Adrenomedullin and Proadrenomedullin N-Terminal 20 Peptide in Spontaneously Hypertensive Rat

Abstract

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...