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Adrenomedullin (ADM) is a novel peptide with actions which include reduction of arterial pressure and interaction with a number of hormone systems. In order to assess possible interactions with the renin-angiotensin system (RAS) and the hypothalamo-pituitary-adrenal (HPA) axis, we have examined neurohumoral responses to hypotensive haemorrhage (15 ml/kg over 15 min) with or without co-infusions of ADM (5.5 pmol/kg per min) in six non-pregnant and eight pregnant conscious sheep. Haemorrhage induced a greater decrease in arterial pressure, but a blunted increase in heart rate in pregnant sheep. There was no significant effect of ADM on haemodynamic responses to haemorrhage in either group. In non-pregnant sheep, haemorrhage-induced activation of both RAS and HPA was significantly augmented by ADM, as indicated by greater increases in plasma renin activity (P<0.01), angiotensin II (P<0.05) and arginine vasopressin (P<0.01). In contrast, ADM did not augment these responses to haemorrhage in pregnant sheep. Rather, plasma concentrations of aldosterone (P=0.039) and adrenocorticotrophic hormone (P=0.012) were decreased by ADM. In conclusion, ADM-induced augmentation of the RAS and HPA responses to hypotensive haemorrhage is abolished in the pregnant state.

The physiological role of adrenomedullin (ADM) in volume and pressure homeostasis remains unclear. Accordingly, we assessed possible modulatory actions of ADM infusions on the neurohumoral response to acute volume loading with dextran in normal conscious sheep. Dextran (15 ml/kg), given with concurrent ADM (5.5 pmol/kg per min--raising plasma ADM from below detection to approximately 10 pmol/l) or vehicle control infusions, induced matched significant (P<0.001 by ANOVA) falls in hematocrit (27-30%) during both ADM and control and similar increases in right atrial pressure (approximately 10 mmHg). Compared with control, both systemic (P=0.033) and pulmonary (P=0.005) arterial pressure and peripheral resistance (P=0.004) were reduced during ADM but were raised post-infusion. The dextran-induced increase in cardiac output was augmented by ADM (P=0.048). Dextran-induced increases in plasma atrial natriuretic peptide (ANP; P=0.008), brain natriuretic peptide (BNP; P=NS) and cyclic guanosine monophosphate (cGMP; P=0.003) were augmented post-ADM infusions. The dextran-induced fall in plasma renin activity (PRA) was attenuated by ADM (P=0.039) whereas plasma aldosterone levels were unaltered. ADM augmented the increase in urinary volume during the second 2-h clearance period post-dextran. Our data indicate that ADM modifies the hemodynamic and hormonal response to an acute volume challenge, enhances natriuretic peptide secretion and reduces systemic vascular resistance. These results provide further evidence that ADM plays a physiological role in volume and pressure homeostasis.

Metabolism of natriuretic peptides is regulated by two degradative pathways: uptake by the clearance receptor (natriuretic peptide receptor C--NPR-C) and hydrolysis by neutral endopeptidase (NEP). Affinity studies favour a dominant role of NPR-C in hormone degradation in several species but do not account for the efficacy of NEP inhibitors in vivo, nor the uniquely prolonged half life (t((1/2))) of human brain natriuretic peptide (hBNP). Postulating that (1) delayed metabolism of hBNP reflects resistance to NEP and (2) interactions between NPR-C and NEP increase enzyme activity, we have used purified ovine and human NEP, plus ovine lung plasma membranes to study the relative importance of receptor and enzyme pathways. We have also related the findings to hormone metabolism in vivo. Binding affinities of atrial natriuretic peptide (ANP), hBNP and ovine BNP (oBNP) to oNPR-C were similar (K(d)=8-16 pM). In contrast, unlike ANP and oBNP, hBNP was not significantly degraded by purified oNEP or plasma membranes. Despite similar (and high) affinity of oNPR-C for oBNP and hBNP, the t((1/2)) of hBNP (12.7 min) was more than fourfold that of oBNP (2.6 min). Although we found no evidence for receptor-enzyme interaction, our results show that the delayed metabolism of hBNP reflects resistance to NEP. These findings have important implications for future treatment strategies in human disease.