Newly Discovered Peptide in Cardiovascular Field: A "New Weapon" for Blood Pressure Reduction and Cardioprotection—Alamandine-(1-5)
Alamandine-(1–5) (abbreviated as Ala-(1–5)) is a novel endogenous pentapeptide recently discovered within the protective axis of the Renin-Angiotensin System (RAS). Its sequence is Ala-Arg-Val-Tyr-Ile. This peptide is generated by the hydrolysis of the C-terminal His-Pro from Alamandine (Ala-Arg-Val-Tyr-Ile-His-Pro) by Angiotensin-Converting Enzyme (ACE) and has been detected in human and rodent plasma (concentration range 0.2–8.7 pg/mL), confirming its identity as a circulating endogenous bioactive peptide.
- Biosynthetic Pathway and Metabolic Characteristics
Ala-(1–5) is primarily generated through two pathways: first, direct hydrolysis of Alamandine by ACE; second, decarboxylation of Ang II to Ang A, followed by its conversion to Alamandine by ACE2, and finally cleavage by ACE to yield Ala-(1–5). ACE inhibitors (e.g., captopril) can completely block its generation, indicating the central role of ACE in this process. Notably, the generation of Ala-(1–5) is extremely rapid, completing conversion in plasma within just 1–3 minutes.
- Unique Multi-Receptor Activation Mechanism
The most significant feature of Ala-(1–5) is its ability to simultaneously activate three receptors of the protective RAS axis: the Mas receptor (IC₅₀ ≈ 1 nmol/L), the MrgD receptor (IC₅₀ ≈ 3 nmol/L), and the AT₂ receptor (IC₅₀ ≈ 100 nmol/L). In cell experiments using cells transfected with these receptors, Ala-(1–5) can stimulate nitric oxide (NO) release, an effect that can be blocked by specific receptor antagonists. Its action exhibits tissue specificity: for example, its contractile effect in aortic rings depends on the MrgD and AT₂ receptors, while its vasodilatory effect in mesenteric microvessels primarily relies on the AT₂ receptor.
- Diverse Biological Functions
- Cardiovascular Regulation:
In the aorta and mesenteric microvessels of spontaneously hypertensive rats (SHR), Ala-(1–5) induces concentration-dependent vasodilation (effective at pM levels), an effect dependent on the NO pathway.
Conversely, it causes contraction in mouse aortic rings, and this contractile effect is enhanced after endothelium removal or NO synthesis inhibition.
- Cardiac Suppressive Effects:
In isolated cardiomyocytes, Ala-(1–5) significantly reduces contraction amplitude, rate, and calcium transient amplitude.
In the Langendorff-perfused heart model, this peptide reduces left ventricular systolic pressure and the rate of contraction, and decreases cardiac output in SHR (by approximately 30%).
- Central Nervous System Modulation:
Intracerebroventricular injection of Ala-(1–5) improves baroreflex sensitivity in SHR, but microinjection into the insular cortex only increases blood pressure without affecting heart rate or sympathetic nerve activity, showing significant differences from its precursor Alamandine.
- Sex-Specific Antihypertensive Effect:
In male SHR, a single intravenous injection of Ala-(1–5) (30 µg/kg) produces a lasting blood pressure-lowering effect (≈30 mmHg, lasting 6 hours), but this response is absent in female SHR, suggesting that estrogen may regulate its effect.
- Application Potential and Future Directions
As the first endogenous peptide confirmed to simultaneously target the Mas, MrgD, and AT₂ receptors, Ala-(1–5) offers new avenues for treating diseases such as hypertension and heart failure. Its tissue-specific effects reveal the complexity of the RAS network, particularly the "bidirectional regulatory" role of ACE in degrading active peptides while generating new active molecules. Future research needs to further investigate its physiological significance, the mechanisms behind sex differences, and its local actions in tissues such as the kidney and lungs.
In summary, the discovery of Ala-(1–5) expands our understanding of the protective axis of the RAS. Its multi-receptor activation characteristics and tissue-specific functions provide a potential new target for the precise treatment of cardiovascular diseases.
Original Article：
【1】Chappell MC. Alamandine-(1-5): The New Peptide of the Alternative Renin-Angiotensin System? Circ Res. 2026 Jan 2;138(1):e327777.
【2】Santos RAS, Dias MTS, Bessa ASM, etc. Identification and Characterization of Alamandine-(1-5), a New Component of the Renin-Angiotensin System. Circ Res. 2026 Jan 2;138(1):e326174.