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Biomedical subjects

F R Edwards

Publications and source records attributed to F R Edwards.

At least 19 recordsLinked to original sources
PubMed2004

An electrical description of the generation of slow waves in the antrum of the guinea-pig.

This paper provides an electrical description of the generation of slow waves in the guinea-pig gastric antrum. A short segment of a circular smooth muscle bundle with an attached network of myenteric interstitial cells of Cajal (ICC-MY) and longitudinal muscle sheet was modelled as three electrical compartments with resistive connexions between the ICC-MY compartment and each of the smooth muscle compartments. The circular smooth muscle layer contains a proportion of intramuscular interstitial cells of Cajal (ICC-IM), responsible for the regenerative component of the slow wave. Hence the equivalent cell representing the circular muscle layer incorporated a mechanism, modelled as a two stage reaction, which produces an intracellular messenger. The first stage of the reaction is proposed to be activated in a voltage-dependent manner as described by Hodgkin and Huxley. A similar mechanism was incorporated into the equivalent cell describing the ICC-MY network. Spontaneous discrete transient depolarizations, termed unitary potentials, are detected in records taken from either bundles of circular smooth muscle containing ICC-IM or from ICC-MY. In the simulation the mean rate of discharge of unitary potentials was allowed to vary with the concentration of messenger according to a conventional dose-effect relationship. Such a mechanism, which describes regenerative potentials generated by the circular muscle layer, also simulated the plateau component of the pacemaker potential in the ICC-MY network. A voltage-sensitive membrane conductance was included in the ICC-MY compartment; this was used to describe the primary component of the pacemaker potential. The model generates a range of membrane potential changes with properties similar to those generated by the three cell types present in the intact tissue.

Animals↗
PubMed2004

An analysis of inhibitory junction potentials in the guinea-pig proximal colon.

Intracellular recordings were made from either sheets or isolated bundles of the circular muscle layer of guinea-pig proximal colon and the responses evoked by stimulating inhibitory nerve fibres were analysed. Inhibitory junction potentials (IJPs), evoked by single stimuli, had two components which could be separated on their pharmacological and temporal characteristics and their voltage sensitivities. The initial component, which was abolished by apamin and reduced in amplitude by pyridoxalphosphate-6-azophenyl-2',4'-disulphonic acid (PPADS), had a brief time course: its amplitude was changed when the external concentration of potassium ions ([K+](o)) was changed. The second component of the IJP had a slower onset than the first component, was abolished by l-nitroarginine (NOLA) and oxadiazolo quinoxalin-1-one (ODQ), an inhibitor of soluble guanylate cyclase: its amplitude was little affected by changing [K+](o) and was increased when the membrane potential of the circular layer was hyperpolarized. The observations suggest that the initial component of the IJP results from the release of ATP which triggers an increase in membrane conductance to K+ and that the second component results from the release of nitric oxide which suppresses a background inward current.

Animals↗
PubMed2003

Electrical coupling between the myenteric interstitial cells of Cajal and adjacent muscle layers in the guinea-pig gastric antrum.

Intracellular recordings were made from short segments of the muscular wall of the guinea-pig gastric antrum. Preparations were impaled using two independent microelectrodes, one positioned in the circular layer and the other either in the longitudinal layer, in the network of myenteric interstitial cells of Cajal (ICCMY) or in the circular layer. Cells in each layer displayed characteristic patterns of rhythmical activity, with the largest signals being generated by ICCMY. Current pulses injected into the circular muscle layer produced electrotonic potentials in each cell layer, indicating that the layers are electrically interconnected. The amplitudes of these electrotonic potentials were largest in the circular layer and smallest in the longitudinal layer. An analysis of electrical coupling between the three layers suggests that although the cells in each layer are well coupled to neighbouring cells, the coupling between either muscle layer and the network of ICCMY is relatively poor. The electrical connections between ICCMY and the circular layer did not rectify. In parallel immunohistochemical studies, the distribution of the connexins Cx40, Cx43 and Cx45 within the antral wall was determined. Only Cx43 was detected; it was widely distributed on ICCMY and throughout the circular smooth muscle layer, being concentrated around ICCIM, but was less abundant in the circular muscle layer immediately adjacent to ICCMY. Although the electrophysiological studies indicate that smooth muscle cells in the longitudinal muscle layer are electrically coupled to each other, none of the connexins examined were detected in this layer.

Algorithms↗
PubMed2003

Mathematical description of regenerative potentials recorded from circular smooth muscle of guinea pig antrum.

