Excitability of canine colon circular muscle disconnected from the network of interstitial cells of Cajal.

The 6 cpm omnipresent slow waves recorded in the circular muscle (CM) layer of canine colon are generated at the submucosal surface of the CM layer. After removal of the submucosal network of interstitial cells of Cajal (ICC), 66% of the CM preparations (25 of 38) were quiescent in Krebs solution. In the presence of carbachol, seven of nine of these spontaneously quiescent CM preparations demonstrated slow wave-like activity with mean frequency, duration and amplitude of 5.9 +/- 0.4 cpm, 2.8 +/- 0.5 s, and 0.8 +/- 0.2 mV, respectively. Similar slow wave-like activities were induced by TEA (seven out of eight quiescent CM preparations) with frequency, duration and amplitude of 6.1 +/- 0.2 cpm, 2.7 +/- 0.5 s, and 1.0 +/- 0.2 mV, respectively, and by BaCl2 (eight of eight quiescent CM preparations) with frequency, duration, and amplitude of 6.3 +/- 0.3 cpm, 1.8 +/- 0.2 s, and 0.5 +/- 0.1 mV, respectively. All the induced activities were abolished in the presence of 1 microM D600. CM preparations with the submucosal ICC network intact (ICC-CM) showed slow wave activity in Krebs solution at a frequency of 6.2 +/- 0.2 cpm, a duration of 3.6 +/- 0.2 s, and an amplitude of 1.0 +/- 0.1 mV (n = 22). When ICC-CM preparations were stimulated by BaCl2, carbachol, or TEA, the slow wave frequency did not change significantly, but the duration increased as well as the amplitude. In the presence of D600, the upstroke of slow waves remained and the frequency was not affected.(ABSTRACT TRUNCATED AT 250 WORDS)     

Pacemaker potentials generated by interstitial cells of Cajal in the murine intestine

Pacemaker potentials were recorded in situ from myenteric interstitial cells of Cajal (ICC-MY) in the murine small intestine. The nature of the two components of pacemaker potentials (upstroke and plateau) were investigated and compared with slow waves recorded from circular muscle cells. Pacemaker potentials and slow waves were not blocked by nifedipine (3 µM). In the presence of nifedipine, mibefradil, a voltage-dependent Ca²⁺ channel blocker, reduced the amplitude, frequency, and rate of rise of upstroke depolarization (dV/dt_max) of pacemaker potentials and slow waves in a dose-dependent manner (1–30 µM). Mibefradil (30 µM) changed the pattern of pacemaker potentials from rapidly rising, high-frequency events to slowly depolarizing, low-frequency events with considerable membrane noise (unitary potentials) between pacemaker potentials. Caffeine (3 mM) abolished pacemaker potentials in the presence of mibefradil. Pinacidil (10 µM), an ATP-sensitive K⁺ channel opener, hyperpolarized ICC-MY and increased the amplitude and dV/dt_max without affecting frequency. Pinacidil hyperpolarized smooth muscle cells and attenuated the amplitude and dV/dt_max of slow waves without affecting frequency. The effects of pinacidil were blocked by glibenclamide (10 µM). These data suggest that slow waves are electrotonic potentials driven by pacemaker potentials. The upstroke component of pacemaker potentials is due to activation of dihydropyridine-resistant Ca²⁺ channels, and this depolarization entrains pacemaker activity to create the plateau potential. The plateau potential may be due to summation of unitary potentials generated by individual or small groups of pacemaker units in ICC-MY. Entrainment of unitary potentials appears to depend on Ca²⁺ entry during upstroke depolarization. pacemaker activity; slow waves; gastrointestinal motility; calcium channel     

Use of a microelectrode array to record extracellular pacemaker potentials from the gastrointestinal tracts of the ICR mouse and house musk shrew (Suncus murinus)

