Review of literature
Gut motility
Gastrointestinal (GI) motility is an integrated process including myoelectrical activity, contractile activity, tone, and transit. These different entities of motility can be generated and modulated by local and circulating neurohumoral substances (Modlin et al., 2000).
Contractile filaments:
Three types of filaments exist: thin actin, thick myosin and intermediate desmin filaments, these filaments interdiget with each other. The essential first step in smooth muscle contraction is phosphorylation of myosin light chain by myosin light chain kinase. Several steps lead to the activation of this enzyme (Makhlouf et al., 1995).
Cytoplasmic Ca2+sequentially binds to the regulatory protein, calmodulin, which eventually greatly enhances the ability of actin to activate myosin Mg2+ -ATPase and bring about the hydrolysis of adenosine triphosphate (ATP) bound to the myosin head. The interaction of myosin and actin with hydrolysis of ATP occurs in a cycle, the essential features of which is a shift in the affinity of myosin for actin (Murphy , 1998).
The signal transduction pathway:
The signal transduction pathway of an external neurohumoral signal into an internal signal is a process that involves sedquential activation of at least three membane proteins: a receptor, a G-protein, and phospholipase C (PLC), which is capable of mobilizing intracellular Ca2+. PLC hydrolyses inositol phospholipids located in the plasma membrane, generating inositol trisphosphate (IP3) and diacylglycerol membrane, generating increase from intraceullar stores, increasing the intracellular Ca2+ concentration (Makhlouf, 1995, Horowitz et al., 1996and Murphy , 1998).
Production of cyclic adenosine monophosphate (cAMP), as by B-adrenergic agonists, cyclic guanylate monophosphate (cGMP), as by nitric oxide(NO), or both as by vasocative intestinal polypeptide (VIP) leads to activation of protein kinase A and G, respectively.(Murphy , 1998).
Electrical properties and slow waves;
The resting membrane potential of muscle cells of the gut is in the range of –40 to –80 mv and is largely determined by activity of the Na+- K+ pump and K+ channels. The plasma membrane contains selective ion channels that can be regulated by membrane potential and by various neurohumoral agents. Especially, voltage-gated Ca2+ and several types of K+ channels had been identified. . Ca2+ channels and Ca2+ activated K+ channels constitute the electrical apparatus that sustains rhythmicity in the smooth muscle. The cycle speed, amplitude and duration depend on: 1) the relative proportions of active Ca2+ and K+ channels modulated by neurohumoral agents, 2) participation of other voltage-gated or ligand-gated channels and 3) coupling of muscle cells to each other and to pacemaker cells (Murphy , 1998 and Makhlouf , 1995).
The basal electrical rhythms (BER) in the gut are characterized by slow waves. A typical slow wave consists of the following sequences: rapid depolarization, partial depolarization, a sustained plateau, and complete repolarization to the resting membrane potential. Spike potentials occur and are superimposed on the slow waves plateau phase, in most cases, when threshold is reached . The ionic determination of the spike potential appears to be membrane Ca2+flux. Excitatory agonists, such as acetylcholine (ACh), stimulate intestinal phasic motor activity by enhancing spike potential activity, resulting in a contractile wave passing down the gut (Makhlouf , 1995).
In human the slow waves oscillate at different frequencies, amplitudes, and duration in different regions of the gut. The frequency is 3cycles/min in the gastric antrum, 12 cycles /min in the duodenum, 8 cycles/min in the ileum and 6-10 cycles/min in the colon(Makhlouf , 1995 and Murphy , 1998).
(Hansen, 2003) The search for the origin of rhythmicity in intestinal contraction has identified pacemaker regions of the slow waves located at the myenteric and submucous borders of circular muscles and contains a network of cells known as the intestitial cells of Cajal (ICC). The ICCs are distinctive population of muscle- like, stellate cells with large nuclei and an abundance of surface caveolae, mitochondriae and rough endoplasmic retirculum. They can be found in both the circular and longitudinal muscle layers from the esophagus to the anus (Hansen, 2003).
ICC cells are equivalent to the Purkinje fibers of the heart. They make contact with each other and with muscle cells and nerve terminals and functions as the pacemakers in GI muscles by initiating rhythmic electrical activity (Vanderwinden, 1999).
ICCs have receptors for many neurohumoral substance such as NO, VIP, ACh and for trachykinin (Kunze & Furness, 1999; Camilleri , 2001 and Keef et al.,2002)
Motility of the small intestine:
The small intestine exhibits two predominant motor patterns: the fasting (interdigestive) pattern and the fed (postprandial) pattern. The pattern at a give time is determined by the presence or absence of a significant amount of nutrients within the small intestine (Hasler et al., 1999b).
