VIP

VIP, short for Vasoactive Intestinal Peptide, is a 28-amino-acid neuropeptide that belongs to the secretin and glucagon superfamily of peptide hormones. It was first isolated from intestinal tissue in the early 1970s, which gave it its name, but it is now known to be produced throughout the body by both neural and lymphoid cells and to be widely distributed in the gut, lungs, and central and peripheral nervous systems ^[1][3]. VIP functions both as a neurotransmitter and as a hormone, and it is a mediator of a remarkably broad range of physiological processes.

VIP exerts its effects by binding two G-protein-coupled receptors, VPAC1 and VPAC2, which are coupled to the adenylate cyclase and cyclic AMP signaling system ^[1]. Through these receptors it acts as a potent systemic and pulmonary vasodilator, a bronchodilator, and a stimulant of secretion, and it plays a homeostatic role in the respiratory system ^[1][2]. Beyond these classical actions, VIP is a major anti-inflammatory and immunomodulatory molecule, sometimes called a neuroimmunopeptide because it links the nervous and immune systems ^[3].

Because of this profile, VIP has been studied as a therapeutic across several fields. In the lungs, inhaled VIP agonists have been investigated for asthma, chronic obstructive pulmonary disease, cystic fibrosis, sarcoidosis, and pulmonary hypertension ^[1][2]. In immunology, VIP has shown therapeutic effects in animal models of autoimmune disease such as rheumatoid arthritis ^[4][5]. VIP is naturally short-lived in the body, so stabilized and inhaled formulations and improved delivery systems have been developed to make it usable as a drug ^[1]. It is not an approved medicine for general use; synthetic VIP is handled as an investigational and compounded peptide, typically administered by inhalation, nasal spray, or injection.

Vasoactive intestinal peptide (VIP) is a signaling peptide used off-label as a nasal spray; it is not an approved therapy for this use, and human safety data outside limited settings are sparse. As a potent vasodilator it can cause flushing, lightheadedness or low blood pressure, headache, and diarrhea. Its long-term safety is not established, and it should be approached cautiously by anyone with cardiovascular or blood-pressure conditions.

Vasoactive intestinal peptide was discovered by Sami I. Said and Viktor Mutt, who first isolated the 28-amino-acid peptide from porcine small intestine in 1970 while searching for vasodilator substances in the gut. It was originally characterized as a systemic and pulmonary vasodilator, and later work established that the human sequence is identical to the porcine form and that VIP is co-synthesized with a related peptide from a shared precursor protein.

Over subsequent decades its biology expanded far beyond digestion to encompass bronchodilation, broad anti-inflammatory and immune-regulating actions, and a defining role as the principal synchronizing signal of the suprachiasmatic nucleus, the brain's master circadian clock. The synthetic analogue aviptadil advanced into clinical study for pulmonary hypertension and, more recently, COVID-19 respiratory failure, though large randomized trials such as TESICO did not establish a clear survival benefit.

VIP is widely respected as a strikingly pleiotropic, homeostatic regulator that touches neural, immune, vascular, and reproductive systems, and it remains a heavily investigated biological signal more than half a century after its discovery. Researchers are drawn to its dual identity as both a potent vasodilator and bronchodilator and a broadly anti-inflammatory neuroimmunopeptide that can steer immune responses toward tolerance.

Its therapeutic appeal was sharpened by the finding that patients with primary pulmonary hypertension are deficient in VIP, framing treatment as replacing a missing endogenous hormone. The honest counterpoint is that much of the therapeutic evidence remains early-stage, its short half-life complicates delivery, and the large aviptadil trials in COVID-19 were inconclusive; nonetheless its rich, homeostatic pharmacology keeps it a compelling subject of ongoing study.