Biological Effects

A wide spectrum of biological effects has been attributed to VIP. Some of these effects are summarized in Table 4.9. Although the full range of VIP functions is still unclear, strong evidence indicates that VIP mediates several basic physiological effects including:

• relaxation of smooth muscle cells

• enhancement of electrolyte and diuresis

• regulation of neuroendocrine and endocrine functions.

Vasoactive intestinal peptide stimulates salt secretion by the mammalian intestine. VIP seems to modulate renal tubular reabsorption, by increasing urine volume, fractional excretion of sodium, chloride and potassium, as well as by os-molar clearance (Rosa et al. 1985).

The effect of VIP in relaxing blood vessels and smooth muscle cells is assumed to be mediated partially by a VIP-induced release of nitric oxide (NO).

Table 4.9 Some actions of VIP

in different organs.

Place of action

Effect

Cardiovascular system

Hypotension, vasodilatation

Liver

Stimulation of water secretion

Pancreas

Release of insulin

Peripheral nervous system

Modulation of the cholinergic transmission

Pituitary, hypothalamus

Release of GH, LH and prolactin

Respiratory system

Bronchodilation, vasodilatation, increased ventilation

Stomach

Suppression of acid production

The suprachiasmatic nucleus (SCN) contains the predominant circadian pacemaker in mammals. Considerable evidence indicates that VPAC(2) and PAC(1), receptors for VIP and PACAP, play critical roles in maintaining and entraining circadian rhythms. Since VIP is expressed diurnally - with high levels during the dark periods - in the ventrolateral portion of the suprachiasmatic nucleus, a brain region responsible for the regulation of circadian rhythms, VIP is considered to play a substantial role in the control of diurnal functions; and VIP signaling between suprachiasmatic neurons is supposed to provide a paracrine reinforcing signal that is essential for sustained rhythm generation. It is thought that the daily VIP rhythm is first generated in the early developed clock-controlled rostral suprachiasmatic neurons and is later regulated by light-dependent neurons of the ventrolateral portion of the suprachiasmatic nucleus (Ban et al. 1997).

Several effects of VIP on sleep have also been described. Central administration of VIP enhances periods of rapid eye movement (REM) and increases the duration of REM sleep. The effects on sleep seem to involve prolactin secretion.

VIP is a well known secretagogue for pituitary prolactin, acting both at the level of both the hypothalamus and the pituitary gland. VIP-mediated prolongation of REM sleep can be prevented by co-administration of antiserum to prolactin.

A wide range of events fundamental to brain development (including cell proliferation, differentiation, neurite outgrowth and neuronal survival) is influenced by VIP. Additionally, VIP is upregulated after neural injury and has potent neuroprotective properties.

VIP also exerts some effects on glia cells. Since VIP expression is confined to neurons and has not been detected in glia, neuroglial communication via VIP seems to be unidirectional.

One prominent glial function influenced by VIP is energy metabolism in astrocytes. VIP (as well as norepinephrine) helps to control local energy homeostasis through the stimulation of glycogenolysis, an effect that occurs within minutes after VIP application in astrocytic cultures (Sorg and Magistretti 1991). Following glycogenolysis, VIP stimulates the resynthesis of glycogen, which peaks at levels which are 5- to 10-fold greater than before treatment. VIP is a neuropeptide that is expressed late in development. In prenatal rat brains, VIP secretion is almost absent, but increases rapidly postnatally, with a maximum about 2 weeks after parturition. In contrast to the delayed appearance of VIP in the brain, VIP-binding sites appear very early in development and are primarily, if not exclusively, localized in the central nervous system.

The presence of abundant VIP-binding sites in early embryonic brains, long before the onset of neuronal VIP expression, indicates that the brain is supplied from peripheral VIP sources during early neurogenesis.

During neurogenesis, VIP stimulates the proliferation and differentiation of brain neurons. The addition of VIP to embryonic mouse spinal cord cultures, for example, was found to increase neuronal survival and activity. Moreover, in vitro studies provide evidence that VIP induces neuronal mitosis and neuronal outgrowth. Blockade of VIP in early postnatal stages can induce neuronal malformation, indicative of some neurogenetic effects of VIP during critical periods of brain development. Interestingly, VIP has neuroprotective effects against exci-totoxic lesions (induced by intracerebral administration of ibotenate) of the developing mouse brain.

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