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Alimentary |
1 Division of Neuroscience, John Curtin School of Medical Research, Canberra, ACT, 0200, Australia
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Abstract |
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(Received 25 October 2005;
accepted after revision 14 December 2005;
first published online 15 December 2005)
Corresponding author G.D.S. Hirst: Division of Neuroscience, John Curtin School of Medical Research, Canberra, ACT, 0200, Australia. Email: david.hirst{at}anu.edu.au
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Introduction |
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The aim of this study was to characterize the pattern of slow wave propagation in the guinea-pig antrum and to explore what parameters might give rise to the slow oro-anal and more rapid circumferential conduction velocities of slow waves in this tissue.
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Methods |
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All procedures used for the acquisition of physiological data from isolated tissues were approved by the Animal Experimentation Ethics Committee at the Australian National University. Guinea-pigs of either sex were stunned, exsanguinated and the stomach removed. In the initial experiments the stomach was first cut along the greater curvature and then along the lesser curvature; one hemi-stomach was immersed in oxygenated physiological saline (composition, mM): NaCl, 120; NaHCO3, 25; NaH2PO4, 1.0; KCl, 5; MgCl2, 2; CaCl2, 2.5; and glucose, 11; bubbled with 95% O2–5% CO2. The fundus and lower pylorus were discarded; the mucosa, followed by the serosa, was dissected away from the remaining tissue. Preparations were pinned, serosal surface uppermost, in a recording chamber with a base consisting of a microscope cover-slip coated with Sylgard silicone resin (Dow Corning Corp., Midland, MI, USA) and viewed with an inverted compound microscope. The antrum was impaled with two independently mounted sharp electrodes, with resistances of 100–140 M
, filled with 0.5 M KCl. The orientation and separation between electrodes were noted. Membrane potential changes (and when appropriate membrane currents) were amplified using an Axoclamp-2B amplifier (Axon Instruments), low-pass filtered (cut-off frequency, 1000 Hz), digitized and stored on computer for later analysis. In some experiments, similar preparations were made but the longitudinal and adhering ICCMY layers were dissected away from most of the preparation, leaving a 3 mm wide band of longitudinal muscle, with the ICCMY network intact, along the greater curvature: regions of tissue devoid of ICCMY were impaled with two independently mounted sharp electrodes, care being taken to impale the same bundle of circular muscle. The separation between electrodes was again determined.
The conduction velocities of pacemaker potentials in the anal and circumferential directions were determined using preparations of longitudinal muscle, with ICCMY attached (see Hirst & Edwards, 2001). Preparations were pinned over a bar stimulating electrode, let into the base of the chamber; a second parallel bar electrode was placed above the tissue (Hirst et al. 2002b). The preparations were orientated so that conduction from the plane of stimulation, with a pulse width of 5 ms and with a stimulus strength adjusted to 110% threshold value, was either in an anal or in a circumferential direction. Intracellular recordings were made using two electrodes, with the separation between recording electrodes being determined. The arrival times of a pacemaker potential at the two points in the ICCMY network was determined from measurements of the 10% rise point of the potential change produced in the longitudinal muscle layer by a pacemaker potential. The conduction velocity was determined by dividing the separation between electrodes by the difference in arrival times. Atropine (1 µM) was added to the physiological saline to abolish the effects of concurrent stimulation of excitatory nerves (see Hirst & Edwards, 2001).
