Adrenomedullin (AM, ADM)

1. Overview

Adrenomedullin (AM or ADM) is a 52-amino acid peptide first isolated in 1993 by Kazuo Kitamura and colleagues from human pheochromocytoma tissue (adrenal medullary tumor) based on its ability to stimulate cAMP production in rat platelets [1]. The peptide was initially identified by its potent hypotensive effect when administered intravenously to rats. Since its discovery, adrenomedullin has emerged as one of the most intensively studied vasoactive peptides in critical care medicine, cardiovascular disease, and biomarker research.

Structurally, adrenomedullin belongs to the calcitonin/CGRP superfamily of peptides, which also includes calcitonin gene-related peptide (CGRP), calcitonin, amylin, and intermedin (adrenomedullin 2). AM contains a characteristic intramolecular disulfide bond between Cys16 and Cys21, forming a six-amino acid ring structure, and an amidated C-terminal tyrosine residue (Tyr52) that is essential for biological activity [1][24]. The peptide is encoded by the ADM gene on chromosome 11p15.4 and is processed from a larger 185-amino acid preprohormone (preproadrenomedullin), which also yields proadrenomedullin N-terminal 20 peptide (PAMP), another biologically active fragment.

Adrenomedullin is not confined to the adrenal medulla; it is widely expressed throughout the body, including in endothelial cells, vascular smooth muscle cells, cardiomyocytes, renal tubular cells, lung epithelium, and the gastrointestinal tract. Its broad expression pattern reflects its diverse physiological roles in vascular homeostasis, organ protection, and immune regulation.

A key development in clinical practice has been the measurement of mid-regional pro-adrenomedullin (MR-proADM), a stable fragment of the adrenomedullin precursor molecule. Because mature AM has a very short circulating half-life (~22 minutes), MR-proADM (half-life of several hours) serves as a practical surrogate biomarker, with commercially available assays (B.R.A.H.M.S MR-proADM KRYPTOR, Thermo Fisher Scientific) now used in clinical settings for prognostication in sepsis, pneumonia, heart failure, and COVID-19.

Molecular Weight

~6,028 Da (52 amino acids)

Structure

52 amino acids with intramolecular disulfide bond (Cys16-Cys21), amidated C-terminal Tyr52

Gene

ADM (chromosome 11p15.4)

Receptor

CLR/RAMP2 (AM1 receptor) and CLR/RAMP3 (AM2 receptor)

Half-life

~22 minutes (circulating); MR-proADM: several hours

Discovery

1993 by Kitamura et al., isolated from human pheochromocytoma

FDA Status

Not approved; enibarcimab (anti-AM antibody) has FDA Fast Track designation for septic shock (2024)

Biomarker Use

MR-proADM commercially available (B.R.A.H.M.S KRYPTOR) for sepsis and pneumonia prognostication

2. Mechanism of Action

Receptor System

Adrenomedullin signals through a unique receptor system discovered by McLatchie et al. in 1998 [25]. Its primary receptors are heterodimers of the calcitonin receptor-like receptor (CLR), a class B G protein-coupled receptor, with receptor activity-modifying proteins (RAMPs):

• AM1 receptor (CLR/RAMP2): The primary, high-affinity adrenomedullin receptor. RAMP2 acts as a chaperone for CLR trafficking to the cell surface and determines ligand specificity for adrenomedullin.
• AM2 receptor (CLR/RAMP3): A secondary adrenomedullin receptor with somewhat broader ligand recognition. CLR/RAMP3 also binds CGRP and intermedin.

When CLR pairs with RAMP1 instead, the complex forms the CGRP receptor. This shared receptor architecture explains the partial overlap in biological activities between AM and CGRP and has important implications for pharmacological targeting.

Vasodilation Pathways

Adrenomedullin is one of the most potent endogenous vasodilatory peptides known. It induces vasodilation through multiple parallel mechanisms depending on the vascular bed:

• Nitric oxide-cGMP pathway: In the rat aorta and kidney, AM-induced vasodilation is mediated through endothelial nitric oxide synthase (eNOS) activation and subsequent cGMP production [4].
• cAMP/PKA pathway: AM directly activates adenylyl cyclase in vascular smooth muscle cells, elevating intracellular cAMP, which activates protein kinase A (PKA) to produce smooth muscle relaxation. This represents an endothelium-independent mechanism of vasodilation.
• Adenosine receptor/KATP channel pathway: In the coronary vasculature, AM-induced vasodilation is initiated through adenosine receptor activation and subsequently mediated through ATP-sensitive potassium (KATP) channels.
• Synergism with natriuretic peptides: AM and B-type natriuretic peptide (BNP) produce synergistic vasodilation, likely mediated through BNP/cGMP-induced inhibition of phosphodiesterase 3 (PDE3), which enhances AM-driven cAMP accumulation.