Regenerative potentials evoked by intracellular current injection in single bundles of circular smooth muscle taken from guinea pig antrum have the characteristics of the secondary regenerative component of the slow wave occurring in the same muscle layer. Such regenerative depolarizations might result from a mechanism that responds to membrane polarization with a delayed increase in the rate of production of unitary potentials detected in this tissue. To test this possibility, a two-stage reaction leading to the formation of an intracellular messenger was proposed. The first forward reaction was voltage-dependent, in the manner described by the Hodgkin-Huxley transient Na conductance formalism, allowing simulation of anode break excitation, stimulus threshold strength-duration characteristics, and refractory behavior. A conventional dose-effect relationship was proposed to describe the dependence of the mean rate of discharge of unitary potentials on messenger concentration. Unitary potentials were modeled as unitary membrane conductance modulations with an empirically derived amplitude distribution and Poisson-distributed intervals. The model reproduces a range of spontaneous and evoked membrane potential changes characteristic of antral circular muscle bundles.

Animals↗
PubMed2003

Involvement of intramuscular interstitial cells in nitrergic inhibition in the mouse gastric antrum.

Intracellular recordings were made from isolated bundles of the circular muscle layer of mouse gastric antrum and the responses evoked by stimulating intrinsic nerve fibres were examined. Transmural nerve stimulation evoked a fast inhibitory junction potential (fast-IJP) which was followed initially by a smaller amplitude long lasting inhibitory junction potential (slow-IJP) and a period of excitation. The excitatory component of the response was abolished by atropine, suggesting that it resulted from the release of acetylcholine and activation of muscarinic receptors. Fast-IJPs were selectively reduced in amplitude by apamin and slow-IJPs were abolished by N(omega)-nitro-L-arginine. Slow-IJPs were associated with a drop in membrane noise, suggesting that inhibition resulted from a reduced discharge of unitary potentials by intramuscular interstitial cells of Cajal (ICC(IM)). The chloride channel blocker, anthracene-9-carboxylic acid, reduced the discharge of membrane noise in a manner similar to that detected during the slow-IJP. When recordings were made from the antrum of W/W(V) mice, which lack ICC(IM), the cholinergic and nitrergic components were absent, with only fast-IJPs being detected. The observations suggest that neurally released nitric oxide selectively targets ICC(IM) causing a hyperpolarization by suppressing the discharge of unitary potentials.

Animals↗
PubMed2002

Pacemaker shift in the gastric antrum of guinea-pigs produced by excitatory vagal stimulation involves intramuscular interstitial cells.

Intracellular recordings were made from isolated bundles of the circular muscle layer of guinea-pig gastric antrum and the responses produced by stimulating intrinsic nerve fibres were examined. After abolishing the effects of stimulating inhibitory nerve terminals with apamin and L-nitroarginine (NOLA), transmural nerve stimulation often evoked a small amplitude excitatory junction potential (EJP) and invariably evoked a regenerative potential. Neurally evoked regenerative potentials had similar properties to those evoked in the same bundle by direct stimulation. EJPs and neurally evoked regenerative potentials were abolished by hyoscine suggesting that both resulted from the release of acetylcholine and activation of muscarinic receptors. Neurally evoked regenerative potentials, but not EJPs, were abolished by membrane hyperpolarization, caffeine and chloride channel blockers. In the intact antrum, excitatory vagal nerve stimulation increased the frequency of slow waves. Simultaneous intracellular recordings of pacemaker potentials from myenteric interstitial cells (ICC(MY)) and slow waves showed that the onset of each pacemaker potential normally preceded the onset of each slow wave but vagal stimulation caused the onset of each slow wave to precede each pacemaker potential. Together the observations suggest that during vagal stimulation there is a change in the origin of pacemaker activity with slow waves being initiated by intramuscular interstitial cells (ICC(IM)) rather than by ICC(MY).

4,4'-Diisothiocyanostilbene-2,2'-Disulfonic Acid↗
PubMed2002

Regenerative component of slow waves in the guinea-pig gastric antrum involves a delayed increase in [Ca(2+)](i) and Cl(-) channels.

Regenerative potentials were initiated by depolarizing short segments of single bundles of circular muscle isolated from the gastric antrum of guinea-pigs. When changes in [Ca(2+)](i) and membrane potential were recorded simultaneously, regenerative potentials were found to be associated with an increase in [Ca(2+)](i), with the increase starting after a minimum latency of about 1 s. Although the increase in [Ca(2+)](i) was reduced by nifedipine, the amplitudes of the regenerative responses were little changed. Regenerative responses and associated changes in [Ca(2+)](i) were abolished by loading the preparations with the Ca(2+) chelator MAPTA-AM. Regenerative potentials were abolished by 2-aminoethoxydiphenyl borate (2APB), an inhibitor of IP(3) induced Ca(2+) release, by N-ethylamaleimide (NEM), an alkylating agent which blocks activation of G-proteins and were reduced in amplitude by two agents which block chloride (Cl(-))-selective channels in many tissues. The observations suggest that membrane depolarization triggers IP(3) formation. This causes Ca(2+) release from intracellular stores which activates Ca(2+)-dependent Cl(-) channels.