The electrical properties of the circular layer were determined using individual bundles of circular muscle (diameter 60–150 µm, length 2.0–3.5 mm; see Suzuki & Hirst, 1999 for details). Preparations were again impaled with two independently mounted sharp electrodes: one was positioned at each end of the single bundle of circular muscle. Current pulses were passed through one electrode and the other was used to measure the resulting electrotonic potentials. The electrotonic potentials could be simulated when the bundle was modelled as an electrically short cable with sealed ends. Jack & Redman (1971) have derived the Laplace transform of the voltage response at the centre of such a cable (length 2 L) to a step of current injected at distance X from the recording electrode (see eqn (A20) (Jack & Redman)). Multiplying this expression by 2 and setting X to L gives the Laplace transform for the voltage response at one end of a cable (length L) to current injection at the other end. Applying substitutions that were used to solve the case for an infinite cable (eqn 3.24 in Jack et al. 1975) and taking the inverse Laplace transform yields the following equation:
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length constant, L cable length measured in length constants and T time measured in time constants. This expression was verified by the method of reflections (see p. 69 in Jack et al. 1975). To fit this expression to a physiologically acquired response, values of equivalent membrane resistance, axial resistance and membrane time constant were varied according to a Simplex algorithm until the best least-squares fit was obtained (Matlab 6.5.1 Release 13; The MathWorks, Natick, MA, USA). During each optimization step, the series of infinite cable responses was summed to account for only the first 20 reflections, as adding further reflection components did not affect the solution. For each bundle the electrical length constant was determined from the values of membrane resistance and axial resistance (eqn 3.10 of Jack et al. 1975), and the asymptotic value of electrotonic conduction velocity in the analogous infinite cable was calculated (p. 34 of Jack et al. 1975). The membrane time constant, electrical length constant and electrotonic conduction velocity of each bundle was determined. In the experiments where the connectivity between nearby bundles of smooth muscle was characterized, segments of circular layer, with the longitudinal and ICCMY layers removed, were isolated. The segments had lengths of 1–1.2 mm and were four or five bundles wide. A bundle at one edge of the preparation was first impaled with two electrodes. Current pulses were passed through one electrode and the resulting electrotonic potentials were recorded using the second electrode: the time course and amplitude was determined from an average of 20 successive electrotonic potentials. Subsequently the recording electrode was withdrawn and the adjacent bundle was impaled: current pulses of the same amplitude were passed through the current-passing electrode and electrotonic potentials were recorded from the adjacent bundle with the second electrode. The process was repeated with the recording electrode being inserted in the next more distant bundle. The connectivity between bundles, termed transfer ratio, was quantified by determining the ratio of steady state amplitudes of electrotonic potentials, produced by injecting constant intensity current pulses into the same and the adjacent muscle bundle.
During each experiment, preparations were constantly superfused with physiological saline solution warmed to 37°C; nifedipine (1 µM) was added to the physiological saline to reduce the amplitudes of the contractions associated with each slow wave or regenerative potential. When the electrical properties of single bundles of smooth muscle and the coupling between nearby bundles of smooth muscle were being determined, caffeine (1 mM) was added to the physiological saline to inhibit the occurrence of unitary potentials and regenerative potentials (Edwards et al. 1999), to ensure only passive cable properties were measured. After caffeine wash-out the frequency of regenerative potentials was increased for up to 30 min; no attempt was made to allow a complete return to control conditions as this meant that the impalements had to be maintained for excessive times. Thus, some of the recordings made from paired bundles of circular muscle give a misleading impression of the natural frequency of generation of regenerative potentials (Fig. 5).
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To determine the distribution of ICCMY in living preparations, preparations were first washed with warmed physiological saline for 30 min. The preparations were then incubated for 15 min with an antibody to CD 117 (rat anti-mouse CD 117 C-kit, Cymbus Biotechnology, Chadlers Ford, UK), diluted 1 in 500 in physiological saline. Subsequently the preparations were washed in warmed physiological saline for 15 min and then incubated in Alexa Fluor 488 (goat-anti-rat; Molecular Probe, Eugene, OR, USA), again diluted 1 in 500 in physiological saline, for 15 min. Preparations were washed with warmed solution and viewed with a confocal microscope, illumination wavelength 488 nm, emission wavelength above 505 nm. The serosal surface of the preparation was first viewed and the microscope focus moved down until ICC were visualized. In control preparations, ICCMY were first detected; subsequently ICCIM were detected in a lower plane of focus. When the longitudinal layer was removed, ICCMY were not detected but ICCIM were apparent.