Endothelial Barrier Stabilization

Beyond vasodilation, one of adrenomedullin's most clinically significant functions is the stabilization of endothelial barrier integrity [7][9]. AM activation of its receptor triggers cAMP elevation in endothelial cells, which:

• Inhibits actin-myosin-based endothelial cell contraction
• Prevents junctional disassembly (VE-cadherin, ZO-1 tight junction proteins)
• Enhances claudin-5 expression at cell-cell contact sites (particularly in the blood-brain barrier)
• Reduces paracellular permeability to macromolecules

This barrier-stabilizing function is dose-dependent and effective against permeability induced by thrombin, hydrogen peroxide, and bacterial toxins such as E. coli hemolysin [7]. This property is particularly relevant in sepsis, where endothelial barrier breakdown drives capillary leak, edema, and organ failure.

Additional Biological Activities

• Diuresis and natriuresis: AM increases glomerular filtration rate and renal blood flow, promoting sodium and water excretion [10].
• Anti-inflammatory effects: AM modulates immune cell function and reduces inflammatory cytokine production.
• Anti-apoptotic effects: AM activates survival signaling pathways in cardiomyocytes, renal tubular cells, and endothelial cells.
• Angiogenesis: AM promotes new blood vessel formation through VEGF-dependent and -independent mechanisms, with implications for both tissue repair and tumor biology.

3. Researched Applications

Sepsis and Septic Shock

Evidence level: Strong (multiple prospective studies, biomarker-guided RCTs)

Adrenomedullin has become one of the most extensively studied biomarkers in sepsis. Plasma levels of both bio-ADM and MR-proADM rise dramatically during sepsis, proportional to disease severity [17][19]. The AdrenOSS-1 prospective multicenter study (583 patients, 24 ICUs) demonstrated that early bio-ADM levels predicted short-term survival and organ failure reversibility, with an inverse relationship to blood pressure and direct correlation with vasopressor requirements [17]. Bio-ADM at ICU admission independently predicted 30-day mortality and organ failure [19].

The therapeutic targeting of AM in sepsis led to the development of adrecizumab (enibarcimab), a humanized non-neutralizing anti-adrenomedullin antibody. Rather than blocking AM activity, adrecizumab binds the N-terminal portion of AM, sequestering it in the circulation and redirecting its activity to stabilize endothelial barriers while reducing its vasodilatory contribution to hypotension. The AdrenOSS-2 trial (301 patients, Phase IIa) demonstrated safety and tolerability at 2 and 4 mg/kg doses, with improvement in organ failure scores [21]. In April 2024, enibarcimab received FDA Fast Track designation for septic shock. In May 2025, a prespecified biomarker-guided subgroup analysis published in the Journal of Critical Care revealed a striking mortality reduction from 24% to 8% in septic shock patients identified using a dual-biomarker enrichment strategy (adrenomedullin for inclusion, dipeptidyl peptidase 3 [DPP3] for exclusion). AdrenoMed is preparing a confirmatory Phase IIb/III clinical trial employing this precision medicine approach.

Heart Failure

Evidence level: Strong (multiple prospective studies including BACH trial)

In heart failure, AM levels rise in proportion to disease severity, reflecting compensatory vasodilation and the body's attempt to counteract elevated filling pressures. The landmark BACH trial (1,641 patients) demonstrated that MR-proADM was superior to BNP for predicting 90-day mortality in patients presenting with acute dyspnea (AUC 0.674 vs 0.606), adding significantly to all clinical variables and outperforming all other biomarkers tested [12]. In chronic heart failure, elevated plasma AM was identified as an independent predictor of prognosis [6].

Hemodynamic studies in heart failure patients showed that AM infusion reduced mean arterial pressure, pulmonary arterial pressure, and systemic and pulmonary vascular resistance while increasing cardiac output [5]. More recently, bio-ADM was shown to track with mean right atrial pressure and associate with systemic congestion independently from NT-proBNP.