1-Fasting motor patterns:
Under unstimulated conditions, during fasting, the small intestine exhibits a prominent cyclic motor pattern known as migrating motor complex (MMC). Other motor patterns that occur less frequently and with less regularity also play important roles in the small intestinal transit (Halser, 1999b).
One-Migrating motor complex (MMC):
The MMC is a stereotypical fasting motor pattern that propels undigested food particles, sloughed enterocytes and mucus into the colon and prevents migration of colonic bacteria into the ileum, so it has been called the intestinal housekeeper (Rees et al., 1982).
The MMC consists of four phases with a combined duration of 84 to 112 minutes. Phase I is a period of motor quiescence, phase II is a period of increasing irregular, uncoordinated contractions, phase III is a period of intense rhythmic contractions, most of which propagate aborally. While phase IV is a brief transition phase from phase III to the quiescence of phase I (Quigley et al., 1990 and Sarna et al., 1993).
The cross-sectional area of the doudenal lumen is greater during phase II than during phase I, suggesting that the intestine plays an accommodative roles for pancreaticobiliary secretions during phase II (Gregersen et al., 1992). Some late duodenal phase III contractions propagate in an oral direction, indicative of a physiologic retroperistatic pump prior to initiation of the next MMC (Bjornsson and Abrahamsson, 1995).
Infusion of NO synthase inhibitors evoke premature MMC activity initially, followed by more rapid MMC cycling, indicating that endogenous NO acts as a physiological inhibitor of fasting motor function (Sarna et al., 1993 and Maczka et al., 1994).
Infusion of NO donor, sodium nitroprusside, disrupts MMC activity in rats, inducting a postprandial-like motor pattern (Rodriguez-Membrilla et al., 1995). Selective VIP-receptor antagonist block the disruptive effect of NO donors, indicating that NO may mediates its action through VIP pthways (Hellstrom and Lijung, 1996).
Two-Giant migrating complex (GMCs):
Giants migrating complex are large contractile waves, observed in the small intestine of experimental animals during hypoxia anaemia, gangrene and aftr laparotomy. Intestinal GMCs are rare in health (0.3/ hour). This activity was initially called peristaltic rush and also called prolonged propagated contractions (Hasler, 1996b).
Small intestinal GMCs are 2 to 3 times greater in amplitude and 4 to 5 times longer in duration than individual intestinal phasic contractions. GMCs typically begin in the jejunum or ileum during fasting, migrate to the ileocecal junction. So they are postulated to evacuate retained debris from the ileum and to prevent coloileal reflux (Kruis et al., 1985).
During diarrhea and fecal uregency, abdominal discomfort correlated with an increased frequency of intestinal GMCs (Jouet et al., 1995).
Three-Discrete clustered contraction (DCCs):
Discrete clustered contractions are intensely propulsive contractions, occur in clusters, which are calledthe minute rhythm or migrating clustered contractions (Kruis et al., 1985). DCCs occur during fasting and after eating and consists of 3 to 10 contractions preceeded and followed by 1 minute of motor quiescence. DCCs together with GMCs are proposed to be a physiologic means of emptying the terminal ileum (Quigely et al., 1984). The DCCs are frequently recorded in irritable bowel syndrome, intestinal pseudo-obstruction and partial small bowel obstruction (Kellow & Phillips, 1987 and Husebye, 1999).
Four-Retrograde peristaltic contractions:
Retrograde peristaltic contractions (RPCs) are contractile complexes develops in the middle to distal small intestine that migrate orally to the duodenum immediately before vomiting. The function of RPCs is to evacuate intestinal contents into the stomach, so that they may be expelled during emesis (Lang et al., 1986 and Cowles & Sarna, 1990).
RPCs exhibit periods of motor inhibition immediately before and after the complex, followed by several phasic contractions and a second inhibitory period. RPCs are most often associated with retiching or vomiting, but they may occur in their absence. Auto-transplantation of segments of the small intestine in dogs indicates that retrograds motor activity is controlled by extrinsic neural pathways (Sha et al., 1996).
2-Fed motility patterns:
The most important features of small intestine digestive motility is that it has no fixed motor pattern. Eating interrupts the interdigestive motor patterns and induces random mechanical contractions which are complex and difficult to describe (Abdel-Hamid et al., 1996b).
Different types of propulsive contractions mixed with nonprpulsive contractions occur in the small intestine in the digestive state, the amplitude and duration of the fed contractions depend on the type of meal. As found in human duodenum, postprandial motility is characterized by irregular phasic pressure waves, which travel only a short distance (Andrews et al., 2001).
