Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH2-terminal20 peptide (PAMP)

Aims To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of h ealthy male volunteers, and to investigate the role of neutral endopeptidas e (NEP) in the metabolism of ADM. Methods On two separate occasions, ADM (1-30 pmol min(-1)) and PAMP (100-30 00 pmol min(-1)) were infused into the brachial artery of eight male subjec ts, and forearm blood flow (FBF) assessed using venous occlusion plethysmog raphy. In a second study, eight male subjects received the same doses of AD M, co-infused with either the NEP inhibitor thiorphan (30 nmol min(-1)) or the control vasoconstrictor noradrenaline (120 pmol min(-1)), on separate o ccasions. Both studies were conducted in a double-blind, randomized manner. Results ADM and PAMP produced a dose-dependent increase in FBF (P less than or equal to 0.002). Based on the dose producing a 50% increase in FBF, ADM was similar to 60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14 +/- 4% (mean +/- s.e. mean) and 2 2 +/- 6%, respectively (P = 0.4). However, the area under the dose-response curve was significantly greater during co-infusion of ADM with thiorphan t han with noradrenaline (P = 0.028), as was the maximum increase in FBF rati o (2.1 +/- 1.0 vs 1.2 +/- 0.2; P = 0.030). Conclusions ADM and PAMP both produce a local dose-related vasodilatation i n the human forearm, but PAMP is similar to 60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. Th ese findings suggest that PAMP may not play a role in the physiological reg ulation of blood flow. However, in pathophysiological conditions such as hy pertension and heart failure, NEP inhibition may exert a beneficial effect by increasing the biological activity of ADM.