The ACCOST-HH trial tested adrecizumab in 150 cardiogenic shock patients but found no significant benefit over placebo for reducing cardiovascular organ support or improving survival at 30 and 90 days [22]. However, biomarker-guided subgroup analyses suggested potential benefit in molecularly defined subgroups.

Community-Acquired Pneumonia

Evidence level: Strong (systematic reviews and meta-analyses)

MR-proADM has emerged as a valuable prognostic marker in community-acquired pneumonia (CAP). Levels correlate with pneumonia severity scores (PSI, CURB-65) and predict treatment failure and mortality with an AUC of 0.73, significantly outperforming CRP and leukocyte count [8]. A systematic review and meta-analysis confirmed that adding MR-proADM to established severity scores significantly improved their prognostic accuracy for both short-term and 1-year mortality.

COVID-19

Evidence level: Moderate (observational studies, early therapeutic trials)

During the COVID-19 pandemic, MR-proADM was rapidly validated as a prognostic biomarker for severe disease. A European multicenter study found mean MR-proADM of 0.841 nmol/L in survivors versus 1.692 nmol/L in non-survivors. A Phase IIa trial of exogenous AM administration in moderate to severe COVID-19 showed reductions in inflammation and organ damage markers [23]. A systematic review and meta-analysis confirmed MR-proADM's reliability as a mortality predictor in hospitalized COVID-19 patients.

Cancer and Tumor Angiogenesis

Evidence level: Moderate (preclinical studies)

Adrenomedullin is upregulated by hypoxia through the HIF-1 pathway and is highly expressed in numerous tumor types including breast, ovarian, hepatocellular, oral squamous cell, and pancreatic cancers. AM promotes tumor angiogenesis by recruiting endothelial cells, pericytes, and myeloid precursor cells. Tumor-associated macrophages and stromal fibroblasts secrete AM in a paracrine manner to support tumor growth. Anti-AM receptor antibodies have shown anti-tumor effects in mouse xenograft models, suppressing angiogenesis and tumor growth [11]. This represents a potential therapeutic avenue, though clinical trials in oncology have not yet been initiated.

Renal Protection

Evidence level: Moderate (animal studies, clinical biomarker data)

AM has renal vasodilatory, natriuretic, and diuretic actions, increasing GFR and renal blood flow [10]. In animal models, AM gene delivery or chronic infusion improved glomerular sclerosis, interstitial fibrosis, and renal arteriosclerosis. The AM-RAMP2 system specifically protects against ER stress-induced renal tubule cell death. In diabetic rats, AM attenuated renal glycogen accumulation and tubular damage.

Migraine

Evidence level: Preliminary (single provocation study)

A randomized crossover study demonstrated that AM infusion provoked migraine-like attacks in migraine patients, confirming AM's role in migraine pathophysiology and its relationship to the CGRP signaling pathway. This finding is significant because several CGRP-targeting drugs (gepants, anti-CGRP monoclonal antibodies) are already FDA-approved for migraine, and AM-specific interventions could offer additional therapeutic approaches.

4. Clinical Evidence Summary

5. Dosing in Research

The following table summarizes doses used in published research studies. These are not therapeutic recommendations. Adrenomedullin (as a direct therapeutic) has completed Phase I trials, and adrecizumab (the anti-AM antibody) has been tested through Phase IIa.

Key pharmacokinetic parameters (human data):

• Metabolic clearance rate: 27.4 +/- 3.6 mL/kg/min
• Circulating half-life: 22 +/- 1.6 minutes
• Apparent volume of distribution: 880 +/- 150 mL/kg
• Cmax reached at end of continuous infusion; dose-dependent
• T1/2 < 60 minutes after cessation of infusion
• MR-proADM half-life: several hours (suitable for clinical biomarker use)

6. Safety and Side Effects

Direct AM Administration

In the Phase I clinical trial in healthy male volunteers, continuous IV infusion of adrenomedullin at 3, 9, and 15 ng/kg/min for up to 12 hours (and 15 ng/kg/min for 7 days) was safe and well tolerated [20]. Key safety findings include:

• Hemodynamic effects: In healthy subjects, AM decreased mean arterial pressure (~16 mmHg) and increased heart rate (~12 bpm). In heart failure patients, effects were more modest (~8 mmHg decrease in MAP, ~5 bpm heart rate increase).
• Adverse events: Only mild adverse events were reported, all tolerable without medical intervention.
• Hemodynamic stability: Despite vasodilatory effects, hemodynamic parameters remained stable throughout the infusion period.