A- Rhythmic segmentation :
Rhythmic segmentation is the most common pattern of small intestinal wall motion observed in fed state, by which short columns of chyme were currently divided and united into a new segment by localized circular muscle contractions that caused temporary local luminal occlusion, over distances less than 1 to 2 cm, associated with to-and-for movement of the contents (Christensen, 1997).
These segmenting contractions occur at a rate of 12/min in the upper jejunum, about 9/min in the midjejunum and 8/ min in the terminal ileum. This seems necessary for aboral propulsion of intestinal contents. This segmenting motor pattern is thought to assist mixing of food with digestive enzymes and maximizes the exposure of food to the mucosa to optimize absorption (andrews and Dent, 2002).
B- Intestinal peristalsis :
Peristalsis was also observed during small intestinal nutrient loading, in combination with rhythmic segmentation. Peristalsis was noted to have two forms, slow advance of chyme over short distances in association with segmentation and rapid transit of chyme over longer distance, sometimes several loops of the small intestine (andrews and Dent, 2002).
Peristaltic reflex:
Peristaltic reflex is a neural mediated reflex demonstrable in the small intestine and colon, which produces aboral propulsion of luminal contents and is evoked by pinching the mucosa and insertion of a solid bolus in the lumen. The peristaltic reflex consists of two phases, the excitatory response proximal to the stimulus, known as the ascending contraction and the distal inhibitory response or descending relaxation (Sims et al., 1998).
The ascending contraction has been characterized by simultaneous shortening of the circular layer and relaxation of the longitudinal muscle, while the descending relaxation involves simultatneous longitudinal muscle contraction and circular relaxation, although the muscle layer response may be more complex (Wood, 1981).
(Sims et al., 1998)(Fig a)
The intrinsic enteric neurons mediate both the afferent and efferent limbs of he peristaltic reflex, but the extrinsic neural, pathways modulates peristaltic reflex activity (Grider et al., 1994). Acetylcholine, substance P and neurokinin A all are mediators of the ascending contraction induce by intense radial stretching (Grider et al., 1994).
The final mediators of the descending relaxation are probably VIP and NO, because both are released upon activation of peristalsis (Grider, 1993). Other modulators of the peristaltic reflex include GABA and pituitary adenyl cyclase activating peptide (PACAP) (Grider and Makhlouf, 1992 and Grider et al., 1994).
Regulation of Gut Motility
The regulation of smooth muscle activity and gut motility takes place at several levels. Neurotransmitter and hormones are the dominating components, which act and interact directly and indirectly on muscle cells to regulate gut motility (Hansen, 2003).
I. Nervous regulation of gut motility:
The gastrointestinal tract is unique among mammalian organs having an intrinsic nervous system called the enteric nervous system (ENS). This system contains reflex pathways that are capable of functioning independently of central control although the CNS normally modifies activity within the gut wall through extrinsic nervous connection: sympathetic and parasympathetic nervous systems (Furness and clerc, 2000).
The enteric nervous system:
The ENS can influence the CNS both through nerve reflexes and the production of neuropeptides. Previous study has also shown a vast overlap of neuropeptide activity in the gut and the brain (Pert et al., 1985). The number of enteric neruons in humans is estimated to be 10-100 million nerve cells, which is about the same number as in the spinal cord (Karasomanoglu et al., 1996).
As in all nervous systems involved in sensory-motor control, the ENS comprises primary afferent neurons sensitive to chemical and mechanical stimuli, interneurones and motorneurones that act on the different effector cells including smooth muscle, pacemaker cells, blood vessels, mucosal glands, and epithelia, and the distributed system of intestinal cells involved in immune responses and endocrine and paracrine functions (Costa et al., 2000).
Structure organization of the enteric nervous system (ENS):
The enteric nervous systems consists of 2 major ganglionated plexuses, myenteric plexus or auerbach’s plexus and submucous plexus or Meissner’s plexus, which are connected by bundles of nerve cell processes . Also, there are series of non ganglionated plexuses which supply effectors tissues of the tubular digestive tract including the longitudinal muscle plexus, the circular muscle plexus, perivascular plexus, plexus of muscularis mucosa and mucosal plexus (Lieweiiyn- Smith et al., 1993).
1-Myenteric plexus:
The myenteric plexus lies between the longitudinal and circular layers of the muscularis externa and forms a continuous network around the circumference of the tubular digestive tract from the upper esophagus to the internal anal sphincter (Furness et al., 1999a).
The ganglia are connected to each other by small bands of nerve strands known as internodal strands forming with ganglia the primary component of the plexus. The secondary component of the plexus constituted of the nerve strands joining with the primary plexus and runs circumferentially, branches from it run into the circular muscle to innervate that layer (Wilson and Costa , 1987).
