Molecular Cloning and Biological Activities of Rat Adrenomedullin, a Hypotensive Peptide

Sakata, Junichiro; Shimokubo, Toru; Kïtamura, Kazuo; Nakamura, Shigeru; Kangawa, Kenji; Matsuo, Hisayuki; Eto, Tanenao

doi:10.1006/bbrc.1993.2132

Cited by 343 publications

(208 citation statements)

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“…PAMP [10][11][12][13][14][15][16][17][18][19][20] also showed considerable hypotensive activity, but PAMP [16][17][18][19][20] and PAMP without the C-terminal amide structure showed little hypotensive activity (unpublished observations). The sequence between the 9th and 20th amino acid of PAMP-20 is well conserved among species [3][4][5]. Taken together, these findings suggest that the C-terminal region including the amide structure of PAMP plays an important role in the biological activity of PAMP.…”

Section: Discussionmentioning

confidence: 67%

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Purification and characterization of PAMP‐12 (PAMP[9–20]) in porcine adrenal medulla as a major endogenous biologically active peptide

et al. 1997

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Proadrenomedullin N-terminal 20 peptide (PAMP-20) is a potent hypotensive peptide processed from the adrenomedullin (AM) precursor. We developed a specific radioimmunoassay which recognizes the C-terminal region of PAMP-20. Using this radioimmunoassay, the distribution of immunoreactive (ir-) PAMP was determined in porcine tissues. High concentrations of ir-PAMP were observed in the adrenal medulla and in the atrium, and these values were comparable to the corresponding concentrations of ir-AM. The concentration of ir-PAMP was almost the same as that of ir-AM in the kidney, while ir-PAMP was significantly lower than ir-AM in the ventricle, lung, and aorta. Reversed-phase high performance liquid chromatography in each porcine tissue sample revealed that two major peaks of ir-PAMP existed: one emerged at a position identical to that of authentic porcine PAMP-20; the other unknown peak was eluted earlier. The unknown peptide was purified to homogeneity from porcine adrenal medulla, and its complete amino acid sequence was determined. This peptide was found to be PAMP[9-20] with a C-terminal amide structure, and was named PAMP-12. Intravenous injections of PAMP-12 in anesthetized rats showed a significant hypotensive effect in a dose-dependent fashion, and the effect was comparable to that of PAMP-20. These data indicate that PAMP-12, a major component of ir-PAMP, is processed from the AM precursor, as is PAMP-20, and may participate in cardiovascular control.

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Section: Discussionmentioning

confidence: 67%

“…A cDNA cloning of an AM precursor (preproadrenomedullin) was carried out in humans, pigs, and rats [3][4][5]. The precursor of porcine AM consists of 188 amino acids, including a 21-residue signal peptide at its N-terminus.…”

Section: Introductionmentioning

confidence: 99%

Purification and characterization of PAMP‐12 (PAMP[9–20]) in porcine adrenal medulla as a major endogenous biologically active peptide

et al. 1997

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“…Adrenomedullin exists not only in naive adrenal medulla, but also in circulating blood and in the kidney (Kitamura et al, 1993a). Messenger RNA of adrenomedullin is expressed in the kidney (Kitamura et al, 1993b;Sakata et al, 1993). We have shown that adrenomedullin is a potent renal vasodilator with a diuretic action (Ebara et al, 1994).…”

Section: Introductionmentioning

confidence: 89%

Attenuation of adrenomedullin‐induced renal vasodilatation by N^G‐nitro L‐arginine but not glibenclamide

Miura

Ebara

Okumura

et al. 1995

British J Pharmacology

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1 The present study was conducted in order to elucidate the in vivo contribution of nitric oxide (NO) and the glibenclamide-sensitive potassium channel in the renal action of adrenomedullin in anaesthetized dogs. 2 Intrarenal arterial infusion of adrenomedullin (20 ng kg' min-) elicited a pronounced increase in renal blood flow with no changes in systemic blood pressure. The renal vasodilator action of adrenomedullin was markedly attenuated by pretreatment with N0-nitro L-arginine (L-NOARG), but this was reversed by continuous infusion of L-arginine. 3 Pretreatment with glibenclamide almost completely blocked the renal vasodilatation induced by lemakalim, but had no effect on the renal vasodilator and diuretic action of adrenomedullin. 4 Intrarenal arterial infusion of adrenomedullin induced diuresis and natriuresis. Diuretic and natriuretic action of adrenomedullin was also attenuated by L-NOARG. L-Arginine partly reversed the effect of L-NOARG and adrenomedullin-induced diuresis and natriuresis. 5 These data indicate that the in vivo renal vasodilator action of adrenomedullin is mediated by the release of NO. The glibenclamide-sensitive potassium channel is not involved in the renal action of adrenomedullin, at least, not in anaesthetized dogs. Since the inhibition of L-NOARG of adrenomedullin-induced diuresis occurred concomitantly with the attenuation of the renal vasodilator action of adrenomedullin, direct involvement of NO in adrenomedullin-induced diuresis remains to be established.

