Apelin
The body's own APJ-receptor peptide: it widens arteries and helps the kidneys shed salt in short human infusion studies, but no apelin drug exists
Apelin is a family of peptides cut from a 77-amino-acid precursor, isolated in 1998 as the natural ligand of the APJ receptor. In short research infusions, [Pyr1]apelin-13 widened arteries through nitric oxide and, in chronic kidney disease, lowered blood pressure and raised kidney blood flow and sodium excretion. It is not an approved drug.
What is it?
Apelin was found in 1998 by researchers searching for the natural partner of APJ, an orphan receptor. They isolated it from bovine stomach extracts and deduced a 77-amino-acid precursor from which the active peptides are cut, the best studied being apelin-36 and the 13-amino-acid form, often with a pyroglutamate at its start, [Pyr1]apelin-13.
Its human evidence comes from infusion studies in Edinburgh. In healthy volunteers, apelin-36 and [Pyr1]apelin-13 widened forearm arteries but not veins, an effect that depended on nitric oxide. In patients with chronic heart failure, forearm vasodilatation to apelin was preserved while the response to acetylcholine was blunted, and apelin-36 injected into a coronary artery increased coronary blood flow. In a 2024 randomised, double-blind trial in chronic kidney disease, [Pyr1]apelin-13 lowered blood pressure by about 4% and vascular resistance by about 12%, raised cardiac output by about 10%, and increased kidney blood flow and sodium excretion.
The infusion work extends beyond the heart. In 19 patients with pulmonary arterial hypertension, [Pyr1]apelin-13 lowered pulmonary vascular resistance and raised cardiac output during catheterisation, and in overweight men a two-hour infusion improved insulin sensitivity during a clamp. Both were single-session studies.
The step from infusion to pill has not worked yet. The oral agonist AMG 986 was well tolerated up to 650 mg a day but showed no clinically meaningful effect in heart failure, and a 2026 review describes setbacks with oral APJ agonists more broadly. Animal work continues, with an analogue reversing severe pulmonary hypertension in rodents and apelin slowing cyst growth in polycystic kidney disease in mice.
Measured in the blood, it is less informative: in advanced heart failure, apelin levels did not predict outcomes, while NT-proBNP did. In mice it has been studied for age-related muscle loss. Apelin itself is a research peptide, not a medicine; the kidney trial's authors argue for trials of long-acting oral apelin agonists instead. As a stroke marker, high early levels went with 52% 28-day mortality against 10% in one study, and it was a poor test for distinguishing types of diabetes insipidus.
Mechanism of Action
Apelin is an endogenous peptide cut from a 77-amino-acid precursor that activates the APJ receptor, widening arteries and increasing the heart's output.
Arterial vasodilation
Apelin widened forearm arteries but not veins in volunteers, through nitric oxide, and lowered vascular resistance in kidney disease and PAH.
Cardiac output
Infusions raised cardiac output and coronary blood flow, including in heart failure patients.
Insulin sensitivity
A two-hour infusion improved insulin sensitivity in overweight men during a glucose clamp.
Published Research
The studies behind apelin, read from their PubMed abstracts.
Chronic kidney disease: randomised, double-blind infusion
Compared with placebo, 30 nmol/min [Pyr1]apelin-13 lowered mean arterial pressure by about 4% and vascular resistance by about 12% and raised cardiac index by about 10%; both doses increased renal blood flow by about 15%, sodium excretion by about 20% and free water clearance by about 10%. In kidney disease only, proteinuria fell by about 25%.
Heart failure patients and volunteers
In randomised, double-blind studies in 18 patients with chronic heart failure, 6 undergoing angiography and 26 volunteers, [Pyr1]apelin-13 widened forearm vessels in patients and controls, and the response was not blunted in heart failure, unlike acetylcholine's; intracoronary apelin-36 increased coronary blood flow.
Arteries, not veins
Apelin-36 and [Pyr1]apelin-13 had no effect on hand-vein diameter but reproducibly widened forearm resistance arteries; blocking nitric oxide attenuated the effect of [Pyr1]apelin-13, while aspirin did not.
Blood apelin does not predict heart-failure outcomes
In patients with advanced heart failure, those above and below the median apelin level reached the primary endpoint at similar rates (16% against 17%); NT-proBNP was the strongest prognostic marker.
