system including the ligand and receptor components may modulate the pathophysiology in hypertension via the effects of AM not only as a circulating factor, but also as a local regulator. This review describes the structure, structure-activity relationships, tissue distribution, receptors, physiological action, and circulating levels of AM and also discusses what is known about the pathophysiological role of AM in hypertension.

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Autoradiographic Studies on the Binding Sites of 125I-Adrenomedullin in Rat Tissues.

Cited by 17 publications

References 16 publications

Adrenomedullin in the Kidney-Renal Physiological and Pathophysiological Roles

Adrenomedullin in the Kidney-Renal Physiological and Pathophysiological Roles

Elevation of two molecular forms of adrenomedullin in plasma and urine in patients with acute myocardial infarction treated with early coronary angioplasty

Adrenomedullin in Hypertension

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