Nerve fiber bundles run through the circular muscle to connect the myenteric plexus with the submucosal plexuses. A tertiary component of the myenteric plexus is found in species in region of the intestine where the longitudinal muscles layer is thin. Myenteric nerve cells also provide nerve fibers to the mucosa, many of which are probably sensory nerve endings and nerve fibers that project to sympathetic ganglia (Furness, 2000).
2-Submucosal plexus:
The submucous plexus is only significant in the small and large intestine. Ganglia are occasionally found in the mucosa, usually in the connective tissue to the muscularis mucosa. Submucous ganglia are smaller and less regularly arranged than are myenteric ganglia (Thomsens et al., 1997). Inner and outer ganglia are found in many species.
The inner plexus is mainly concerned with control of fluid movement and that the outer plexus contribute to control of motility. Most secretomotor and enteric vasodilator neurons have their cells bodies in the submucous plexus (Neild et al., 1990).
Some neurons, notably intrinsic primary afferent neurons, project from the myenteric plexus. Other submucous neurons probably supply the muscularis mucosa of the small and large intestines. Submucous neuons supply a few fibers to the inner circular muscle in some species. In the stomach, almost entirely lack submucous ganglia, the intrinsic innervation of the muscoa and muscularis mucosa come from the myenteric plexus (Kirchgessner and Gershon, 1988).
Transmitter multiplicity of enteric neurons:
Individual autonomic neurons contain several possible neurotransmitter, as well as neurons-specific proteins. The transmission process is described asplurichemical as more than one substance is involved and identified by immunohistochemical localization (Furness et al., 1999a).
Colocalised substances do not have equal role as transmitter that is if several transmitter substances are released together from a neuron, they make different contributions to the transmission process. One (or sometimes more) substance has the major role in transmission, this substance is the primary transmitter, the other substance have subsidiary or modifying (Furness et al., 1999a).
Some neurons contain more than one primary transmitter and several subsidiary transmitters or neuromodulators. A broad range of experiments suggests that the primary transmitters are constant between species and that many of the species difference in neuronal chemistry are probably differences in subsidiary transmitter or neuromodulators (McConalogue and Furness, 1994).
Possible neurotransmitters in enteric neurons:
a- Established neurotransmitter / Site1-Acetylcholine (ACh). / -Transmitter of
-Several enteric motor neurons.
-Enteric interneuron.
-Parasympathetic input.
2-Adenosine triphosphate (ATP) and related nucleotides. / -As cotransmitter from inhibitory muscle motor neurons
-A transmitter at neuronal synapses
3-Gastrin related peptide / - Motor neurons to gastrin cells.
4-Nitric oxide (NO) / - Transmitter from enteric inhibitory neurons to muscle
5-Norepinephrine / - Primary transmitter of sympathetic postganglion neurons to GIT.
6-Tachykinins (substance P and gene related products). / -Excitatory motor neurons to muscles.
-Cotransmitter with ACh.
-Transmitter from intrinsic afferent neurons.
7-Vasoactive intestinal peptide (VIP) and gene related products / -Cotransmitter in enteric inhibitory neurons to muscle.
-Transmitter of noncholinergic secretomotor neurons.
-Transmitter of vasodilator neurons.
8-Pituitary adenyl cyclase activating peptide (PACAP) / Cotransmitter of inhibitory neurons.
B- Equivocal transmitter
1- Calcitonin gene related gene products / -In enteric neurons.
- Some extrinsic sensory neurons.
2- Cholecystokinin / - Present as octapeptide (CCK-8) its transmitter role not established.
3- Dynorphine and related gene products / - Poor evidence as transmitter.
4- Encephalin and related gene products / - Possible a neurotransmitter.
5- Galanin / -Poor evidence as transmitter
6- Gastrin related peptide / -present in enteric neurons through the gut.
-In gastric antral muscoa referred as (mammalian Bombesin).
7- Glutamate. / - Contributes to excitatory transmission between neurons.
8- Gama –aminobutyric acid (GABA) / - Found in variable type of neurons, not established as transmitter.
9-5-hydroxytryptamin (serotonin). / - A transmitter, its role is not known.
10- Neuropeptide Y / - Colocalised with noradrenaline in sympathetic vasoconstrictor neurons, also in enteric neurons.
11- Neuromedin U / -No evidence of transmitter role.
12- Neurotensin / - Not seems to be a transmitter.
13- Nitric oxide synthases (NOS) / - Present in interneurons and inhibitory motor neurons.
14- Somatostatin. / -Not appear to be primary transmitter
(Furness et al., 1999a)