Adrecizumab (Enibarcimab)

In Phase I and Phase IIa trials:

• No overt safety signals at doses of 0.5-8 mg/kg (Phase I) and 2-4 mg/kg (Phase IIa) [16][21].
• Despite inducing large increases in circulating AM, adrecizumab did not cause hypotension.
• Well tolerated in both healthy volunteers and critically ill patients with septic shock or cardiogenic shock.

Theoretical Concerns

• Hypotension risk: As a potent vasodilator, excessive AM could theoretically cause clinically significant hypotension, particularly in volume-depleted patients.
• Tumor promotion: AM's angiogenic and anti-apoptotic properties raise theoretical concerns about promoting tumor growth in patients with occult malignancies, though this has not been observed in clinical trials.
• Migraine provocation: AM infusion has been shown to trigger migraine-like attacks in susceptible individuals.

7. Regulatory Status

United States (FDA): Adrenomedullin is not approved as a therapeutic agent. However, enibarcimab (formerly adrecizumab, HAM8101), developed by AdrenoMed AG (Germany), received FDA Fast Track designation in April 2024 for the treatment of septic shock. The company is proceeding toward Phase IIb clinical trials. Adrenomedullin is also being investigated in clinical trial NCT06072118 for CADASIL (cerebral autosomal dominant arteriopathy).

European Union: No marketing authorization for AM as a therapeutic. Clinical trials with adrecizumab have been conducted across multiple EU member states. MR-proADM is commercially available as an in vitro diagnostic biomarker (B.R.A.H.M.S MR-proADM KRYPTOR, Thermo Fisher Scientific).

Japan: Adrenomedullin was originally discovered in Japan, and Japanese researchers have conducted Phase I trials. AM infusion therapy for acute myocardial infarction and peripheral arterial disease has been explored in Japanese clinical studies. PEG-ADM (pegylated adrenomedullin) is being investigated for ARDS in a Phase 2a/b trial.

Biomarker regulatory status: MR-proADM assays are CE-marked for in vitro diagnostic use in Europe and are used clinically for sepsis and pneumonia risk stratification. They are not FDA-cleared for diagnostic use in the United States.

8. Related Peptides

See also: CGRP (Calcitonin Gene-Related Peptide), Calcitonin, Amylin (IAPP), Intermedin (Adrenomedullin 2), BNP (B-type Natriuretic Peptide)

Adrenomedullin belongs to the calcitonin/CGRP superfamily, and its pharmacology is closely intertwined with that of CGRP. The shared CLR receptor component means that drugs targeting the CGRP pathway (including gepants and anti-CGRP antibodies approved for migraine) may have indirect effects on AM signaling. Intermedin (adrenomedullin 2) shares the CLR/RAMP3 receptor and has overlapping cardiovascular protective effects. BNP acts synergistically with AM on vasodilation through complementary second messenger systems.

