J.E.T. Fox-Threlkeld

Peptide YY stimulates circular muscle contractions of the isolated perfused canine ileum by inhibiting nitric oxide release and enhancing acetylcholine release

Peptide YY (PYY) and neuropeptide Y (NPY), infused into the quiescent isolated perfused canine ileum, dose-dependently increased phasic activity of the circular muscle and decreased tonic output of immunoreactive vasoactive intestinal peptide (VIP) in the venous effluent. The contractions subsided before the prolonged inhibition of VIP output. Motor excitation by PYY, an abundant neuropeptide in this tissue, was reduced by blockade of muscarinic or nicotinic receptors, or inhibition of nitric oxide (NO) synthase, despite continued inhibition of VIP output. A combination of atropine and hexamethonium eliminated the PYY-induced decrement in VIP output and left motor excitation unchanged. Blockade of NO synthase eliminated motility increases under these conditions. Intracellular microelectrode recordings of myenteric plexus-free circular muscle strips found no effect of NPY on the resting membrane potential, or on the field stimulation-induced inhibitory junction potential. Inhibition of VIP release plays no essential role in changing motility. These results suggest that PYY/NPY induce motility by stimulating release of acetylcholine and inhibiting NO release at a locus proximal to but not on nerve terminals.

Galanin inhibition of vasoactive intestinal polypeptide release and circular muscle motility in the isolated perfused canine ileum

The role of porcine galanin, infused arterially into isolated perfused canine ileal segments, in modulating the tonically elevated neural release of vasoactive intestinal polypeptide and possible concomitant motor actions dependent on vasoactive intestinal polypeptide modulation was studied. Galanin infusions (9-minute) inhibited vasoactive intestinal polypeptide release in a concentration-dependent manner (maximum during minutes 8-10) irrespective of the absence (quiescence) or presence of phasic circular muscle contractions induced by local electrical field stimulation of nerves. During quiescence, galanin induced phasic contractions in four of five segments beginning in the 8th minute of the infusion. During stimulated contractions, galanin inhibited phasic motor activity within 2 minutes of initiation of the infusion; this inhibition may result from direct smooth previously reported muscle inhibition. Thus galanin may inhibit both neural release of vasoactive intestinal polypeptide and circular muscle motility directly. The delayed period of phasic activity initiated by galanin during quiescence may be related to inhibition of vasoactive intestinal polypeptide release, freeing the muscle from tonic inhibition by vasoactive intestinal polypeptide. Because galanin and vasoactive intestinal polypeptide are colocalized in some enteric nerves, galanin may regulate vasoactive intestinal polypeptide release by negative feedback.

Stimulation of circular muscle motility of the isolated perfused canine ileum: Relationship to VIP output

Perfusion of ileal segments with tetrodotoxin; opioids, Met-enkephalin and dynorphin; and alpha 2 adrenoceptor agonist, BHT920, increased motility concomitant with the decreased VIP output into the venous effluent reported previously. This suggested that increased motility resulted from release of the muscle from tonic inhibition when VIP output was reduced sufficiently. However, blockade of nicotinic receptors also reduced VIP output but did not induce motility. Thus release of myogenic activity from inhibition is not a sufficient explanation for increased motility and a further excitatory mediator is required. Field stimulation of nerves increased VIP output and delayed distal contractions, suggesting that VIP does participate in the canine ileal distal inhibition reflex.

Mechanism of noncholinergic excitation of canine ileal circular muscle by motilin

In the isolated perfused canine ileal segment, exogenous motilin infused for 9 min, at concentrations from 10(-10) M and 10(-8) M, increased circular muscle motility concomitant with inhibiting tonic VIP release, maximum at 10(-8) M. Both effects increased with increasing motilin concentrations. Atropine 10(-7) M pretreatment did not alter these responses. Naloxone 10(-7) M pretreatment eliminated both the increase in motor activity and the inhibition of VIP levels. Thus the nonmuscarinic neural pathway responsible for motor activation by motilin probably involves the stimulation of release of opiates, which in turn inhibit the release of VIP. Reduction of tonic inhibition of the muscle by continuous VIP release may in part account for increases in motor activity induced by motilin.

Chapter 24 - Vasoactive Intestinal Polypeptide

VIP is a neuropeptide found in many organs. It appears to play a major role in vasodilation, epithelial secretion, as a neurotransmitter and neuromodulator, and as a relaxing agent in those smooth muscles which possess receptors and which relax when internal levels of cAMP are raised. Many of the claims for a major role as the non-adrenergic, non-cholinergic inhibitory transmitter have recently been seriously disputed. The best candidate for this role at present is NO. However, since NO and VIP are frequently colocalized, the release and action of these two transmitters may be complementary. One further complicating feature of the studies on VIP is the locus and action of its homologue, pituitary adenylyl cyclase activating peptide (PACAP). Few studies on localization are available which use antisera distinguishing these two peptides. Careful pharmacological studies comparing the action describe at least three potential receptors, recognizing VIP more, equi- or less potently than PACAP. Identification of physiological functions of VIP output await the availability of a highly selective and potent competitive antagonist.