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      Comparison of Plasma Levels of Mature Adrenomedullin and Natriuretic Peptide as Markers of Cardiac Function in Hemodialysis Patients with Coronary Artery Disease

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          Background: It has been suggested that, like ANP and BNP, high plasma levels of mature adrenomedullin (mAM) indirectly reflect the severity of heart failure or renal failure. However, the relationship between mAM levels and hemodynamics and cardiac function has not been examined in hemodialysis (HD) patients with coronary artery disease (CAD). The best marker, among mAM, ANP and BNP, for left-ventricular function in those patients is also unclear. Patients and Methods: Plasma levels of mAM, total AM (tAM), ANP and BNP were determined before HD in chronic HD patients with CAD (group 1; n = 17) and were compared with those of HD patients without cardiac disease (group 2; n = 22). We examined their relationship to hemodynamics and cardiac function in group 1 using data obtained by cardiac catheterization. Results: Plasma levels of ANP and BNP were significantly higher in group 1 than in group 2, but there was no significant difference in plasma levels of mAM and tAM between the two patient groups. Plasma levels of both mAM and tAM significantly correlated with right atrial pressure (RAP), and only plasma tAM levels correlated with pulmonary artery pressure (PAP) and pulmonary artery wedge pressure (PAWP). However, no correlations were found between levels of the two forms of AM and ejection fraction (EF). In contrast, plasma ANP and BNP levels significantly correlated with both PAP and PAWP, and also with EF, although they did not correlate with RAP. The correlation of PAP and PAWP with ANP and BNP levels was closer than that with tAM levels. The most significant correlation was between BNP levels and EF (r = –0.756, p < 0.0001). Conclusions: Our results suggest that the mAM level may be less useful than natriuretic peptide levels as a marker of cardiac function in HD patients with CAD, and that the BNP level might be the best indicator of left-ventricular function. In addition, cardiac disease such as CAD may have a minor impact on mAM levels compared to renal failure.

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          Most cited references 6

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          Endothelial cells actively synthesize and secrete adrenomedullin.

          This study demonstrates active production of adrenomedullin (AM) in cultured vascular endothelial cells (ECs). To identify the origin of plasma AM and its functional relationship to vascular smooth muscle cells (VSMCs), we checked production of AM in a series of tissues and cell lines and found immunoreactive (ir-) AM in culture media of rat, porcine, human and bovine ECs. Ir-AM was accumulated linearly for up to 48 hours in the culture medium of rat ECs, and the secretion rate of AM was almost comparable to that of endothelin-1. By gel filtration and reverse phase high performance liquid chromatography, ir-AM in the culture medium was shown to have chromatographic behavior indistinguishable from that of synthetic rat AM. By RNA blot analysis of rat tissue, the most highly positive band was detected in cultured ECs, at an intensity 20 to 40 fold higher than that in adrenal gland. Based on these data as well as the presence of AM specific receptor on VSMCs, AM secreted from ECs is deduced to act directly on VSMCs, regulating vascular tone.
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            Production and secretion of adrenomedullin from vascular smooth muscle cells: augmented production by tumor necrosis factor-alpha.

             H Shoji,  K. Kangawa,  T Eto (1994)
            In this study, we demonstrate production and secretion of adrenomedullin (AM) from cultured vascular smooth muscle cells (VSMCs). In addition to endothelial cells (ECs), we found immunoreactive (ir-) AM in culture media of rat and bovine VSMCs in the survey for AM-producing cells. Although the secretion level of ir-AM was at most 1/6 that of rat ECs, all the examined VSMCs were shown to produce AM. By gel filtration, reverse phase high-performance liquid chromatography, and biological characterization, ir-AM in the culture medium was identified to be rat AM of 50 residues. By RNA blot analysis, a positive band of AM mRNA was detected in cultured VSMC at an intensity 3-4 fold higher than that in adrenal gland. Gene expression and production of AM were markedly augmented by tumor necrosis factor-alpha. Based on these data as well as the presence of AM specific receptors on VSMCs, AM secreted from VSMC is deduced to function as an autocrine or paracrine regulator in vascular cell communication.
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              Plasma adrenomedullin during acute changes in intravascular volume in hemodialysis patients.

              Adrenomedullin, is a potent vasorelaxant that is highly expressed in the adrenal medulla, kidney, heart and lung. Since there is indirect evidence that hypervolemia enhances the release of this peptide, we measured plasma adrenomedullin in 9 uremic patients on chronic dialysis treatment and in 10 healthy subjects matched for age and gender. Measurements were performed in baseline conditions, after isotonic fluid subtraction (by isolated ultrafiltration) and during a 70 degrees tilt. Tilt was performed in volume-depleted state, that is, after isolated ultrafiltration (UF). In the control experiment patients underwent sham UF (UF = 0) followed by a period of supine resting identical to the one they had spent in tilted position in the active experiment. Adrenomedullin was measured on pre-extracted plasma samples (Sep-Pak C-18 cartridges) by a specific RIA for human adrenomedullin 1-52. The average plasma adrenomedullin was 2.6 times higher (P < 0.01) in uremic patients (103 +/- 8 pg/ml) than in healthy subjects (39 +/- 7 pg/ml). After fluid subtraction (-2.6 +/- 0.2 liter) adrenomedullin fell to 79. +/- 8 pg/ml (P = 0.02) but remained well above the upper limit of the 95% CI in normal subjects (52 pg/ml). There was no relationship between adrenomedullin and ANF changes. In the control experiment sham UF did not modify plasma adrenomedullin. Tilt did not significantly change plasma adrenomedullin either in dialysis patients or healthy subjects. Plasma adrenomedullin is markedly raised in uremic patients on dialysis, which confirms that the kidney has a major role in the clearance of this peptide. However, the fall in plasma adrenomedullin after isolated UF indicates that the plasma concentration of this peptide is influenced by the body fluid volume status. Whether or not adrenomedullin participates in the counter-regulatory response to fluid subtraction in uremic patients remains to be explored by specific antagonists of this substance.

                Author and article information

                S. Karger AG
                October 2002
                18 October 2002
                : 92
                : 4
                : 832-839
                Second Department of Internal Medicine, University of Occupational and Environmental Health, School of Medicine, Yahatanishi-ku, Kitakyushu, Japan
                65459 Nephron 2002;92:832–839
                © 2002 S. Karger AG, Basel

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                Figures: 1, Tables: 4, References: 34, Pages: 8
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