VIP (vasoactive intestinal peptide) is a 28-amino-acid neuropeptide, first isolated from porcine small intestine by Said and Mutt in 1970, that signals through two class B G protein-coupled receptors — VPAC1 and VPAC2 — and, with lower potency, the PAC1 receptor shared with PACAP. In laboratory research it is used as a reference agonist for studying cAMP-coupled VPAC signaling, suprachiasmatic nucleus circadian synchrony, and cytokine regulation in immune cell cultures. This article reviews the peptide's structure, receptor pharmacology, published preclinical and clinical literature, and handling considerations for VIP supplied as a laboratory reference standard. All information is provided strictly for in-vitro and laboratory research use only. Last reviewed: July 2026.
What Is VIP (Vasoactive Intestinal Peptide)?
VIP is a linear 28-residue peptide. Its published sequence is His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn, with a C-terminal amide.
The peptide was identified in 1970, when Said and Mutt reported in Science the isolation from hog small intestine of a polypeptide producing systemic vasodilation, hypotension, increased cardiac output, and respiratory stimulation — properties chemically distinct from the kinins, substance P, glucagon, and secretin. The name "vasoactive intestinal peptide" reflects that first-described vasodilatory activity, but VIP is now understood to be far more widely distributed than the gut: it is expressed in central and peripheral neurons, including a defined population of suprachiasmatic nucleus (SCN) neurons, and it is present in autonomic nerves innervating airway, vascular, and glandular tissue.
VIP belongs to the secretin/glucagon peptide superfamily and shares approximately 68% sequence identity with PACAP-27, which is the structural basis for its overlapping receptor pharmacology.
Receptor Pharmacology: VPAC1, VPAC2, and PAC1
The current authoritative reference for this receptor family is the IUPHAR Review 1 by Harmar and colleagues, published in the British Journal of Pharmacology in 2012, which formalized the nomenclature used below.
- VPAC1 — binds VIP and PACAP with comparable high affinity. Broadly expressed in lung, intestinal epithelium, liver, T lymphocytes, and CNS.
- VPAC2 — also binds VIP and PACAP with comparable affinity, but has a distinct distribution (SCN, smooth muscle, pancreatic islets, mast cells, subsets of lymphocytes).
- PAC1 — strongly prefers PACAP over VIP, typically by two to three orders of magnitude, and is therefore not the principal VIP receptor.
Structural basis of binding
Structural work has clarified how the peptide engages the receptor. A 2020 report in Nature Communications described a cryo-electron microscopy structure of an activated human VIP1 (VPAC1) receptor–Gs complex, stabilized using a NanoBiT tethering strategy, showing the peptide N-terminus inserted into the transmembrane binding pocket while the C-terminal region is held by the receptor's extracellular domain. This two-domain binding model is characteristic of class B GPCRs and explains why C-terminal truncations of VIP typically collapse affinity.
Published Research Findings
Circadian biology: the most-cited VIP literature
The strongest and most reproducible body of VIP research is in circadian neuroscience. In a 2005 Nature Neuroscience paper, Aton, Colwell, Harmar, Waschek, and Herzog examined SCN neurons from mice lacking either VIP or the VPAC2 receptor. Recording from individual neurons, they reported that VIP signaling is required both to sustain rhythmicity in a substantial fraction of SCN neurons and to maintain synchrony among the neurons that remain rhythmic — and that daily application of a VPAC2 agonist restored rhythmicity and synchrony in VIP-deficient slices. This established VIP as the principal coupling factor of the mammalian master clock and is the reason VIP and VPAC2-selective agonists are standard tools in SCN slice and organotypic culture work.
Immunoregulation
VIP is one of the better-characterized endogenous anti-inflammatory neuropeptides. A 2007 review by Anderson and Delgado in Annals of the Rheumatic Diseases summarizes the mechanistic case: in cultured macrophages and dendritic cells VIP acting through VPAC1/VPAC2 and cAMP/PKA downregulates production of TNF-α, IL-6, IL-12, and nitric oxide while increasing IL-10, and in T-cell systems it biases differentiation toward regulatory phenotypes.
The most direct human evidence for that mechanism comes from a 2010 phase II study by Prasse and colleagues in the American Journal of Respiratory and Critical Care Medicine. In 20 patients with histologically proven active sarcoidosis treated with nebulized VIP for four weeks, TNF-α production by cells isolated from bronchoalveolar lavage fluid was significantly reduced, and the number of BAL CD4⁺CD127⁻CD25⁺ T cells with regulatory activity significantly increased. Parallel in-vitro experiments showed VIP converting naive CD4⁺CD25⁻ T cells into CD4⁺CD25⁺FoxP3⁺ regulatory T cells. This was an open-label study of 20 patients with no placebo arm, so it is best read as mechanistic confirmation rather than efficacy evidence.
Pulmonary vascular biology
In 2003, Petkov and colleagues reported in the Journal of Clinical Investigation that VIP was deficient in serum and lung tissue from patients with primary pulmonary hypertension, and that VIP administration produced pulmonary vasodilation. This finding drove roughly two decades of interest in VIP analogs for pulmonary vascular and inflammatory lung conditions.
The clinical record has been largely negative
An important counterweight for anyone reading VIP literature: the largest rigorous trial of a synthetic VIP (aviptadil) was negative. The NIH-sponsored TESICO trial (part of ACTIV-3b), published in The Lancet Respiratory Medicine in 2023, randomized adults hospitalized with COVID-19-associated acute hypoxaemic respiratory failure to intravenous aviptadil or placebo. The independent data and safety monitoring board recommended stopping the aviptadil comparison in May 2022 for futility, and the published analysis found no evidence that intravenous aviptadil improved the primary 90-day ordinal outcome.
