VIP

VIP (vasoactive intestinal peptide), also written vasoactive intestinal polypeptide, is a 28-amino-acid neuropeptide. Said and Mutt isolated it from hog small intestine in 1970 and reported systemic vasodilation, a fall in blood pressure, increased cardiac output, respiratory stimulation and raised blood glucose (Said and Mutt, 1970).

It belongs to the secretin/glucagon superfamily and signals through two class B G protein-coupled receptors, VPAC1 and VPAC2, which respond to VIP and PACAP with high affinity; a third, PAC1, is selective for PACAP (Harmar et al., 2012). The human precursor also carries a second, 27-residue peptide, PHM-27 (Itoh et al., 1983).

The sequence and C-terminal amide are from UniProt P01282; formula and weight are for the amidated peptide, PubChem CID 16140438. The PubChem records holding both CAS numbers draw a free acid instead (C₁₄₇H₂₃₇N₄₃O₄₃S, 3326.8 g/mol).

Published work on VIP falls into five areas; each summary names its model. Mechanistic evidence comes mostly from knockout mice and tissue preparations, and human studies appear as research history, with findings as the papers reported them.

Immune and inflammatory signaling

In DBA mice with experimental arthritis, VIP reduced the incidence and severity of arthritis and abolished joint swelling and cartilage and bone destruction, with downregulation of both inflammatory and autoimmune components (Delgado et al., 2001). In an open-label phase II study, all 20 participants, people with active sarcoidosis, inhaled nebulized VIP for four weeks. Bronchoalveolar lavage cells produced less TNF-alpha and regulatory CD4+CD127-CD25+ T cells increased, and in culture VIP converted naive CD4+CD25- T cells into CD4+CD25+FoxP3+ regulatory T cells (Prasse et al., 2010). Models: mice, T cells in culture and one small open human study.

Airway and pulmonary research

VIP is a co-transmitter of airway relaxation with nitric oxide. Mice lacking the VIP gene spontaneously showed airway hyperresponsiveness to methacholine, with cell infiltrates and higher inflammatory cytokines in lavage fluid; VIP given intraperitoneally for two weeks virtually eliminated the hyperresponsiveness and reduced airway inflammation in sensitized and challenged knockout mice (Szema et al., 2006).

In 20 people with pulmonary hypertension, one inhalation of aviptadil during right-heart catheterization caused small, temporary but significant selective pulmonary vasodilation without changing systemic blood pressure, an effect the authors called modest and short-lived (Leuchte et al., 2008). Models: knockout mice and one acute human study.

Circadian timing in the suprachiasmatic nucleus

The suprachiasmatic nucleus (SCN) is the mammalian master circadian pacemaker. Mice lacking the VPAC2 receptor could not sustain normal rest/activity rhythms, lost circadian expression of mPer1, mPer2, mCry1 and arginine vasopressin in the SCN, and failed to induce mPer1 and mPer2 in response to light at night (Harmar et al., 2002).

In VIP-deficient and VPAC2-deficient mice, about half of SCN neurons lost circadian firing rhythms and rhythmic neurons fell out of synchrony; daily application of a VPAC2 agonist restored rhythmicity and synchrony in VIP-deficient neurons but not in VPAC2-deficient ones (Aton et al., 2005). Models: knockout mice and their SCN neurons; animal data only.

Gut secretion and VIPoma

In rabbit ileal mucosa, VIP raised cyclic AMP about fivefold and drove net chloride and sodium secretion, with a similar cyclic AMP rise in human ileal mucosa (Schwartz et al., 1974). VIP was elevated in plasma, tissue or both in 28 of 30 people with chronic watery diarrhea, whose tumors included pancreatic islet-cell adenomas and bronchogenic carcinomas, and the authors called it a probable mediator of the watery-diarrhea syndrome (Said and Faloona, 1975); VIP-secreting tumors are known as VIPomas.

In five healthy volunteers, a 10-hour infusion raised plasma VIP into the syndrome's range, and every subject developed profuse secretory diarrhea; fecal bicarbonate loss caused hyperchloremic metabolic acidosis (Kane et al., 1983). Models: rabbit and human gut tissue, human samples and one infusion study.

Aviptadil clinical history

In a placebo-controlled trial at 10 US hospitals, 196 people with COVID-19 respiratory failure were randomized 2:1 to three days of intravenous aviptadil or placebo. The primary endpoint, alive and free of respiratory failure at day 60, did not reach statistical significance (odds ratio 1.6, 95% CI 0.86 to 3.11); the authors also reported two-fold odds of survival at day 60 (p = 0.035), and one author listed an NRx Pharmaceuticals affiliation (Youssef et al., 2022). The NIH-funded TESICO trial randomized adults with COVID-19 hypoxemic respiratory failure at 28 US sites to intravenous aviptadil or placebo.

Among 461 participants, the odds ratio for a better day-90 recovery category was 1.11 (95% CI 0.80 to 1.55, p = 0.54). Deaths by day 90 were 38 percent with aviptadil and 36 percent with placebo, and a day-5 composite of death and serious adverse outcomes was 63 and 56 percent, respectively (p = 0.10).

The monitoring board recommended stopping the aviptadil comparison for futility (Brown et al., 2023). In a randomized, double-blind trial at nine centers, 80 hospitalized adults with COVID-19 received inhaled aviptadil or placebo; time to discharge, the primary endpoint, was 7.8 days with aviptadil versus 10 with placebo (p = 0.049) (Esendagli et al., 2025). Models: human randomized trials.