What Is VIP? The Gut Peptide That Is Really a Neurotransmitter

Guides · Gut and nervous-system peptides

VIP, or vasoactive intestinal peptide, is a 28-amino-acid signalling molecule that relaxes smooth muscle, opens blood vessels and drives secretion in the gut and airways. Its name is also slightly misleading. VIP was found in intestinal extracts, so it got filed with the gut hormones, but it does not behave like a hormone at all. It works as a locally released neurotransmitter, and the only time it circulates like a hormone is when a tumour forces it to – which produces one of the more dramatic syndromes in endocrinology.

What is VIP?

VIP is encoded by the VIP gene on chromosome 6q25.2. The gene produces a 170-residue precursor that is cut into VIP itself and two related peptides, PHM-27 and PHV-42. Mature VIP is 28 residues long, ending in an asparagine amide, and its sequence is identical in humans, mice and rats – an unusual degree of conservation that suggests the molecule is doing something the body cannot easily tolerate changes to.

VIP was isolated from hog small intestine by Sami Said and Viktor Mutt, and reported in Science in 1970. The original abstract lists what struck them about it: systemic vasodilation, a fall in blood pressure, increased cardiac output, respiratory stimulation and a rise in blood glucose. It also states plainly that the new peptide was chemically distinct from the kinins, substance P, glucagon and secretin. The full sequence followed in the early 1970s.

VIP belongs to what is usually called the secretin superfamily, alongside PACAP, secretin, glucagon, GLP-1, GLP-2, GIP and GHRH. Its closest relative by far is PACAP, with which it shares roughly 68 percent sequence identity – close enough that the two peptides share receptors, which is where a lot of the interesting pharmacology lives.

Why VIP is not really a hormone

The cleanest evidence is the concentration. A hormone is defined by travelling through the blood to reach a distant target, and it has to be present in the blood at concentrations high enough to do something there. Normal plasma VIP sits below 20 pmol/L, roughly 70 pg/mL – low enough that circulating VIP is not plausibly the main way the molecule works.

Instead VIP is released from nerve terminals onto the tissue immediately next to them. It is a major transmitter of the enteric nervous system, it is found in nerves supplying the airways and blood vessels, it is expressed in the suprachiasmatic nucleus of the hypothalamus, and it is made by immune cells. This is neurotransmitter behaviour, not endocrine behaviour, and it explains why VIP shows up in so many apparently unrelated physiological stories.

What VIP does

The through-line is relaxation and secretion. In the gut, VIP is a principal transmitter of the non-adrenergic, non-cholinergic inhibitory nerves, working alongside nitric oxide to relax smooth muscle, including sphincters, and to drive intestinal fluid secretion. In the airways, that same inhibitory pathway is the only neural bronchodilator system humans have. In blood vessels it produces vasodilation, which is what gave the peptide the “vasoactive” in its name.

Two other roles are worth knowing. In the suprachiasmatic nucleus, VIP signalling through the VPAC2 receptor is essential for keeping the body clock coherent; mice lacking VPAC2 cannot sustain normal circadian rest and activity rhythms and lose the circadian expression of core clock genes. And in the immune system VIP is broadly immunomodulatory, with VPAC1 expressed constitutively on several immune cell types while VPAC2 appears on activation.

The disease that proves the point about relaxation and secretion is achalasia, where the inhibitory myenteric neurons containing VIP and nitric oxide synthase are lost. Without them the lower oesophageal sphincter has nothing telling it to relax.

Three receptors, shared two ways

VIP and PACAP act through three class B G-protein-coupled receptors, all of which couple to Gs and raise cyclic AMP. VPAC1 and VPAC2, encoded by VIPR1 and VIPR2, bind VIP and both PACAP forms with comparable affinity. PAC1, encoded by ADCYAP1R1, is the odd one out: PACAP is at least a hundred times more potent there than VIP.

The naming reflects this. VPAC stands for VIP and PACAP receptor, because the two peptides genuinely share those. PAC1 is PACAP’s receptor. As with most clean pharmacological divisions there is a caveat, and IUPHAR states it directly: at least one splice variant of the human PAC1 receptor has been reported to respond to VIP with affinity comparable to PACAP.

This receptor overlap is the reason it is difficult to attribute an effect to VIP rather than PACAP in tissue where both are present, and it is also why selective VPAC2 agonists have been of interest as a way to isolate one branch of the biology.

