VIP (Vasoactive Intestinal Peptide)

Vasoactive intestinal peptide is a 28-residue neuropeptide first isolated from porcine small intestine by Said and Mutt and reported in Science in 1970, where it was characterised as a polypeptide producing systemic vasodilation, hypotension, increased cardiac output and respiratory stimulation, chemically distinct from the kinins, substance P, glucagon and secretin [1]. It belongs to the secretin/glucagon superfamily and is closely related to pituitary adenylate cyclase-activating polypeptide (PACAP). The native peptide is amidated at its C-terminus; the PubChem entry for the synthetic analogue aviptadil lists C147H237N43O43S, 3326.8 g/mol for the free-acid form [7].

Receptors and signalling

The IUPHAR review by Harmar and colleagues describes three class B G-protein-coupled receptors in this system: VPAC1 and VPAC2, which bind VIP and PACAP with comparable affinity, and PAC1, which is selective for PACAP. VPAC1 and VPAC2 couple principally to Gs and raise intracellular cyclic AMP, with additional phospholipase C coupling reported in some systems. Receptor distribution is broad: VPAC1 predominates in lung, intestinal epithelium and many immune cells, VPAC2 in smooth muscle, the suprachiasmatic nucleus and parts of the vasculature [2].

Neuroimmune and pulmonary biology

The review literature on immune function, summarised by Delgado and Ganea, describes VIP as released by both neurons and immune cells and as acting on macrophages, dendritic cells and T-cell subsets, with reported effects on cytokine production and on the balance between inflammatory and regulatory phenotypes in cell and rodent models [3]. In the lung, receptor expression on alveolar type II cells is the basis for the hypothesis that drove COVID-19 trials: that VIP signalling might protect surfactant-producing cells during acute injury.

Physiological range of the peptide

The breadth of the receptor distribution explains the breadth of the reported actions, and also why VIP has resisted development as a drug. It relaxes vascular and airway smooth muscle, stimulates intestinal and pancreatic secretion, contributes to non-adrenergic non-cholinergic neurotransmission in the gut, and acts within the suprachiasmatic nucleus in circadian timing, where VPAC2 signalling synchronises the firing of pacemaker neurons [2]. Pathological overproduction gives a recognised clinical picture: VIP-secreting tumours cause a profuse secretory diarrhoea with hypokalaemia, which is the clearest demonstration of the peptide potency in humans. Any systemic exposure therefore carries obligate cardiovascular and gastrointestinal effects, a constraint that shaped the infusion protocols used in the respiratory trials.

Aviptadil in COVID-19 — what the controlled trials showed

Synthetic VIP, as aviptadil, was tested in COVID-19-associated acute hypoxaemic respiratory failure. The definitive controlled study is TESICO, part of the ACTIV-3b programme, a randomised placebo-controlled trial at 28 US sites published in The Lancet Respiratory Medicine in 2023. It found no evidence that intravenous aviptadil improved clinical outcomes compared with placebo [4]. An accompanying editorial in the same journal, titled as a negative trial for vasoactive intestinal peptide in COVID-19-associated acute hypoxaemic respiratory failure, set the result against the earlier, smaller sponsor-reported studies that had generated interest in the compound [5]. Aviptadil has not been approved for COVID-19 in the United States.

Earlier clinical history

The longest-running clinical use of synthetic VIP is in a combination product for erectile dysfunction, in which aviptadil 25 micrograms is paired with phentolamine mesylate for intracavernosal injection, marketed in several European countries as Invicorp. A 2008 review in BJU International describes the rationale: the VIP component acts mainly on the veno-occlusive mechanism with little effect on arterial inflow, while phentolamine increases arterial inflow [6]. That product is approved in some European jurisdictions and is unrelated to any respiratory indication.

What the research does not establish

The largest, best-controlled respiratory trial of synthetic VIP was negative, so claims that it treats acute lung injury are not supported. Most immunological findings are from cell culture and rodent models and have not been translated into controlled human outcome data. The peptide has a very short circulating half-life and is degraded rapidly, which constrains what any in-vitro observation implies about systemic effects. No controlled human evidence supports use in chronic inflammatory conditions, mould-related illness, chronic fatigue syndromes or cognitive indications, despite frequent claims to that effect outside the peer-reviewed literature.

Format. Supplied as a lyophilised powder in a sealed vial. The certificate of analysis states net peptide content and purity; vial mass includes counter-ion and residual moisture.

Reconstitution. This 28-residue peptide is reconstituted in aqueous diluent; add the diluent slowly down the vial wall and swirl gently until fully dissolved rather than shaking, since agitation promotes aggregation in peptides of this length. Work out volumes with the reconstitution calculator.

Storage. Store the sealed lyophilised vial at −20°C, protected from light, and equilibrate to room temperature before opening. Reconstituted solutions are refrigerated, protected from light and used promptly; VIP is a comparatively labile peptide, so single-use aliquots are preferred to repeated freeze–thaw cycles.

Handling. Maintain aseptic technique, use a fresh needle per withdrawal, and record lot number and reconstitution date on each aliquot. For in-vitro laboratory research only — not for human or veterinary use.