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“…These findings imply a possible role of AM in modulating cardiovascular homeostasis. The structures of porcine (Kitamura et al 1994b), rat (Sakata et al 1993) and mouse (Okazaki et al 1996) AM showed a well-conserved amino acid sequence among species, particularly in the ring structure and the C-terminal amidated tyrosine residue, suggesting the importance of these two portions of the AM molecule for its biological activity. In fact, both the ring and C-terminal amide structures were reported to be essential for the receptor binding and the production of intracellular cAMP, a major second messenger of AM, in cultured vascular smooth muscle cells (Eguchi et al 1994).…”

Section: Introductionmentioning

confidence: 98%

Molecular forms of circulating adrenomedullin in patients with congestive heart failure

Hirayama

Kïtamura²,

Imamura³

et al. 1999

Journal of Endocrinology

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In the biosynthesis of adrenomedullin (AM), an intermediate form, AM(1-52)-glycine-COOH (iAM), is cleaved from proAM and subsequently processed to a biologically active mature form, AM(1-52)-NH 2 (mAM), by enzymatic amidation. We recently reported that immunoreactive AM in human plasma consists of mAM and iAM. To clarify the pathophysiological roles of mAM and iAM in heart failure, we established an assay method to specifically detect mAM, and we determined the plasma concentrations of mAM and iAM in 68 patients with congestive heart failure (CHF). The plasma mAM concentrations of the CHF patients classified as being class I or II of New York Heart Association (NYHA) functional classification were significantly greater than those of the 28 healthy controls, and a further increase was noted in the class III or IV patients. Similar increases in plasma iAM were also observed in these patients compared with controls. The increased plasma mAM and iAM in 12 patients with exacerbated CHF were significantly reduced by treatment of their CHF for 7 days. In addition, the plasma concentrations of both mAM and iAM were significantly correlated with pulmonary capillary wedge pressure, pulmonary artery pressure, right atrial pressure, cardiothoracic ratio, heart rate, and the plasma concentrations of atrial and brain natriuretic peptides in the CHF patients. Thus the plasma concentrations of both mAM and iAM were increased progressively in proportion to the severity of CHF. These results suggest that, though the role of iAM remains to be clarified, mAM acts against the further deterioration of heart failure in patients with CHF.

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Molecular Cloning and Biological Activities of Rat Adrenomedullin, a Hypotensive Peptide

Cited by 343 publications

References 0 publications

Purification and characterization of PAMP‐12 (PAMP[9–20]) in porcine adrenal medulla as a major endogenous biologically active peptide

Purification and characterization of PAMP‐12 (PAMP[9–20]) in porcine adrenal medulla as a major endogenous biologically active peptide

Attenuation of adrenomedullin‐induced renal vasodilatation by N^G‐nitro L‐arginine but not glibenclamide

Molecular forms of circulating adrenomedullin in patients with congestive heart failure

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Molecular Cloning and Biological Activities of Rat Adrenomedullin, a Hypotensive Peptide

Cited by 343 publications

References 0 publications

Purification and characterization of PAMP‐12 (PAMP[9–20]) in porcine adrenal medulla as a major endogenous biologically active peptide

Purification and characterization of PAMP‐12 (PAMP[9–20]) in porcine adrenal medulla as a major endogenous biologically active peptide

Attenuation of adrenomedullin‐induced renal vasodilatation by NG‐nitro L‐arginine but not glibenclamide

Molecular forms of circulating adrenomedullin in patients with congestive heart failure

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Attenuation of adrenomedullin‐induced renal vasodilatation by N^G‐nitro L‐arginine but not glibenclamide