CLINICAL-STUDIES ON THE SITES OF PRODUCTION AND CLEARANCE OF CIRCULATING ADRENOMEDULLIN IN HUMAN-SUBJECTS

Adrenomedullin is a novel hypotensive peptide, newly discovered in pheochromocytoma. Because immunoreactive adrenomedullin is present in human plasma, adrenomedullin may play a role in regulating blood pressure. A recent report showed that human adrenomedullin mRNA is expressed not only in pheochromocytoma but also in the normal adrenal medulla, kidney, lung, and ventricle. However, whether or not these organs actually release adrenomedullin into the circulation remains unknown. To investigate the sites of production and degradation of adrenomedullin in human subjects, we obtained blood samples from various sites and measured immunoreactive adrenomedullin concentrations. In study 1, blood samples were obtained from the infrarenal inferior vena cava, suprarenal inferior vena cava, superior vena cava, right atrium, right ventricle, pulmonary artery, pulmonary capillary, left ventricle, and aorta during cardiac catheterization in 15 patients with ischemic heart disease (67+/-10 years). In study 2, blood samples were taken from the infrarenal inferior vena cava, suprarenal inferior vena cava, right and left renal veins, and left adrenal vein in 5 hypertensive patients (42+/-14 years) suspected of having renovascular hypertension. In study 3, peripheral venous blood samples were obtained in 2 patients (males, 45 and 36 years old) with pheochromocytoma at rest and during hypertensive attacks. Plasma adrenomedullin concentrations were measured by a newly developed radioimmunoassay. In study 1, there were no significant differences in plasma adrenomedullin concentrations in various sites of the right-side circulation. There was no step-up of plasma adrenomedullin levels in the coronary sinus. However, the plasma concentration of adrenomedullin in aorta was slightly but significantly lower than in pulmonary artery. In study 2, there was no difference of plasma adrenomedullin levels between right and left renal veins and aorta. The plasma concentration of adrenomedullin in left adrenal vein tended to be higher than in aorta, but not significantly. In study 3, the plasma adrenomedullin concentration did not increase at rest or even during a hypertensive attack in patients with pheochromocytoma, even though epinephrine and norepinephrine rose markedly. These results suggest that the adrenal glands, lungs, kidneys, and heart may not be the main sources of circulating adrenomedullin, despite the fact that these organs express adrenomedullin mRNA. The pulmonary circulation, however, may be one of the sites of adrenomedullin clearance.