Adrenomedullin (ADM) in the human forearm vascular bed: effect of neutral endopeptidase inhibition and comparison with proadrenomedullin NH₂‐terminal 20 peptide (PAMP)

Abstract

Aims To compare the haemodynamic responses of proadrenomedullin N-terminal 20 peptide (PAMP) and adrenomedullin (ADM) in the forearm vascular bed of healthy male volunteers, and to investigate the role of neutral endopeptidase (NEP) in the metabolism of ADM. Methods On two separate occasions, ADM (1±30 pmol min x1 ) and PAMP (100±3000 pmol min x1 ) were infused into the brachial artery of eight male subjects, and forearm blood¯ow (FBF) assessed using venous occlusion plethysmography. In a second study, eight male subjects received the same doses of ADM, co-infused with either the NEP inhibitor thiorphan (30 nmol min x1 ) or the control vasoconstrictor noradrenaline (120 pmol min x1 ), on separate occasions. Both studies were conducted in a double-blind, randomized manner. Results ADM and PAMP produced a dose-dependent increase in FBF (Pj0.002). Based on the dose producing a 50% increase in FBF, ADM was y60 times more potent than PAMP. Thiorphan and noradrenaline produced similar reductions in FBF of 14t4% (mean t s.e. mean) and 22t6%, respectively (P=0.4). However, the area under the dose±response curve was signi®cantly greater during co-infusion of ADM with thiorphan than with noradrenaline (P=0.028), as was the maximum increase in FBF ratio (2.1t1.0 vs 1.2t0.2; P= 0.030). Conclusions ADM and PAMP both produce a local dose-related vasodilatation in the human forearm, but PAMP is y60 times less potent than ADM. In addition, NEP inhibition potentiates the haemodynamic effects of ADM. These ®ndings suggest that PAMP may not play a role in the physiological regulation of blood¯ow. However, in pathophysiological conditions such as hypertension and heart failure, NEP inhibition may exert a bene®cial effect by increasing the biological activity of ADM.

Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure

“…[5][6][7][8][9] Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. [10][11][12] Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling. 13,14 Combined inhibition of the renin-angiotensin system and neprilysin had effects that were superior to those of either approach alone in experimental studies, 15,16 but in clinical trials, the combined inhibition of ACE and neprilysin was associated with serious angioedema.…”

Rationale and design of TRANSITION: a randomized trial of pre‐discharge vs. post‐discharge initiation of sacubitril/valsartan

“…It is indicated for use in patients with chronic heart failure with reduced ejection fraction (HFrEF) of New York Heart Association (NYHA) Class II–IV and is recommended as a replacement for an ACEI or an ARB, usually in conjunction with a beta‐blocker and an MRA 10, 33. Sacubitril inhibits neprilysin, which degrades vasoactive peptides including natriuretic peptides (NPs), bradykinin, and adrenomedullin 34, 35, 36. Enhanced levels of NPs exert physiologic effects through binding to NP receptors and the augmented generation of cyclic guanosine monophosphate, thereby enhancing diuresis, natriuresis and myocardial relaxation and anti‐remodelling, countering the effect of renin–angiotensin–aldosterone over‐stimulation.…”

Use of sacubitril/valsartan in acute decompensated heart failure: a case report

“…However, costly long‐term, continuous inodilator infusions may be required for refractory HF (stage D) patients with severe systolic dysfunction, depressed cardiac output, and end‐organ mal‐perfusion while awaiting mechanical circulatory support (MCS) or heart transplantation (HT) 2. The angiotensin receptor blocker–neprilysin inhibitor, sacubitril/valsartan, is a novel therapy that can increase levels of endogenous vasoactive peptides 3, 4. Compared with enalapril, sacubitril/valsartan reduced the composite endpoint of cardiovascular death or HF hospitalization and is recommended as an alternative for angiotensin‐converting enzyme inhibitors and angiotensin receptor blockers in patients with chronic HF with reduced ejection fraction (HFrEF) and New York Heart Association class II–III symptoms 5, 6.…”