BackgroundThe rhythmic contraction and relaxation of smooth muscles in the gastrointestinal (GI) tract is governed by pacemaker electrical potentials, also termed slow waves, which are calcium currents generated by interstitial cells of Cajal (ICCs). Malfunction of pacemaker rhythms contributes to a number of clinically challenging gastrointestinal motility disorders.MethodA microelectrode array (MEA) was used to record slow waves in vitro from intact GI tissues freshly isolated from the ICR mouse and Suncus murinus. The effects of temperature, extracellular calcium and potassium concentrations on pacemaker potentials were quantified using spatiotemporal metrics.ResultsPacemaker frequency decreased from the duodenum to the ileum in the mouse, but this phenomenon was less significant in Suncus murinus. In both the mouse and Suncus murinus, the stomach had a much lower pacemaker frequency than the intestine. Propagation velocity and amplitude were highest in the proximal intestine. Temperature significantly increased pacemaker frequency in the intestinal tissues of both species. Removal of Ca²⁺ from the medium inhibited pacemaker potential and increasing the Ca²⁺ concentration increased pacemaker frequency in the mouse ileum. Increasing K⁺ concentration decreased pacemaker frequency in the absence of nifedipine.ConclusionsThe MEA allows efficient investigation of gut pacemaker frequency and propagation.     

RhoA/ROCK pathway is the major molecular determinant of basal tone in intact human internal anal sphincter

The knowledge of molecular control mechanisms underlying the basal tone in the intact human internal anal sphincter (IAS) is critical for the pathophysiology and rational therapy for a number of debilitating rectoanal motility disorders. We determined the role of RhoA/ROCK and PKC pathways by comparing the effects of ROCK- and PKC-selective inhibitors Y 27632 and G? 6850 (10(-8) to 10(-4) M), respectively, on the basal tone in the IAS vs. the rectal smooth muscle (RSM). Western blot studies were performed to determine the levels of RhoA/ROCK II, PKC-α, MYPT1, CPI-17, and MLC(20) in the unphosphorylated and phosphorylated forms, in the IAS vs. RSM. Confocal microscopic studies validated the membrane distribution of ROCK II. Finally, to confirm a direct relationship, we examined the enzymatic activities and changes in the basal IAS tone and p-MYPT1, p-CPI-17, and p-MLC(20), before and after Y 27632 and G? 6850. Data show higher levels of RhoA/ROCK II and related downstream signal transduction proteins in the IAS vs. RSM. In addition, data show a significant correlation between the active RhoA/ROCK levels, ROCK enzymatic activity, downstream proteins, and basal IAS tone, before and after ROCK inhibitor. From these data we conclude 1) RhoA/ROCK and downstream signaling are constitutively active in the IAS, and this pathway (in contrast with PKC) is the critical determinant of the basal tone in intact human IAS; and 2) RhoA and ROCK are potential therapeutic targets for a number of rectoanal motility disorders for which currently there is no satisfactory treatment.     

Pacemaking activity is regulated by membrane stretch via the CICR pathway in cultured interstitial cells of Cajal from murine intestine

Membrane stretch is an important stimulus in gastrointestinal (GI) motility regulation, but the relationship between membrane stretch and the pacemaking activity of GI smooth muscle is poorly understood. We examined the effect of intestinal distension on slow waves and the effect of membrane stretch on pacemaker currents in cultured intestinal interstitial cells of Cajal (ICCs) from murine small intestine. At organ level, intestinal distension significantly increased amplitude of slow and fast waves, and enhanced frequencies of fast but not slow waves. At the cellular level, membrane stretch-induced by hyposmotic cell swelling (MSHC) depolarized membrane potential and activated large inward holding current, but suppressed amplitude of pacemaker potential or pacemaking current. External Ca²⁺-free solution abolished pacemaker current and blocked MSHC-induced inward holding current. However, a sustained inward holding current was activated and the amplitude of pacemaker current was increased by high ethylene glycol tetraacetic acid (EGTA) in pipette. Then MSHC also potentiated the inward holding current. MSHC significantly increased amplitude of rhythmic Ca²⁺ transients and basal intracellular Ca²⁺ concentration ([Ca²⁺]_i). 2-APB blocked both pacemaker current and Ca²⁺ transients but did not alter the effect of MSHC on pacemaker current and Ca²⁺ transients. In contrast, ryanodine inhibited Ca²⁺ transients but not pacemaker current, and completely blocked MSHC-induced inward holding current and MSHC-induced increase of basal [Ca²⁺]_i. These results suggest that intestinal distension potentiates intestinal motility by increasing the amplitude of slow waves. Membrane stretch potentiates pacemaking activity via releasing Ca²⁺ from calcium-induced calcium release (CICR) in cultured intestinal ICCs.     

