The active molecular form of plasma adrenomedullin is extracted in the pulmonary circulation in patients with mitral stenosis: possible role of adrenomedullin in pulmonary hypertension

Abstract

Adrenomedullin (AM), a novel hypotensive peptide, preferentially dilates pulmonary vessels rather than systemic vessels. This suggests the possibility that AM is a circulating hormone which participates in regulation of the pulmonary circulation. A recent study revealed that two molecular forms of AM, i.e. a mature, active form of AM (AM-m) and an intermediate, inactive, glycine-extended form of AM (AM-Gly), circulate in human plasma. In the present study we investigated the production and clearance sites and pathophysiological significance of the two molecular forms of AM in the pulmonary circulation in patients with mitral stenosis. We measured the plasma levels of AM-m and total AM (AM-T; AM-m+AM-Gly) using a recently developed specific immunoradiometric assay, and thus calculated plasma AM-Gly levels, in blood samples obtained from the femoral vein, pulmonary artery, left atrium and aorta of 28 consecutive patients with mitral stenosis (20 females and eight males; age 53+/-10 years). Patients with mitral stenosis had significantly higher venous concentrations of AM-T, AM-Gly and AM-m than age-matched normal controls (AM-T, 15.9+/-2.5 and 10.6+/-2.1 pmol/l respectively; AM-Gly, 14.0+/-2.1 and 9.8+/-1.9 pmol/l respectively; AM-m, 1.9+/-0.6 and 1.1+/-0.3 pmol/l respectively; each P<0.001). There was a significant decrease in the concentrations of AM-m and AM-T between the pulmonary artery and the left atrium (AM-T, 16.1+/-2.7 and 14.0+/-2.4 pmol/l respectively; AM-m, 2.0+/-0.6 and 0.7+/-0.2 pmol/l respectively; each P<0.001); however, there were no differences in plasma AM-Gly levels between the pulmonary artery and the left atrium (14.1+/-2.3 and 13.5+/-2.3 pmol/l respectively). The venous concentrations of AM-m, AM-Gly and AM-T showed similar correlations with mean pulmonary artery pressure (AM-T, r=0.67; AM-Gly, r=0.63; AM-m, r=0.59; each P<0.001) and total pulmonary vascular resistance (AM-T, r=0.77; AM-Gly, r=0.70; AM-m, r=0.75; each P<0.001). These results suggest that the plasma concentration of AM-m is increased in parallel with those of AM-Gly and AM-T, and that the main site for clearance of AM-m from the plasma is the lung; the extracted AM-m in the lungs may help to attenuate the increased pulmonary arterial resistance in secondary pulmonary hypertension due to mitral stenosis.

Biodistribution, plasma kinetics and quantification of single-pass pulmonary clearance of adrenomedullin

“…The systemic hypotensive action of AM can however be abolished after intravenous compared with intra-arterial infusion [8], suggesting that the lungs can clear circulating AM and modulate its circulating levels. Many studies have confirmed that AM is cleared by the pulmonary circulation [9][10][11][12]. The relative contribution of the lungs to AM clearance in comparison with other organs has not been systematically evaluated and, more specifically, single-pass pulmonary clearance of AM has not been quantified in vivo.…”

Adrenomedullin in Hypertension

“…Using this kit we and other investigators found that plasma AM-T levels in normal human plasma are about 10 fmol/mL [102,106]. In hypertension, renal failure, congestive heart failure, acute myocardial infarction and pulmonary hypertension, both plasma AM-Gly and AM-m levels are increased and the ratio of AM-Gly to AM-m does not significantly change [107,101,108]. Nishikimi et al measured the two molecular forms of AM in rat cardiac tissue and plasma using this system.…”

“…Nishikimi et al also reported that the lung is a major site of AM clearance in man [93]. Furthermore, the same group reported that active mature AM (AM-m), a 52-amino acid peptide with a C-terminal amide structure, is specifically extracted in the pulmonary circulation [101,102].…”

Direct Measurement of Glycine-Extended Adrenomedullin in Plasma and Tissue Using an Ultrasensitive Immune Complex Transfer Enzyme Immunoassay in Rats

“…We used three anti-AM monoclonal antibodies (23,24): one recognized the ring structure (rAdR-2; anti-rat AM [8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23]), one the C-terminal amide structure (AdC-1; anti-AM[46-52]NH2), and one the middle portion (AdM-2; anti-AM [25][26][27][28][29][30][31][32][33][34][35][36]) of the molecule. These antibodies were gifted from Shionogi & Co., Ltd., Osaka, Japan.…”

“…For rat AM-t, 10 fmol of anti AM [25][26][27][28][29][30][31][32][33][34][35][36]Fab -β-D-galactosidase conjugate (as an antibody-enzyme) was substituted for anti-AM[46-52]NH2 Fab -β-D-galactosidase conjugate, and IEMA was carried out as described above.…”