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.
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.
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.
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.