Inhibitory innervation of colonic smooth muscle cells and interstitial cells of Cajal

The effect of neural inhibition on the electrical activities of circular and longitudinal colonic smooth muscle was investigated. In addition, a comparative study was carried out between circular muscle preparations with and without the "submucosal" and "myenteric plexus" network of interstitial cells of Cajal (ICC) to study innervation of the "submucosal" ICC and to investigate whether or not the ICC network is an essential intermediary system for inhibitory innervation of smooth muscle cells. Electrical stimulation of intrinsic nerves in the presence of atropine caused inhibitory junction potentials (ijps) throughout the circular and longitudinal muscle layers. The ijp amplitude depended on the membrane potential and not on the location of the muscle cells with respect to the ICC network. Neurally mediated inhibition of the colon resulted in a reduction in amplitude and duration of slow wave type action potentials in circular and abolishment of spike-like action potentials in longitudinal smooth muscle, both resulting in a reduction of contractile activity. With respect to mediation by ICC, the study shows (i) "submucosal" ICC receive direct inhibitory innervation and (ii) circular smooth muscle cells can be directly innervated by inhibitory nerves without ICC as necessary intermediaries. The reversal potential of the ijp in colonic smooth muscle was observed to be approximately -76 mV, close to the estimated potassium equilibrium potential, suggesting that the nerve-mediated hyperpolarization is caused by increased potassium conductance.     

Characterization of in vitro gutlike organ formed from mouse embryonic stem cells

Using an embryoid body (EB) culture system, we have made a functional organlike cluster: the "gut" from embryonic stem (ES) cells (ES gut). There are many types of ES clusters, because ES cells have a pluripotent ability to develop into a wide range of cell types. Before inducing specific differentiation by exogenously added factors, we characterized comprehensive physiological and morphological properties of ES guts. Each ES gut has a hemispherical (or cystic) structure and exhibits spontaneous contractions [mean frequency: 13.5 ± 8.8 cycles per min (cpm)]. A dense distribution of interstitial cells of Cajal (ICC) was identified by c-Kit immunoreactivity, and specific subcellular structures of ICC and smooth muscle cells were identified with electron microscopy. ICC frequently formed close contacts with the neighboring smooth muscle cells and occasionally formed gap junctions with other ICC. Widely propagating intracellular Ca²⁺ concentration oscillations were generated in the ES gut from the aggregates of c-Kit immunopositive cells. Plateau potentials, possibly pacemaker potentials in ICC, and electrical slow waves were recorded for the first time. These events were nifedipine insensitive, as in the mouse gut. Our present results indicate that the rhythmic pacemaker activity generated in ICC efficiently spreads to smooth muscle cells and drives spontaneous rhythmic contractions of the ES gut. The present characterization of physiological and morphological properties of ES gut paves the way for making appropriate models to investigate the origin of rhythmicity in the gut. intracellular calcium concentration oscillation; interstitial cells of Cajal; peristalsis     

The effects of H2O2 on electromechanical activity of the ileum longitudinal muscle