Pulmonary arterial hypertension
In a double-blind crossover study of 19 patients with PAH during right heart catheterisation, intravenous [Pyr1]apelin-13 lowered pulmonary vascular resistance and raised cardiac output, more so in those on a PDE5 inhibitor.
Insulin sensitivity in overweight men
In 16 overweight men, a 2-hour [Pyr1]apelin-13 infusion during an insulin clamp improved insulin sensitivity at 30 nmol/kg, with a borderline effect at 9 nmol/kg and no side effects seen.
AMG 986, an oral apelin agonist
In healthy subjects and heart failure patients, the small-molecule apelin receptor agonist AMG 986 was well tolerated up to 650 mg a day, but produced no clinically meaningful effects in heart failure.
Not a test for diabetes insipidus
In 38 patients with polyuria-polydipsia, apelin fell more with hypertonic saline in primary polydipsia than in AVP deficiency, but it distinguished the two far worse than copeptin (AUC 49% to 61% against 97%).
Empagliflozin in chronic SIAD
In 14 patients with chronic syndrome of inappropriate antidiuresis, empagliflozin did not change apelin or the apelin/copeptin ratio but raised copeptin.
Stroke mortality
In ischaemic cerebrovascular disease, apelin at or above 70.47 pg/mL in the first 24 hours went with 52.2% 28-day mortality against 10.0% below it.
Fetal growth restriction
Maternal apelin did not predict outcomes in early-onset fetal growth restriction, but placental apelin expression was lower in those delivering preterm.
Exercise in obese women
In 24 obese middle-aged women, aerobic and resistance training reduced weight and body fat and changed apelin-12 levels.
Ageing muscle
Apelin production, induced by muscle contraction, fell with age in humans and rodents; mice lacking apelin or its receptor had marked loss of muscle function with age, and restoring apelin signalling improved muscle function in old mice.
Apelin and Elabela in heart disease
The review summarises apelin-APJ signalling across heart and vascular disease and notes that evidence for apelin analogues as treatments remains limited.
Why heart failure translation stalled
A 2026 review notes setbacks with orally active APJ agonists and points to pharmacokinetics, altered receptor biology in advanced disease and poor patient selection as challenges.
An analogue in severe PAH
In a severe rodent model, an apelin analogue reversed pulmonary vascular remodelling and right heart failure and nearly normalised pulmonary pressures, rebalancing BMPR2 and TGF-β receptor signalling.
Polycystic kidney disease
In mice with polycystic kidney disease, apelin inhibited cyst growth and improved kidney function.
Dosing Data
Apelin is a research peptide. Human studies infused [Pyr1]apelin-13 intravenously for single sessions.
Educational information, not medical advice. Each dose above is tagged with its source: an approved label, a published human study, animal data, or amounts reported by users. None is a recommendation for you. An unapproved compound has no established safe or effective human dose, and products sold for “research use only” are not made or tested for people. Talk to a doctor before acting on anything on this site, including before you start, stop or change any medicine or dose. Full medical disclaimer.
Side Effects & Contraindications
Reported Side Effects
From the human infusion studies, which were short.
Contraindications & Cautions
Apelin is not a medicine. These cautions follow from the evidence.
Legal Status
Apelin is a research peptide with no approval anywhere.
Frequently Asked Questions
?What does apelin do?
It is the natural ligand of the APJ receptor. In human infusion studies it widened arteries through nitric oxide and, in kidney disease, lowered blood pressure and increased kidney blood flow and sodium excretion.
?Is apelin a treatment for heart failure?
Not yet. Short infusions had favourable effects on blood vessels and heart function, but no apelin drug has been approved, and blood apelin levels did not predict outcomes in advanced heart failure.
?Is apelin approved?
No. It is a research peptide; FDA's Drugs@FDA database and EMA's register have no entry for it.
?Has apelin been tried for pulmonary hypertension?
Only in a single-session study: in 19 patients with PAH, [Pyr1]apelin-13 lowered pulmonary vascular resistance and raised cardiac output during catheterisation. An analogue reversed severe PAH in rodents.
?Are there apelin pills?
Oral APJ agonists have been tested. AMG 986 was well tolerated in healthy people and heart failure patients but produced no clinically meaningful effect, and a 2026 review describes setbacks with this approach.