Regulatory status as of 2026
As a freshness marker for readers tracking this field: as of mid-2026, no VIP-based product has received FDA or EMA marketing approval for any indication. Aviptadil holds orphan-drug and fast-track designations in the United States but was never approved, and compounded VIP preparations are not FDA-approved. VIP therefore remains an investigational and unapproved compound whose evidence base is strongest in mechanistic and preclinical work.
Why VIP Is Difficult to Work With: Stability and Half-Life
Any laboratory using VIP should account for its very short biological persistence. In the earliest human pharmacokinetic study — Domschke and colleagues, Gut, 1978 — plasma VIP levels after cessation of intravenous infusion fell by first-order kinetics with an average disappearance half-time of approximately one minute, with an apparent metabolic clearance rate near 9 mL/kg/min and an apparent volume of distribution of roughly 14 mL/kg.
This rapid proteolytic degradation is the central reason the peptide has proven hard to develop, and it is why much of the medicinal-chemistry literature focuses on stabilized analogs: backbone modification, N-methylation, peptide stapling, and long-acting VPAC2-selective agonists. For in-vitro work it means that VIP concentrations in serum-containing media should not be assumed constant over long incubations, and that time-course experiments benefit from independent verification of peptide integrity.
Common Research Applications
In laboratory settings VIP is used chiefly as a reference agonist for VPAC-receptor signaling. Reported application areas include:
- cAMP accumulation and PKA-reporter assays in VPAC1- or VPAC2-expressing cell lines
- SCN slice and dispersed-neuron circadian rhythm studies, typically alongside VPAC2-selective agonists and Vip/Vipr2 knockout controls
- Cytokine profiling in macrophage, dendritic cell, and T-cell cultures (TNF-α, IL-6, IL-12, IL-10 endpoints)
- Smooth-muscle relaxation and vascular tone studies in isolated tissue preparations
- Receptor binding, competition, and selectivity assays against PACAP-27 and PACAP-38
- Structural and biophysical work on class B GPCR two-domain peptide binding
Storage & Handling
Dynamite Research Peptides supplies VIP as a lyophilized powder. Store the sealed vial at −20 °C or below, protected from light and moisture. Reconstitute immediately before use with a sterile solvent as indicated on the Certificate of Analysis (COA), keep reconstituted material refrigerated, and avoid repeated freeze–thaw cycles, which degrade peptide integrity. Because VIP is a basic, protease-sensitive 28-mer, aliquot after reconstitution rather than repeatedly sampling a single vial, and consider low-binding tubes — long, basic peptides can adsorb measurably to standard polypropylene at low working concentrations. Handle with appropriate personal protective equipment in a ventilated laboratory setting.
Conclusion
VIP is a well-characterized 28-amino-acid neuropeptide whose value in research is as a canonical agonist for the VPAC1/VPAC2 receptor pair and as the established coupling signal of the suprachiasmatic nucleus. Its mechanistic literature — cAMP-coupled class B GPCR signaling, Treg induction, cytokine suppression, smooth-muscle relaxation — is deep and reproducible, while its clinical translation record is thin and, in the one large randomized trial, negative. Our VIP is high-purity, third-party tested, and ships with a COA so experimental results stay reliable and reproducible.
Frequently Asked Questions
What is VIP (vasoactive intestinal peptide)?
VIP is a 28-amino-acid neuropeptide isolated from porcine small intestine by Said and Mutt in 1970. It is a member of the secretin/glucagon superfamily and acts as an agonist at the VPAC1 and VPAC2 receptors.
What receptors does VIP act on?
VIP binds VPAC1 and VPAC2 with comparable high affinity, and PAC1 with substantially lower affinity. All three are class B GPCRs that couple primarily to Gs, raising intracellular cAMP.
Can VIP be used to distinguish VPAC1 from VPAC2 effects?
No. VIP is essentially non-selective between VPAC1 and VPAC2, so subtype attribution in the published literature relies on selective agonists or antagonists, receptor knockout or knockdown models, or both.
What is VIP's role in circadian rhythm research?
Work published in Nature Neuroscience in 2005 showed that mice lacking VIP or the VPAC2 receptor have SCN neurons that lose both rhythmicity and synchrony, and that a VPAC2 agonist restores both. VIP is therefore regarded as the principal coupling factor of the mammalian master clock.
Why is VIP considered unstable?
Human pharmacokinetic data published in Gut in 1978 reported a plasma disappearance half-time of about one minute due to rapid proteolytic degradation. This short half-life is the main reason stabilized analogs dominate the medicinal-chemistry literature.
Is VIP an approved drug?
No. As of 2026 no VIP-based product has been approved by the FDA or EMA for any indication. The synthetic VIP aviptadil holds orphan-drug and fast-track designations but was not approved, and the large randomized TESICO trial reported in 2023 was negative.
What is the purity level of Dynamite Research Peptides' VIP?
Our VIP is typically 99%+ pure, verified by HPLC analysis. Detailed purity data is provided on the Certificate of Analysis (COA) included with each product.
What research applications is VIP suitable for?
It is used in VPAC-receptor cAMP signaling assays, suprachiasmatic nucleus circadian studies, immune cell cytokine and regulatory T-cell research, isolated smooth-muscle preparations, and receptor binding and selectivity work against PACAP.
All products are for research use only — not for human or animal consumption, and not for diagnostic or therapeutic use.