The effects of H2O2 on electrical and mechanical activity of the longitudinal layer from the guinea-pig ileum were studied using sucrose-gap technique and the influence of H2O2 on ionic current was investigated in single smooth muscle cells by the patch-clamp method. In most of the preparations tested, the spontaneous activity observed was composed of slow waves with superimposed action potentials (APs). Both were resistant to tetrodotoxin and atropine. H2O2 (1 mmol/l) evoked sustained 3-5 mV membrane depolarisation, doubled the amplitude of the slow waves and increased their frequency, augmented the APs and reduced their splitting. These changes were accompanied with significant contraction, which had an amplitude comparable to that of the tonic component of 50 mmol/l K+-induced contraction. Calcium-free solution caused membrane depolarisation, reduction of the slow wave amplitude and frequency, disappearance of APs and decreased the mechanical tension of the preparations. Application of H2O2 (1 mmol/l) into the zero-calcium bath solution recovered the APs, which was accompanied by a low amplitude contraction. H2O2 (up to 1 mmol/l) increased the L-type calcium current (I(Ca)) both under conventional whole-cell patch-clamp configuration and under amphotericin-perforated patches by 16 +/- 3%. These data demonstrated that contractile response of the ileum longitudinal smooth muscle preparation evoked by H2O2 was mainly due to the enhanced electrical activity.     

Vasoactive intestinal polypeptide inhibits pacemaker activity via the nitric oxide-cGMP-protein kinase G pathway in the interstitial cells of Cajal of the murine small intestine

Interstitial cells of Cajal (ICCs) are pacemaker cells that activate the periodic spontaneous depolarization (pacemaker potentials) responsible for the production of slow waves in gastrointestinal smooth muscle. The effects of vasoactive intestinal polypeptide (VIP) on the pacemaker potentials in cultured ICCs from murine small intestine were investigated by whole-cell patch-clamp techniques. Addition of VIP (50 nM-1 microM) decreased the amplitude of pacemaker potentials and depolarized resting membrane potentials. To examine the type of receptors involved in ICC, we examined the effects of the VIP1 agonist and found that it had no effect on pacemaker potentials. Pretreatment with VIP1 antagonist (1 microM) for 10 min also did not block the VIP (50 nM)-induced effects. On the other hand exposure to 1H-(1,2,4)oxadiazolo(4,3-A)quinoxalin- 1-one (ODQ, 100 microM), an inhibitor of guanylate cyclase, prevented VIP inhibition of pacemaker potentials. Similarly KT-5823 (1 microM) or RP-8-CPT-cGMPS (10 microM), inhibitors of protein kinase G (PKG) blocked the effect of VIP (50 nM) on pacemaker potentials as did N-nitro-L-arginine (L-NA, 100 mM), a non-selective nitric oxide synthase (NOS) inhibitor. These results imply that the inhibition of pacemaker activity by VIP depends on the NO-cGMP-PKG pathway.     

Distribution of interstitial cells of Cajal in tunica muscularis of the canine rectoanal region

Electrical and mechanical activity of the circular muscle layer in the rectoanal region of the gastrointestinal tract undergoes considerable changes in the site of dominant pacemaking activity, frequency, and waveform shape. The present study was performed to determine whether changes in the structural organization of the circular layer or in the density, distribution, and ultrastructure of interstitial cells of Cajal (ICC) could account for this heterogeneity in electrical and mechanical activities. Light microscopy revealed that the structural organization of the circular muscle layer underwent dramatic morphological changes, from a tightly packed layer with poorly defined septa in the proximal rectum to one of discrete muscle bundles separated by large septae in the internal anal sphincter. Kit immunohistochemistry revealed a dense network of ICC along the submucosal and myenteric borders in the rectum, whereas in the internal anal sphincter, ICC were located along the periphery of muscle bundles within the circular layer. Changes in electrical activity within the circular muscle layer can be partially explained by changes in the structure of the muscle layer and changes in the distribution of ICC in the rectoanal region of the gastrointestinal tract.     

Visceral muscles and myogenic activity in the hindgut of the cockroach,Leucophaea maderae

