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 dining 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 adrenal gland (Sugo et al., 1994a; Sugo et al., 1994b). This hypothesis is consistent with the results described above.
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