References
- [pubmed] Chapman FA, et al. "Cardiovascular and renal effects of apelin in chronic kidney disease: a randomised, double-blind, placebo-controlled, crossover study." Nat Commun, 2024;15(1):8387. PMID: 39402039.
- [pubmed] Japp AG, et al. "Acute cardiovascular effects of apelin in humans: potential role in patients with chronic heart failure." Circulation, 2010;121(16):1818-27. PMID: 20385929.
- [pubmed] Japp AG, et al. "Vascular effects of apelin in vivo in man." J Am Coll Cardiol, 2008;52(11):908-13. PMID: 18772060.
- [pubmed] Dalzell JR, et al. "Do plasma concentrations of apelin predict prognosis in patients with advanced heart failure?." Biomark Med, 2014;8(6):807-13. PMID: 25224937.
- [pubmed] Vinel C, et al. "The exerkine apelin reverses age-associated sarcopenia." Nat Med, 2018;24(9):1360-1371. PMID: 30061698.
- [pubmed] Gao S, et al. "Therapeutic potential of apelin and Elabela in cardiovascular disease." Biomed Pharmacother, 2023;166:115268. PMID: 37562237.
- [pubmed] Tatemoto K, et al. "Isolation and characterization of a novel endogenous peptide ligand for the human APJ receptor." Biochem Biophys Res Commun, 1998;251(2):471-6. PMID: 9792798.
- [fda] FDA. Drugs@FDA (openFDA): no application for apelin. Read September 30, 2026.
- [other] European Medicines Agency. Medicines register: no entry for apelin. Read September 30, 2026.
- [pubmed] Brash L, et al. "Short-Term Hemodynamic Effects of Apelin in Patients With Pulmonary Arterial Hypertension." JACC Basic Transl Sci, 2018;3(2):176-186. PMID: 29876530.
- [pubmed] Gourdy P, et al. "Apelin administration improves insulin sensitivity in overweight men during hyperinsulinaemic-euglycaemic clamp." Diabetes Obes Metab, 2018;20(1):157-164. PMID: 28681996.
- [pubmed] Winkle P, et al. "A First-in-Human Study of AMG 986, a Novel Apelin Receptor Agonist, in Healthy Subjects and Heart Failure Patients." Cardiovasc Drugs Ther, 2023;37(4):743-755. PMID: 35460392.
- [pubmed] Alfonso DM, et al. "The Apelin-APJ Axis in Heart Failure: Mechanistic Insights, Clinical Evidence, and Translational Challenges." Cardiovasc Drugs Ther, 2026. PMID: 42455245.
- [pubmed] Bizzozero CA, et al. "Apelin levels in patients with polyuria-polydipsia syndrome upon copeptin stimulation tests." Eur J Endocrinol, 2024;191(5):491-498. PMID: 39425917.
- [pubmed] Monnerat S, et al. "Apelin and Copeptin Levels in Patients With Chronic SIAD Treated With Empagliflozin." J Endocr Soc, 2024;8(7):bvae106. PMID: 38872994.
- [pubmed] Işık K, et al. "The Role of High Serum Apelin Levels Within the First 24 h in Predicting 28-Day and Long-Term Mortality in Ischemic Cerebrovascular Disease." J Clin Med, 2026;15(16). PMID: 42652872.
- [pubmed] Braun N, et al. "Placental apelin expression is low in early-onset fetal growth restriction but there is no association between maternal circulating apelin and pregnancy outcome." Placenta, 2026;181:26-36. PMID: 42061341.
- [pubmed] Jang SH, et al. "Effects of aerobic and resistance exercises on circulating apelin-12 and apelin-36 concentrations in obese middle-aged women: a randomized controlled trial." BMC Womens Health, 2019;19(1):23. PMID: 30696454.
- [pubmed] Vu J, et al. "Apelin analog treatment reverses severe pulmonary arterial hypertension and right ventricular heart failure." JCI Insight, 2026;11(15). PMID: 42313476.
- [pubmed] Nyimanu D, et al. "Apelin inhibits cyst growth and improves kidney function in mice with polycystic kidney disease." bioRxiv, 2026. PMID: 41958979.
Sources & Citations
Studies were read from their PubMed abstracts; apelin has no label. Read October 7, 2026.
Medical Disclaimer: This content is for educational and informational purposes only. It is not medical advice, and nothing here is an instruction to obtain or use any compound. Talk to a licensed clinician about your own situation.