Summary The hindgut of the Madeira cockroach contains an intricate network of longitudinal and circular muscles that are distinctive for each region. In the rectum, the longitudinal muscles are symmetrically arranged in 6 distinct bands, while the circular muscles appear as a uniform layer over the rectal pads. In the colon, the muscle fibers are arranged in an irregular lattice with the longitudinal fibers generally superimposed on the circular ones but with an evident weaving between the layers. In addition to these muscle layers, a delicate, superficial network of muscle-like fibers covers many portions of the colon and rectum.In spite of the bewilderingly complex motile activity of deganglionated hindguts, all activity could be classified under 4 basic types after cinematographic analysis: segmentation, compression, peristalsis, or reverse peristalsis or a combination thereof. Although much of the activity that occurred was seemingly random, there was an evident rhythmicity that spontaneously arose and ended in several types of motility during the course of observations. The defined modes of activity seemed to be completely myogenic in nature, as all 4 categories were readily observed in hindguts 30 min after treatment with tetrodotoxin (10^–6 g/ml). Each region of the hindgut seemed to have its own particular rhythm.Action potentials were recorded both intracellularly and extracellularly from all regions of the hindgut; amplitude usually ranged between 10 and 20 mV for intracellular recordings, and such spike potentials were often preceded by a slow depolarizing pre-potential. Generally, however, the depolarization was abrupt. Transmembrane potentials from the visceral muscle fibers were never truly at rest. Slow, continuous fluctuations (3–8 mV) were common. At times, plateau-type action potentials were recorded, but generally the repolarization contour was almost linear with time. Contractions were evoked by action potentials but not by the slow, rhythmic fluctuations in the membrane potential.No particular region or structure in the hindgut showed an exclusive pacemaker function. However, there was an evident gradient of increased excitability progressing in an caudal direction from the ileum.In a sodium-free saline, the amplitude of action potentials was remarkable enhanced from 5 to 10 min after the initial change. Even after a 20 min exposure, action potentials were still often present although their frequency and amplitude dropped. Tetrodotoxin (10^–6g/ml) had no. pronounced effect on frequency or amplitude of action potentials. However, spike potentials ceased within 1.5 min after exposure to a sodium and calcium-free saline. When such preparations were re-exposed to a sodium-free saline containing normal calcium, the action potentials reappeared, suggesting that calcium might be a current-carrying ion. Although action potentials in a calcium-free medium showed variability, we generally saw a marked reduction in amplitude of potentials within 5 min. We further observed that 2 mM manganous ion completely abolished action potentials within 2 min. Thus, it seems likely that sodium is not the sole current-carrying ion in cockroach hindgut muscle.The authors express their indebtedness to Ms. Susan Swann, Mr. Gerald Holt, Mr. David Owens, and Ms. Mary Strand for their competent technical assistance.     

Integrative control of rectoanal reflex in guinea pigs through lumbar colonic nerves

The aim of the present study was to analyze the neuromodulation of rectoanal reflex activity by lumbar sympathetic nerves in guinea pigs. The mechanical activities of the rectum were recorded with a balloon connected to a pressure transducer, and those of the internal anal sphincter (IAS) were recorded with a custom-made strain gauge force transducer. Gradual and sustained rectal distension evoked the rectoanal reflex, causing cholinergic contractions of the rectum and synchronous nitrergic relaxations of the IAS. Section of the lumbar colonic nerves enhanced both rectal contractions and IAS relaxations. Section of the 13th thoracic cord abolished both rectal contractions and IAS relaxations, but section of the lumbar colonic nerves restored them. Lumbar sympathectomy and pithing sacral cords greatly diminished these rectal contractions and IAS relaxations, but the intrinsic reflex component remained. NG-nitro-L-arginine methyl ester enhanced the intrinsic reflex-mediated contraction of the rectum and abolished reflex-mediated relaxation of the IAS and converted into cholinergic contractions. The present results indicate that the extrinsic lumbar inhibitory outflow causes marked inhibition of the rectoanal reflex via the lumbar colonic nerves.     

A technique to locate the pacemaker in smooth muscles

A technique was developed to locate the site of slow-wave origin (pacemaker) in a sheet of smooth muscle tissue. Evoked slow waves were used to measure conduction velocities in the two dimensions of sheets of smooth muscle. These conduction velocities were used to "triangulate" to the pacemaker site by an iterative minimization process. The model was tested by triangulating to events evoked from known regions within sheets of canine gastric muscle. The technique was used to determine the sites of origin of spontaneous slow waves and the shift in the spontaneous pacemaker caused by localized injury. This technique will be useful in locating pacemaker regions and to study the factors that affect the origin and frequency of slow waves in syncytial tissues. The triangulation technique should be applicable to intact organs as well as isolated sheets of muscle.     

