Vasoactive Intestinal Peptide

VASOACTIVE INTESTINAL PEPTIDE

Vasoactive intestinal peptide (VIP) is a 28-amino-acid peptide that belongs to the glucagon-secretin family of peptides. VIP is widely distributed in the central and peripheral nervous systems, where it functions as one of the major peptide neurotransmitters. It is present in cholinergic presynaptic neurons in the central ner-vous system, and in peripheral peptidergic neurons innervating diverse tissues including the heart, lungs, gastrointestinal and urogenital tracts, skin, eyes, ovaries, and thyroid gland. Many blood vessels are innervated by VIP neurons. VIP is also present in key organs of the immune system including the thymus, spleen, and lymph nodes. Although VIP is present in blood, where it undergoes rapid degradation, it does not appear to function as a hormone. VIP participates in a wide variety of biologic functions including metabolic processes, secretion of endocrine and exocrine glands, cell differentiation, smooth muscle relaxation, and the immune response.

VIP exerts significant effects on the cardiovascular system. It produces marked vasodilation in most vascular beds and in this regard is more potent on a molar basis than acetylcholine. In the heart, VIP causes coronary vasodilation and exerts positive inotro-pic and chronotropic effects. It may thus participate in the regula-tion of coronary blood flow, cardiac contraction, and heart rate.

The effects of VIP are mediated by G protein-coupled recep-tors; two subtypes, VPAC1 and VPAC2, have been cloned from human tissues. Both subtypes are widely distributed in the central nervous system and in the heart, blood vessels, and other tissues. VIP has a high affinity for both receptor subtypes. Binding of VIP to its receptors results in activation of adenylyl cyclase and formation of cAMP, which is responsible for the vasodilation and many other effects of the peptide. Other actions may be mediated by inositol trisphosphate synthesis and calcium mobilization. VIP can also bind with low affinity to the VIP-like peptide pituitary adenylyl cyclase-activating peptide receptor, PAC1.

VIP analogs with longer half-lives than the native peptide are now available for research use. An example is stearyl-Nle¹⁷-VIP. These drugs have potential as therapeutic agents for cardiovascu-lar, pulmonary, gastrointestinal, and nervous system diseases. They may also be effective in treating various inflammatory diseases and diabetes. Indeed, some VIP derivatives are currently undergoing preclinical and clinical testing for the treatment of type 2 diabetes and chronic obstructive pulmonary disease. Unfortunately, their use is currently limited by several issues including poor oral avail-ability, rapid metabolism in the blood, and hypotension. VIP receptor antagonists are also being developed.