Statistical methods
All data are expressed as means ±S.E.M. Student's t test was used to determine if data sets differed, with a P value < 0.05 taken to indicate a significant difference. Caffeine, atropine sulphate and nifedipine (obtained from Sigma Chemical Co.) were used in these experiments.
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Results |
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When intracellular recordings were made from the circular layer of antrum, anal to the corpus, regular discharges of slow waves were recorded. Those recorded close to the greater curvature had dominant initial components whereas these were less apparent with more distal recordings (Fig. 1Ac and Bc). Slow waves had amplitudes in the range 27.8–42.3 mV (mean ±S.E.M., 37.3 ± 1.9 mV, n= 7), where each n value represents a measurement from a separate preparation. Slow waves occurred at frequencies in the range 3.7–5.0 waves min–1 (4.5 ± 0.2 waves min–1, n= 7): cells had peak negative potentials in the range –59 to –74 mV (–71.1 ± 1.2 mV, n= 7). When paired recordings were made from the antrum, with the two electrodes both positioned near the greater curvature, slow waves of similar amplitude were detected at each point (Fig. 1Aa and b). On each occasion a slow wave was first detected by the electrode nearer the corpus, indicating that the dominant pacemaker region lay in the corpus (Hashitani et al. 2005). When the conduction velocity of the slow waves in the oro-anal direction was determined, from measurements of electrode separation and the time difference between times to 50% peak amplitude of the slow waves (Fig. 1Ac), it lay in the range 1.6–3.1 mm s–1 (2.5 ± 0.3 mm s–1, n= 7). When paired recordings were made from the antrum, with one electrode positioned near the greater curvature and the other towards the lesser curvature, slow waves of similar amplitude were again detected at each point. On each occasion a slow wave was first detected at the electrode nearer the greater curvature. When the conduction velocity of the spread of slow waves in a circumferential direction was calculated (Fig. 1Bc), it lay in the range 4.4–35.1 mm s–1 (13.9 ± 4.3 mm s–1, n= 7). Using a paired t test, the values of conduction velocity in the anal and circumferential directions were found to be significantly different. Thus, as has been found in other species (Sanders & Publicover, 1989), the circumferential conduction velocity of slow waves in the guinea-pig antrum was faster than that in the anal direction.
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One explanation for the difference between the anal and circumferential conductions velocities of slow waves could be that pacemaker potentials, generated in the ICCMY network, have different intrinsic conduction velocities in the two directions. This possibility was tested by determining the conduction velocity of pacemaker potentials in preparations where the circular layer had been removed. The network of ICCMY was excited along a line and the arrival of the evoked pacemaker potential at two separate distances determined; measuring the length of conduction and conduction time allowed a determination of conduction velocity. Because of the difficulty in recording pacemaker potentials at two separate locations, the depolarizations generated by pacemaker potentials in the longitudinal layer, termed follower potentials (Dickens et al. 1999), were recorded from the longitudinal muscle layer. In these preparations, follower potentials, generated at a point in the longitudinal layer have very similar onset times to that of the pacemaker potentials which generate them (Fig. 2A and B; see also Hirst & Edwards, 2001). When recordings were made at two separate points, the relative onset times of individual spontaneous pairs of follower potentials varied from wave to wave. An example is shown in the lower part of Fig. 2C–F. It can be seen that during the first spontaneous follower potential, the onset of depolarization recorded by the electrode closer to the stimulating bar, illustrated with the continuous line, preceded that of the follower potential recorded with the more distant electrode, illustrated with a dashed line (Fig. 2C and D). Conversely during the second spontaneous follower potential, the depolarization was first detected by the more distant electrode (Fig. 2C and E). When the network of interstitial cells was stimulated electrically along a line, invariably the follower potential was first detected at the recording electrode nearer the stimulating electrode (Fig. 2C and F). These observations suggest that pacemaker potentials originate spontaneously at various points in an isolated patch of ICCMY network and then propagate through the network (Hirst & Edwards, 2001; Hennig et al. 2004; Ward et al. 2004). However, when the ICCMY network is excited, pacemaker potentials originate at the line of stimulation and conduct in a reproducible manner through the network (see also Fig. 3).