TRPC4 is an essential component of the nonselective cation channel activated by muscarinic stimulation in mouse visceral smooth muscle cells

Classical transient receptor potential channels (TRPCs) are thought to be candidates for the nonselective cation channels (NSCCs) involved in pacemaker activity and its neuromodulation in murine stomach smooth muscle. We aimed to determine the role of TRPC4 in the formation of NSCCs and in the generation of slow waves. At a holding potential of -60 mV, 50 mM carbachol (CCh) induced INSCC of amplitude [500.8+/-161.8 pA (n=8)] at -60 mV in mouse gastric smooth muscle cells. We investigated the effects of commercially available antibodies to TRPC4 on recombinant TRPC4 expressed in HEK cells and CCh-induced NSCCs in gastric smooth muscle cells. TRPC4 currents in HEK cells were reduced from 1525.6+/-414.4 pA (n=8) to 146.4+/-83.3 pA (n=10) by anti-TRPC4 antibody and INSCC amplitudes were reduced from 230.9+/-36.3 pA (n=15) to 49.8+/-11.8 pA (n=9). Furthermore, INSCC in the gastric smooth muscle cells of TRPC4 knockout mice was only 34.4+/-10.4 pA (n=8) at -60 mV. However, slow waves were still present in the knockout mice. Our data suggest that TRPC4 is an essential component of the NSCC activated by muscarinic stimulation in the murine stomach.     

刺激大鼠蓝斑核区对胃电和胃运动的影响

用乌拉坦麻醉的大鼠,同步描记血压、胃电和胃运动,观察了刺激蓝斑核区对胃电和胃运动的影响,分析了其作用途径。实验结果表明,刺激蓝斑核区后血压平均升高60.5mmHg(P<0.001);胃电慢波的振幅由对照的0.52mV 减弱到0.18mV(P<0.001)。快波的振幅和频率也减少。胃内压平均下降到对照值的29.9％(P<0.001)。在横断颈髓的动物刺激蓝斑核区后血压的升高幅度明显减弱,平均升高9mmHg,升压效应的潜伏期明显延长;胃电慢波的振幅由对照的0.53mV 减弱到 0.24mV(P<0.001)。胃内压平均下降到对照值的45.1％。对胃电和胃运动的这种抑制效应可被切断迷走神经所完全消除。在事先切断迷走神经但脊髓仍保留完整的动物,刺激蓝斑核区使胃内压平均下降36.6％(P<0.01)。根据以上结果认为,蓝斑核区可能参与对胃电和胃运动的中枢性调节。此调节机制可能经由脊髓和迷走两条通路实现。     

Na(+) current contribution to the diastolic depolarization in newborn rabbit SA node cells

Isolated newborn, but not adult, rabbit sinoatrial node (SAN) cells exhibit spontaneous activity that (unlike adult) are highly sensitive to the Na(+) current (I(Na)) blocker TTX. To investigate this TTX action on automaticity, cells were voltage clamped with ramp depolarizations mimicking the pacemaker phase of spontaneous cells (-60 to -20 mV, 35 mV/s). Ramps elicited a TTX-sensitive current in newborn (peak density 0.89 +/- 0.14 pA/pF, n = 24) but not adult (n = 5) cells. When depolarizing ramps were preceded by steplike depolarizations to mimic action potentials, ramp current decreased 54.6 +/- 8.0% (n = 3) but was not abolished. Additional experiments demonstrated that ramp current amplitude depended on the slope of the ramp and that TTX did not alter steady-state holding current at pacemaker potentials. This excluded a steady-state Na(+) window component and suggested a kinetic basis, which was investigated by measuring TTX-sensitive I(Na) during long step depolarizations. I(Na) exhibited a slow but complete inactivation time course at pacemaker voltages (tau = 33.9 +/- 3.9 ms at -50 mV), consistent with the rate-dependent ramp data. The data indicate that owing to slow inactivation of I(Na) at diastolic potentials, a small TTX-sensitive current flows during the diastolic depolarization in neonatal pacemaker myocytes.     

