CIRCULATINGADRENOMEDULLIN

Toshio Nishikimi
Department of Hypertension and Cardiorenal Medicine, Dokkyo University School of Medicine, Mibu,

Tochigi 321 -0293, Japan

1. ADRENOMEDULLINASSAYS

In the first report about adrenomedullin (AM) by Kitamura et al (Kitamura

et al., 1993a), plasma AM levels were measured by radioimmunoassay after
digestion with trypsin. It was found that plasma AM levels in humans were
19 fmol/mL. The same group developed a simpler radioimmunoassay
system after extraction of plasma (Kitamura et al.,1994). In that report,
plasma levels of AM were 3.3 finol/mL. Other investigators also developed
their own radioimmunoassay systems using polyclonal antibodies and
reported that the plasma levels of AM were 3 - 8 fmol/mL. In general, these
assay systems reported in the literature appear to have been carefully
validated, with evidence presented from high performance liquid
chromatography analysis to show that immunoreactive AM from human
plasma coelutes with authentic human AM (Kohno et al.,1996; Lewis et al.,
1998). Therefore, the absolute plasma levels of AM in the normal human
appear to be consistent. Various studies have shown that the plasma levels of
AM in the normal human are 1 -10 fmol/mL. In general, they revealed that
sex or age does not affect the plasma AM levels. However, recent
observations showed that plasma AM levels increase in association with
aging in the normal human, especially in humans over 70 years old (Kato et
al., 2002). No circadian variation of plasma AM levels was found in normal
humans (Nishikimi et al., 2001).

2. ORIGIN AND METABOLIC SITES OF ADRENOMEDULLIN

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(1) Origin of circulating adrenomedullin

AM was initially discovered in human pheochromocytoma by monitoring

the cAMP activity in rat platelets (Kitamura et al.,1993a). AM mRNA is
highly expressed not only in pheochromocytoma but also in normal adrenal
medulla, kidney, lungs, and ventricle (Kitamura et al., 1993b). However,
whether these organs secrete AM into circulation or not was not initially
fully understood. To investigate the sites of production and clearance of AM
in humans, we took samples of both arterial and venous blood across the
adrenal gland, kidney, lung, and heart and measured plasma AM
concentrations by radioimmunoassay (Nishikimi et al., 1994). There was no
step-up of plasma AM concentration in the coronary sinus, renal vein, or
adrenal vein. There were no significant differences in plasma AM
concentrations among the various sites of the right side of the heart
including the inferior portion of the inferior vena cava, superior portion of
the inferior vena cava, superior vena cava, right atrium, right ventricle, and
pulmonary artery. Plasma AM levels in the aorta were slightly but
significantly lower than those in pulmonary artery. Furthermore, in a patient
with a pheochromocytoma, no change in plasma AM concentration was
seen during a hypertensive attack, although both epinephrine and
norepinephrine concentrations increased markedly (Nishikimi et al., 1994).
Subsequent studies supported the notion that the AM level in the adrenal
vein was not increased and does not contribute to the main source of plasma
AM (Kato et al., 1995; Minami et al., 2002). Although it has been shown
that AM is cosecreted with catecholamines, at least by bovine chromaffin
cells in culture (Katoh et al., 1994), these data suggest that the adrenal
medulla is unlikely to be a significant source of circulating AM. Thus,
although AM peptide and mRNA expression are widely distributed in
various tissues and organs, the main source of plasma AM in vivo is now
thought to be the vasculature, because AM mRNA is more prominently
expressed in vascular endothelial cells and smooth muscle cells than in the