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Passive electrical properties of the circular muscle layer
The previous observations suggest that the rapid circumferential conduction of slow waves, detected in intact antral preparations, reflects some aspect of the properties of the circular muscle layer of the antrum. The subsequent experiments were designed to examine these properties. Single isolated bundle of muscles, dissected from the circular layer, were impaled with two electrodes, one placed at each end of the bundle. When the recordings of membrane potential were inspected, they displayed similar discharges of noise although individual unitary potentials would often have larger amplitudes at one or other of the recording electrodes. Current pulses, passed through one electrode, invariably evoked electrotonic potentials that were detected by the electrode at the other end of the bundle. After suppressing the discharge of membrane noise by adding caffeine (1 mM) to the physiological fluid, the time course and amplitude of the electrotonic potential was determined from the average of 20 successive sweeps (Fig. 4). In preliminary experiments the relationship between amplitudes of electrotonic potentials and intensity of injected current was examined. It was found that the relationship was linear provided the membrane potential did not become more negative than –80 mV. The membrane time constant and electrical length constant of each bundle were determined by computation (see Methods). The result from an experiment is shown in Fig. 4. In this example the preparation had a length of 2.1 mm. The two electrodes were inserted, one at either end of the preparation (Fig. 4A); a current, 5 nA, was passed for 1 s through one electrode (Fig. 4C). The electrotonic potential, recorded with the other electrode, could be best described if it was assumed that the bundle had a membrane time constant of 260 ms and an electrical length constant of 3.4 mm (Fig. 4B). From this experimental series, circular muscle bundles were found to have resting membrane potentials in the range –57 to –67 mV (–62.2 ± 1.0 mV, n= 10), their membrane time constants were in the range 190–280 ms (235 ± 10 ms, n= 10) and their electrical length constants were in the range 2.1–4.2 mm (3.0 ± 0.2 mm, n= 10). When their passive conduction velocities were calculated (Jack et al. 1975), they were found to lie in the range 19.5–31.9 mm s–1 (25.2 ± 1.4 mm s–1, n= 10). These experiments show that the electrical properties of bundles of circular muscle are such that in the intact stomach they will readily allow the circumferential transfer of electrical activity.
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In the next set of experiments the connectivity between adjacent bundles of circular muscle was examined. Short sections of the circular layer, containing some four or five adjacent bundles of muscle, were impaled with two electrodes. When both electrodes were placed in the same bundle, an irregular discharge of regenerative potentials, with very similar time courses and amplitudes, was detected by both electrodes (Fig. 5Aa and b). The discharge of regenerative potentials was suppressed by caffeine (1 mM) and the input resistance of the impaled bundle determined by passing current pulses (Fig. 5D) through one electrode and measuring the change in membrane potential with the other electrode (Fig. 5C). Subsequently caffeine was washed away, the recording electrode was removed and the adjacent muscle bundle was impaled. In many of the preparations, 10 of 17, even though the shapes of regenerative potentials in the adjacent bundles differed somewhat, both bundles discharged regenerative potentials synchronously (Fig. 5Ba and b). When the discharge of regenerative potentials was again suppressed by caffeine (1 mM) current pulses injected into one bundle produced electrotonic potentials in the other bundle with amplitudes 20–70% of those detected when both electrodes were in the same bundle (Figs 5C and 7C).
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The grouped results from this series of experiments are shown in (Fig. 7D). Together they show that although many bundles were electrically connected to their neighbours, invariably signals were attenuated between bundles. Moreover, at several points in the circular layer, areas of electrical discontinuity existed which prevent transmission of electrical activity in an oro-anal direction in the circular layer. Thus, whilst supporting the circumferential transfer of electrical activity, the poor connections between neighbouring bundles will hinder or prevent the oro-anal conduction of slow waves.
