|Budget Amount *help
¥8,000,000 (Direct Cost : ¥8,000,000)
Fiscal Year 1998 : ¥1,800,000 (Direct Cost : ¥1,800,000)
Fiscal Year 1997 : ¥2,000,000 (Direct Cost : ¥2,000,000)
Fiscal Year 1996 : ¥4,200,000 (Direct Cost : ¥4,200,000)
(1) Immunoreactive AM in human plasma :
Significantly higher concentrations of adrenomedullin (AM) and PAMP were shown in the cardiovascular and renal diseases. We have demonstrated that most of the AM immunoreactivity in human plasma represents the glycine-extended AM (iAM), intermediate form, and that the concentration of mature AM (mAM) is much lower than that of iAM, Both the mAM and iAM levels in plasma were found to be elevated in patients with heart failure or renal failure at almost the constant ratio. The elevation of plasma AM was closely related to severity of the diseases, suggesting not only the role of AM acting against further deterioration of the diseases
(2) Cardiovascular effects of AM :
Chronically infused AM has a potent hypotensive effect in both WKY rats and SHR without an increase in urinary volume or Na+ excretion at a plasma AM concentration within the physiological limit. In addition, chronically infused adrenomedullin had a hypotensive effect accompanied by sign
ificant reductions of plasma renin activity and plasma aldosterone concentration in 2K-lC hypertensive and sham-operated rats.
We have demonstrated that cultured neonatal rat cardiomyocytes produce and secrete AM, and the secreted AM inhibits the protein synthesis of these cells. Thus, AM may act on cardiomyocytes as an autocrine or a paracrine factor modulating the cardiac growth.
(3) Distribution and molecular form of PAMP :
The distribution of immunoreactive (ir-) PAMP was determined in porcine tissues. High concentrations of ir-PAMP were observed in the adrenal medulla. Reversed-phase high performance liquid chromatography in each porcine tissue sample revealed that two major peaks of ir-PAMP existed : one emerged at a position identical to that of authentic porcine PAMP ; the other unknown peak was eluted earlier. The unknown peptide was purified to homogeneity from porcine adrenal medulla, and its complete amino acid sequence was determined. This peptide was found to be PAMP[9-20] with a C-terminal amide structure, and was named PAMP-12. Intravenous injections of PAMP-12 in anesthetized rats showed a significant hypotensive effect in a dose-dependent fashion. These data indicate that PAMP-12, a major component of ir-PAMP, is processed from the AM precursor, as is PAMP-20, and may participate in cardiovascular control. Less