9. References

1. [1] Kitamura K, Kangawa K, Kawamoto M, Ichiki Y, Nakamura S, Matsuo H, Eto T. (1993). Adrenomedullin: a novel hypotensive peptide isolated from human pheochromocytoma. Biochemical and Biophysical Research Communications. DOI PubMed
2. [2] Cockcroft JR, Noon JP, Gardner-Medwin J, Bennett T. (1995). Pulmonary vasodilation to adrenomedullin: a novel peptide in humans. British Journal of Clinical Pharmacology. PubMed
3. [3] Hirata Y, Hayakawa H, Suzuki Y, Suzuki E, Ikenouchi H, Kohmura O, et al. (1995). Mechanisms of adrenomedullin-induced vasodilation in the rat kidney. Hypertension. PubMed
4. [4] Nishikimi T, Karasawa T, Inaba C, et al. (1999). Role of nitric oxide-cGMP pathway in adrenomedullin-induced vasodilation in the rat. Hypertension. PubMed
5. [5] Lainchbury JG, Troughton RW, Lewis LK, Yandle TG, Richards AM, Nicholls MG. (2000). Hemodynamic, renal, and hormonal effects of adrenomedullin infusion in patients with congestive heart failure. Clinical Science. PubMed
6. [6] Pousset F, Masson F, Chavirovskaia O, et al. (2000). Plasma adrenomedullin, a new independent predictor of prognosis in patients with chronic heart failure. European Heart Journal. PubMed
7. [7] Hippenstiel S, Witzenrath M, Schmeck B, et al. (2003). Adrenomedullin reduces endothelial hyperpermeability. Circulation Research. DOI PubMed
8. [8] Schuetz P, Christ-Crain M, Morgenthaler NG, et al. (2006). Pro-adrenomedullin to predict severity and outcome in community-acquired pneumonia. Critical Care. DOI PubMed
9. [9] Hocke AC, Temmesfeld-Wollbrueck B, Suttorp N, Hippenstiel S. (2007). Adrenomedullin and endothelial barrier function. Thrombosis and Haemostasis. PubMed
10. [10] Nishikimi T. (2007). Adrenomedullin in the kidney-renal physiological and pathophysiological roles. Current Medicinal Chemistry. PubMed
11. [11] Ouafik LH, Sauze S, Boudouresque F, et al. (2009). Targeting adrenomedullin receptors with systemic delivery of neutralizing antibodies inhibits tumor angiogenesis and suppresses growth of human tumor xenografts in mice. FASEB Journal. PubMed
12. [12] Maisel A, Mueller C, Nowak RM, Peacock WF, et al. (2011). Midregion prohormone adrenomedullin and prognosis in patients presenting with acute dyspnea: results from the BACH trial. Journal of the American College of Cardiology. DOI PubMed
13. [13] Valenzuela-Sanchez F, Valenzuela-Mendez B, Rodriguez-Gutierrez JF, et al. (2016). New role of biomarkers: mid-regional pro-adrenomedullin, the biomarker of organ failure. Annals of Translational Medicine. PubMed
14. [14] Marino R, Struck J, Maisel AS, Magrini L, Bergmann A, Di Somma S. (2014). Plasma adrenomedullin is associated with short-term mortality and vasopressor requirement in patients admitted with sepsis. Critical Care. PubMed
15. [15] Geven C, Kox M, Pickkers P. (2018). Adrenomedullin and adrenomedullin-targeted therapy as treatment strategies relevant for sepsis. Frontiers in Immunology. PubMed
16. [16] Geven C, Peters L, Bergmann A, Pickkers P. (2018). Safety, tolerability and pharmacokinetics/pharmacodynamics of the adrenomedullin antibody adrecizumab in a first-in-human study and during experimental human endotoxaemia. British Journal of Clinical Pharmacology. DOI PubMed
17. [17] Mebazaa A, Geven C, Hollinger A, et al. (2018). Circulating adrenomedullin estimates survival and reversibility of organ failure in sepsis: the AdrenOSS-1 study. Critical Care. DOI PubMed
18. [18] Geven C, Bergmann A, Kox M, Pickkers P. (2019). Vascular effects of adrecizumab - a non-neutralizing anti-adrenomedullin antibody. Shock. PubMed
19. [19] Deniau B, Takagi K, Geven C, et al. (2019). Circulating biologically active adrenomedullin predicts organ failure and mortality in sepsis. Annals of Intensive Care. PubMed
20. [20] Kita T, Kitamura K. (2020). Safety, Tolerability, and Pharmacokinetics of Adrenomedullin in Healthy Males: A Randomized, Double-Blind, Phase 1 Clinical Trial. Drug Design, Development and Therapy. PubMed
21. [21] Laterre PF, Barber SM, Engelman DT, Hagiwara S, et al. (2021). Safety and tolerability of non-neutralizing adrenomedullin antibody adrecizumab (HAM8101) in septic shock patients: the AdrenOSS-2 phase 2a biomarker-guided trial. Intensive Care Medicine. DOI PubMed
22. [22] Karakas M, Ademi E, Gerin F, et al. (2022). Single-dose of adrecizumab versus placebo in acute cardiogenic shock (ACCOST-HH). The Lancet Respiratory Medicine. DOI PubMed
23. [23] Blet A, Deniau B, Geven C, et al. (2022). Adrenomedullin Therapy in Moderate to Severe COVID-19. Biomedicines. DOI PubMed
24. [24] Nishikimi T, Nakagawa Y. (2022). Translational studies of adrenomedullin and related peptides regarding cardiovascular diseases. Hypertension Research. DOI PubMed
25. [25] McLatchie LM, Fraser NJ, Main MJ, et al. (1998). RAMPs regulate the transport and ligand specificity of the calcitonin-receptor-like receptor. Nature. DOI PubMed