Circumferential conduction velocity of slow waves in regions of antrum devoid of ICCMY
One explanation for the rapid circumferential conduction of slow waves is that slow waves are initiated in each circular muscle bundle by the slowly travelling descending wave of pacemaker potentials in the ICCMY network. The passive electrical properties of the circular layer then readily allow the circumferential transfer of depolarization. If ICCIM alone could sustain the rapid circumferential propagation of slow waves, the circumferential conduction velocity would then depend on the electrical properties of the circular layer and the activation kinetics of ICCIM but might not be influenced by the conduction of pacemaker potentials within the ICCMY network. To test this idea, slow waves were recorded from regions of antrum that lacked ICCMY (see Methods). Briefly, most of the longitudinal layer was removed with a band, 3 mm wide, adjacent to the greater curvature being left intact. Preparations were labelled with an antibody to CD 117 and inspected to check whether the ICCMY network had been retained near the greater curvature and had been removed circumferentially (Fig. 8A and C); this was found to be the case in each of the preparations examined (n= 6). In this set of experiments, slow waves, recorded from the region of tissue with ICCMY intact (Fig. 8B), had amplitudes in the range 30.3–39.8 mV (33.7 ± 1.4 mV, n= 6) and occurred at frequencies in the range 3.4–4.5 waves min–1 (4.0 ± 0.2 waves min–1, n= 6): cells had peak negative potentials in the range –64 to –69 mV (–66.3 ± 0.8 mV, n= 6). When recordings were made from regions of the circular layer where the longitudinal layer and ICCMY network had been removed, slow waves were invariably detected (Fig. 8D). Slow waves, recorded from regions devoid of ICCMY, had amplitudes in the range 32.0–36.3 mV (33.6 ± 1.0 mV, n= 6) and occurred at frequencies in the range 3.5–4.4 waves min–1 (4.0 ± 0.2 waves min–1, n= 6): cells had peak negative potentials in the range –64 to –70 mV (–67.2 ± 0.9 mV, n= 6). Using paired t tests, the amplitudes, frequencies and peak negative potentials of slow waves recorded from regions where ICCMY were absent were found not to differ significantly from those recorded from tissues with ICCMY present.
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Discussion |
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After removing the circular layer, pacemaker potentials propagate slowly through the ICCMY network whatever the direction of spread. Thus, when the conduction velocity of evoked pacemaker potentials was measured, the conduction velocity in either the anal or circumferential direction was about 3 mm s–1 (Fig. 3). This value of conduction velocity is the same as that determined using calcium imaging techniques to monitor the progression of spontaneous pacemaker potentials through the ICCMY network; again, the conduction velocity in different directions was found to be the same (Hennig et al. 2004). Why pacemaker potentials propagate so slowly in the ICCMY network is not understood. It seems unlikely that this results from poor electrical coupling between neighbouring ICCMY. Neurobiotin readily spreads from an impaled myenteric interstitial cell to neighbouring ICCMY (Dickens et al. 1999). Abundant deposits of connexion-43 are located within the ICCMY network (Cousins et al. 2003) and electron micrographs indicate the presence of numerous gap junctions between nearby ICCMY (Jimenez et al. 1999; Horiguchi et al. 2001). Given that the conduction velocities of pacemaker potentials in the oro-anal and circumferential directions are similar in preparations consisting only of the longitudinal layer and the ICCMY network (Fig. 3), it seems unlikely that the conduction velocity depends critically on current flow through the longitudinal layer since the electrical length constants of the longitudinal muscle layer differ markedly in the oro-anal and circumferential directions (Cousins et al. 1993). This problem is explored in the accompanying paper (Edwards & Hirst, 2006).
