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Adrenomedullin is a new bioactive peptide recently isolated from pheochromocytoma. We report on the rat adrenomedullin distribution and molecular forms in various tissues and plasma. Using a sensitive radioimmunoassay system for rat adrenomedullin, high concentrations of immunoreactive rat adrenomedullin were detected in adrenal gland, lung and cardiac atrium. In lung and atrium, the immunoreactivity concentration in rat was about 610 times higher than that in human. The mean plasma concentration of immunoreactive rat adrenomedullin was 3.60 f 0.34 fmol/ml (mean + S.D.). Analysis in adrenal gland, lung and atrium with reverse-phase and gel-filtration high-performance liquid chromatography showed that most immunoreactive rat adrenomedullin emerged as a single peak at a position exactly identical to that of the authentic rat adrenomedullin peptide, synthesized according to the sequence predicted from the cDNA.

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The aim of this study was to investigate the regional distribution, molecular forms, and gene expression of adrenomedullin in the rat gastrointestinal tract and to examine physiological changes in gastric adrenomedullin after 24-h fasting. The tissue concentration was measured by radioimmunoassay. The molecular forms were analyzed by high performance liquid chromatography. mRNA levels were quantified by Northern blotting and cells positive for adrenomedullin immunoreactivity were localized by immunohistochemistry. A high concentration of adrenomedullin was found in stomach, cecum, and colon (450-520 fmol/g wet tissue). Adrenomedullin immunoreactivity was also detected in duodenum, jejunum, and ileum (200-250 fmol/g wet tissue). Transcripts of the adrenomedullin gene were widely expressed throughout the gastrointestinal tract. The major form of adrenomedullin immunoreactivity in stomach and colon corresponded precisely with authentic adrenomedullin peptide. Adrenomedullin immunoreactive cells were present in the gastrointestinal endocrine system. The concentration and mRNA level of gastric adrenomedullin after fasting were significantly increased compared with findings in controls. Adrenomedullin is ubiquitous in the gastrointestinal tract, and may be produced by endocrine cells. The results suggest that adrenomedullin, through its potent vasodilating activity, may play some role, in the stomach including the regulation of the mucosal blood flow.

Adrenomedullin (AM), a novel hypotensive peptide, is suggested to be involved in defense mechanisms against hypertension, however, the detail mechanisms have not been clarified. To elucidate whether AM synthesis would be altered in a salt dependent hypertension, we have investigated the AM concentration and AM messenger RNA (mRNA) level in tissues of Dahl salt-sensitive rats on either low- or high-salt intake. The AM concentration in cardiac ventricle of the high-salt group was significantly higher than that of the low-salt group. The plasma AM concentration was also significantly higher in the high-salt group than in the low-salt group. Furthermore, the plasma AM concentration correlated well with the weight of left ventricle. RNA blot analysis revealed that the AM mRNA level in cardiac ventricle of the high-salt group was higher than that of the low-salt group. These results suggest that AM participates in the pathophysiology of salt dependent hypertension and plays a role in cardiac hypertrophy.

Adrenomedullin (AM) is a novel hypotensive peptide originally isolated from the pheochromocytoma tissue of humans. To examine the pathophysiological role of AM in primary aldosteronism (PA), the plasma concentration of AM in patients with PA was measured with a specific radioimmunoassay and compared to that in age- and sex-matched healthy normotensive subjects. In addition, the concentrations of AM as well as catecholamines in the plasma from both the adrenal vein and the inferior vena cava (IVC) were measured to determine whether or not the circulating AM in these PA patients is supplied from the adrenal medulla, which contains a much higher concentration of AM than any other human tissue does. The plasma concentration of AM in the PA patients (4.57 +/- 0.32 fmol/mL, n = 6) was significantly (P < .01) higher than that in the healthy subjects (3.06 +/- 0.20 fmol/mL, n = 12). A significant positive correlation (r = 0.62, P < .01) was observed between the mean blood pressure and the plasma AM level. The AM concentration in plasma from the adrenal vein was almost the same level as that from the IVC although the concentrations of both epinephrine and norepinephrine in the adrenal vein were much higher than those in the IVC. Therefore, it seems unlikely that the plasma AM in the PA patients is mainly supplied from the adrenal medulla. Judging from the potent hypotensive activity of AM, the present findings suggest that AM participates in defense mechanisms acting against the elevation of blood pressure in the patients with PA.

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Adrenomedullin (AM) is a novel hypotensive peptide isolated from an extract of human pheochromocytoma tissue. The precursor for AM (preproadrenomedullin) is 185 amino acids in length. In addition to AM, proadrenomedullin contains a unique 20 residue sequence in the Nterminal region. This peptide was termed proadrenomedullin N-terminal 20 peptide (PAMP). PAMP also has hypotensive activity and was reported to suppress catecholamine secretion in cultured bovine cells. The present study was designed for an understanding of the role of AM and PAMP. Tissue concentrations and gene expression levels of these peptides were examined in spontaneously hypertensive rat (SHR). Furthermore, we studied the hemodynamic effects and pharmacokinetics of AM in SHR.Eight-week-old SHR and age-matched Wistar-Kyoto rat (WKY) were used in the measurement of the tissue AM and PAMP levels. Concentrations of immunoreactive AM and PAMP were measured using specific and sensitive radioimmunoassay in tissues of SHR and WKY. Expression levels of preproadrenomedullin messenger RNA in tissues were also compared between SHR and WKY by Northern blot analysis. In the study of dose-response relationship, rat AM (0.1, 0.3, 1.0 and 3.0nmol/kg) was injected intravenously to anesthetized SHR and WKY and mean blood pressure (MBP) and heart rate (HR) were recorded. In the hemodynamic study, rat AM (0.03nmol/kg/min) was infused for 30 min. In addition to MBP and HR, cardiac output was measured by the thermodilution method. The plasma half-life of rat AM in both strains rats was examined by the measurement of plasma AM concentrations after a bolus injection of rat AM (1.0 nmol/kg).The immunoreactive AM concentrations of adrenal gland and cardiac atrium were significantly higher in SHR than in WKY. The immunoreactive PAMP concentrations of cardiac atrium and ventricle were increased in SHR. The concentrations of AM and PAMP in lung were decreased in SHR. The preproadrenomedullin messenger RNA levels in adrenal gland, cardiac atrium and cardiac ventricle were higher than those of WKY. The depressor effect in bolus injection of AM was significant at the dose of 0.3nmol/kg in both strains. Administration of higher doses of AM resulted in a prolonged reduction in MBP, which tended to be more sustained in SHR . An intravenous infusion of rat AM dose-dependently reduced the MBP with a concomitant fall in total peripheral resistance index and an increase in cardiac index in both strains rats. Per cent changes in these parameters were not different between SHR and WKY. The plasma half-life of rat AM in SHR was similar to that in WKY.AM has a potent vasorelaxant activity in both SHR and WKY. Although the hemodynamic responsiveness to exogenous AM and its pharmacokinetics in SHR were comparable with those in WKY, the depressor effect of high-dose AM was more prolonged in SHR. Furthermore , the synthesis of AM and PAMP were increased in adrenal gland and heart. These findings suggest that AM and PAMP participate in the mechanism to counteract the blood pressure elevation...