VIPoma: what happens when VIP does circulate

A VIPoma is a neuroendocrine tumour that secretes VIP into the bloodstream. The clinical picture is severe watery secretory diarrhoea, potassium loss and metabolic acidosis, reduced gastric acid, and flushing. It is known by two other names in the older literature, Verner-Morrison syndrome and WDHA syndrome, the latter standing for watery diarrhoea, hypokalaemia and achlorhydria.

About three quarters of VIPomas sit in the pancreas, where they account for roughly 0.6 to 1.5 percent of pancreatic neuroendocrine neoplasms. Median age at presentation is around 50. In children and young adults, VIP-secreting neuroblastoma and related tumours are the more likely source. Pancreatic VIPomas can occur in MEN1, but the association is often overstated: they are present in fewer than 1 percent of MEN1 patients.

Plasma VIP is elevated in every patient with the syndrome, and in one series of 52 pancreatic VIPoma patients the median was 188 pmol/L against a normal ceiling around 20. Causality is not in doubt here, because healthy volunteers given porcine VIP developed secretory diarrhoea within hours. Management begins with replacing fluid and electrolytes, and somatostatin analogues such as octreotide and lanreotide reduce both the flushing and the diarrhoea – a nice illustration of somatostatin as the body’s general-purpose off switch.

Why VIP is a hard drug target

Two properties work against it. The first is speed: VIP’s half-life in plasma is under a minute, which means any therapeutic use needs either continuous infusion or serious engineering. The second is that its most prominent action, vasodilation and a fall in blood pressure, is intrinsic to the molecule rather than an incidental off-target effect. It was one of the first things Said and Mutt described in 1970. A drug whose headline pharmacology is hypotension is difficult to give to patients who are already unstable.

Aviptadil, and a lesson in reading evidence

Aviptadil is synthetic VIP, and during the COVID-19 pandemic it was promoted as a treatment for COVID-related respiratory failure under the names RLF-100 and Zyesami. Company announcements described large survival benefits. Those announcements were not peer-reviewed.

The NIH-run randomised trial, ACTIV-3b / TESICO, enrolled 473 patients across 28 US sites between April 2021 and May 2022. For the day-90 clinical outcome the odds ratio was 1.11 with a p-value of 0.54. Cumulative mortality at 90 days was 38 percent on aviptadil against 36 percent on placebo. The day-5 safety composite was numerically worse on aviptadil, at 63 percent against 56 percent, though not significantly so. The data monitoring board recommended stopping the aviptadil comparison for futility on 25 May 2022.

No aviptadil product has been approved by the FDA for any respiratory indication, and no positive confirmatory trial has been published since. Aviptadil combined with phentolamine is a different matter: as an intracavernosal injection for erectile dysfunction it is approved in some European markets, including the UK, where it is accepted for restricted use in men who have not responded to oral PDE5 inhibitors. That is a separate product with a separate route and indication, and it tells you nothing about the respiratory programme.

Frequently asked questions

Is VIP the same as PACAP?

No, but they are close relatives, sharing roughly 68 percent of their sequence and two of their three receptors. The practical difference is PAC1, which PACAP activates far more potently than VIP does. Our PACAP explainer covers the other side of the pair.

Why is VIP measured in blood tests if it is not a hormone?

Precisely because a high level is abnormal. Plasma VIP is part of the gut-hormone panel used when a neuroendocrine tumour is suspected, and its diagnostic value comes from the fact that VIP should not be circulating at meaningful concentrations in the first place.

Is VIP available as a peptide product?

Aviptadil, the synthetic form, exists as a pharmaceutical in some markets for erectile dysfunction, and has been trialled intravenously for respiratory failure without success. There is no approved VIP product for general use, and VIP’s sub-minute half-life makes it a poor candidate for anything outside a controlled clinical setting. Nothing here is a recommendation to obtain or use it.

What does the “vasoactive” in the name refer to?

Systemic vasodilation and a drop in blood pressure, which were among the first effects described when the peptide was isolated in 1970. The same property is a large part of why it has been difficult to develop as a drug.

Informational only – not medical advice · 21+. VialHelp does not sell peptides and does not recommend any product, brand or protocol. Nothing on this page describes a treatment.