Each pacemaker potential passively depolarizes adjacent circular muscle bundles (Cousins et al. 2003); when depolarized, each bundle of circular muscle initiates a regenerative response (Suzuki & Hirst, 1999). The passive electrical properties of the layer are such that they support the rapid circumferential spread of depolarization (Fig. 4). In most excitable cells, where voltage-dependent ion-selective channels are activated, the active conduction velocity is much faster than the electrotonic conduction velocity (Jack et al. 1975). However, the regenerative component of the slow wave involves release of calcium ions from internal stores and has slow activation kinetics (Suzuki & Hirst, 1999; Edwards & Hirst, 2003; Edwards & Hirst, 2005). Under these circumstances the active conduction velocity of regenerative responses will approach the electrotonic conduction velocity, in this case about 25 mm s–1. Furthermore, since circular muscle bundles are organized into ‘muscle units’, with regions of poor coupling between bundles being frequent (Figs 6 and 7), excitation will not spread over large distances in the oro-anal direction. The finding that slow waves of normal amplitude readily conduct in a circumferential direction in antral regions of tissue where the ICCMY network has been removed (Figs 8 and 9) indicates that the circular muscle layer alone is capable of sustaining the propagation of slow waves. Similar observations have been made in the pyloric region of guinea-pig stomach (van Helden & Imtiaz, 2003). In the dog antrum, slow waves propagate with similar conduction velocities and there the process is voltage dependent and depends on calcium entry (Ward et al. 2004). Presumably a similar mechanism underlies the conduction of slow waves in the guinea-pig antrum but this point has not been addressed in this study. Since smooth muscle cells do not contain sets of ion channels capable of generating slow waves (Farrugia, 1999), the propagation of slow waves must be sustained by ICCIM. In the antrum of mutant mice that lack ICCIM, waves of rhythmical depolarization are only detected in areas of tissue near to the ICCMY network: at the lesser curvature, where ICCMY are absent, little electrical activity is detected (Hirst et al. 2002a). However, when ICCIM are present, slow waves of normal amplitude are detected in all regions, even when the density of ICCMY is very low (Hirst et al. 2002a). These observations indicate that ICCIM normally sustain the propagation of slow waves in the mouse antrum in the region near the lesser curvature. In several species, histological studies indicate that two separate groups of ICC are associated with smooth muscle cells in the circular layer. In the dog antrum, ICCIM and ICC with a septal location (ICCSEP) have been described (Horiguchi et al. 2001). ICCIM are present in guinea-pig antrum (Burns et al. 1997) and they alone could be responsible for the conduction of slow waves along the circular layer. Alternatively, if both ICCIM and ICCSEP are present in guinea-pig antrum, both could contribute to the circumferential spread of slow waves.
The conduction velocity of slow waves in the circumferential direction is the same whether the ICCMY network is present or absent (Figs 1 and 9), suggesting that ICCMY are only involved in the initiation of slow waves rather than in their conduction. If this view is correct, the role of ICCMY, located away from the region of greater curvature, may be to detect any changes in the frequency of regenerative responses in the circular layer and coordinate activity if the dominant pacemaker is shifted to the circular layer, as can happen during excitatory nerve activity (Hirst et al. 2002b).
In summary, our observations suggest that the rapid circumferential conduction of slow waves can be explained largely on the basis of the electrical properties of the circular muscle layer. Each wave of pacemaker depolarization is initiated at the interface between the corpus and the antrum (Hashitani et al. 2005); it then conducts slowly in an anal direction through the ICCMY network (Fig. 10). As the pacemaker potential passes over successive circular muscle units, it passively depolarizes each muscle unit. The passive wave of pacemaker depolarization activates ICCIM and they initiate the regenerative component of the slow wave. A wave of depolarization spreads more rapidly in a circumferential direction, so activating successive ICCIM: these in turn generate a rapidly propagating circumferentially directed slow wave (Fig. 10). Thus, together the two sets of ICC generate a slowly descending ring of contraction in the intact stomach.
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References |
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TopAbstractIntroductionMethodsResultsDiscussionReferences |
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