Electrophysiological Studies of the Antrum Muscle Fibers of the Guinea Pig Stomach

The membrane potentials of single smooth muscle fibers of various regions of the stomach were measured, and do not differ from those measured in intestinal muscle. Spontaneous slow waves with superimposed spikes could be recorded from the longitudinal and circular muscle of the antrum. The development of tension was preceded by spikes but often tension appeared only when the slow waves were generated. Contracture in high K solution developed at a critical membrane potential of -42 mv. MnCl₂ blocked the spike generation, then lowered the amplitude of the slow wave. On the other hand, withdrawal of Na⁺, or addition of atropine and tetrodotoxin inhibited the generation of most of the slow waves but a spike could still be elicited by electrical stimulation. Prostigmine enhanced and prolonged the slow wave; acetylcholine depolarized the membrane without change in the frequency of the slow waves. Chronaxie for the spike generation in the longitudinal muscle of the antrum was 30 msec and conduction velocity was 1.2 cm/sec. The time constant of the foot of the propagated spike was 28 msec. The space constants measured from the longitudinal and circular muscles of the antrum were 1.1 mm and 1.4 mm, respectively.     

Are interstitial cells of Cajal plurifunction cells in the gut?

The proposed functions of the interstitial cells of Cajal (ICC) are to 1) pace the slow waves and regulate their propagation, 2) mediate enteric neuronal signals to smooth muscle cells, and 3) act as mechanosensors. In addition, impairments of ICC have been implicated in diverse motility disorders. This review critically examines the available evidence for these roles and offers alternate explanations. This review suggests the following: 1) The ICC may not pace the slow waves or help in their propagation. Instead, they may help in maintaining the gradient of resting membrane potential (RMP) through the thickness of the circular muscle layer, which stabilizes the slow waves and enhances their propagation. The impairment of ICC destabilizes the slow waves, resulting in attenuation of their amplitude and impaired propagation. 2) The one-way communication between the enteric neuronal varicosities and the smooth muscle cells occurs by volume transmission, rather than by wired transmission via the ICC. 3) There are fundamental limitations for the ICC to act as mechanosensors. 4) The ICC impair in numerous motility disorders. However, a cause-and-effect relationship between ICC impairment and motility dysfunction is not established. The ICC impair readily and transform to other cell types in response to alterations in their microenvironment, which have limited effects on motility function. Concurrent investigations of the alterations in slow-wave characteristics, excitation-contraction and excitation-inhibition couplings in smooth muscle cells, neurotransmitter synthesis and release in enteric neurons, and the impairment of the ICC are required to understand the etiologies of clinical motility disorders.     

Peripheral pacemakers and patterns of slow wave propagation in the canine small intestine in vivo

In an anesthetized, open-abdomen, canine model, the propagation pattern of the slow wave and its direction, velocity, amplitude, and frequency were investigated in the small intestine of 8 dogs. Electrical recordings were made using a 240-electrode array from 5 different sites, spanning the length of the small intestine. The majority of slow waves propagated uniformly and aborally (84%). In several cases, however, other patterns were found including propagation in the oral direction (11%) and propagation block (2%). In addition, in 69 cases (3%), a slow wave was initiated at a local site beneath the electrode array. Such peripheral pacemakers were found throughout the entire intestine. The frequency, velocity, and amplitude of slow waves were highest in the duodenum and gradually declined along the intestine reaching lowest values in the distal ileum (from 17.4+/-1.7 c/min to 12.2+/-0.7 c/min; 10.5+/-2.4 cm/s to 0.8+/-0.2 cm/s, and 1.20+/-0.35 mV to 0.31+/-0.10 mV, respectively; all p<0.001). Consequently, the wavelength of the slow wave was strongly reduced from 36.4+/-0.8 cm to 3.7 +/- 0.1 cm (p<0.001). We conclude that the patterns of slow wave propagation are usually, though not always, uniform in the canine small intestine and that the gradient in the wavelength will influence the patterns of local contractions.