Animals↗
PubMed2001

Generation of slow waves in the antral region of guinea-pig stomach--a stochastic process.

1. Slow waves were recorded from the circular muscle layer of the antral region of guinea-pig stomach. Slow waves were abolished by 2APB, an inhibitor of IP(3)-induced Ca2+ release. 2. When the rate of generation of slow waves was monitored it was found to vary from cycle to cycle around a mean value. The variation persisted after abolishing neuronal activity with tetrodotoxin. 3. When simultaneous recordings were made from interstitial cells in the myenteric region (ICC(MY)) and smooth muscle cells of the circular layer, variations in the rate of generation of slow waves were found to be linked with variations in the rate of generation of driving potentials by ICC(MY). 4. A preparation was devised which consisted of the longitudinal muscle layer and ICC(MY). In this preparation ICC(MY) and smooth muscle cells lying in the longitudinal muscle layer generated driving potentials and follower potentials, synchronously. 5. Driving potentials had two components, a rapid primary component that was followed by a prolonged plateau component. Caffeine (3 mM) abolished the plateau component; conversely reducing the external concentration of calcium ions [Ca2+](o) mainly affected the primary component. 6. Analysis of the variations in the rate of generation of driving potentials indicated that this arose because both the duration of individual driving potentials and the interval between successive driving potentials varied. 7. It is suggested that the initiation of pacemaker activity in a network of ICC(MY) is a stochastic process, with the probability of initiating a driving potential slowly increasing, after a delay, from a low to a higher value following the previous driving potential.

Animals↗
PubMed2001

Intercellular electrical communication among smooth muscle and endothelial cells in guinea-pig mesenteric arterioles.

1. Current clamp studies using two patch electrodes and morphological observations have been performed in guinea-pig mesenteric arterioles to evaluate intercellular electrical couplings. 2. In electron micrographs, preparations were found to have a single layer of smooth muscle cells. Typical gap junctions were readily observed between endothelial cells only. 3. While immunoreactivity to connexin 40 was strongly expressed on the membranes of endothelial cells only, that to connexin 43 was expressed on both smooth muscle and endothelial cell membranes. 4. Neurobiotin injected into a smooth muscle cell diffused into several neighbouring smooth muscle cells while that injected into an endothelial cell diffused into many endothelial cells. 5. Acetylcholine-induced hyperpolarizations were conducted from endothelial cells to smooth muscle cells with a relative amplitude of 80.1 %. Ba(2+)-induced action potentials were conducted in the opposite direction with a relative amplitude of 92.4 %. 6. An electrotonic potential produced in a smooth muscle cell by current injection diminished steeply with distance as it spread along the muscle layer, plateauing at distances beyond 25 microm. An electrotonic potential produced in an endothelial cell spread within the intima with virtually no reduction. Electrotonic potentials could conduct through myoendothelial couplings, which seemed to behave as ohmic resistors without rectification. 7. The coupling resistance between adjacent smooth muscle cells was estimated to be at least 90 MOhms and that between a smooth muscle cell and the whole endothelial layer to be 0.9 GOhms. 8. The results indicate that although the resistance of myoendothelial couplings is appreciable, the endothelium may be important as a low resistance path connecting many smooth muscle cells.

Animals↗
PubMed2001

Selective knockout of intramuscular interstitial cells reveals their role in the generation of slow waves in mouse stomach.

1. Intracellular recording techniques were used to compare the patterns of electrical activity generated in the antral region of the stomachs of wild-type and W/W(V) mutant mice. Immunohistochemical techniques were used to determine the distribution of c-kit-positive interstitial cells of Cajal (ICC) within the same region of the stomach. 2. In wild-type mice interstitial cells were found at the level of the myenteric plexus (ICC(MY)) and distributed within the smooth muscle bundles (ICC(IM)). In these preparations slow waves, which consisted of initial and secondary components, were detected. 3. In W/WV mutant mice ICC(MY) could be identified at the level of the myenteric plexus but ICC(IM) were not detected within smooth muscle bundles. Intracellular recordings revealed that smooth muscle cells generated waves of depolarization; these lacked a secondary component. 4. These results indicate that the secondary regenerative component of a slow wave is generated by ICC(IM). Thus the depolarization arising from the pacemaker cells, ICC(MY), is augmented by ICC(IM), so causing a substantial membrane depolarization in the circular muscle layer. Rather than contributing directly to rhythmical electrical activity, smooth muscle cells appear to depolarize at the command of the two subpopulations of ICC.

Animals↗
PubMed2001

Parallel metabotropic pathways in the heart of the toad, Bufo marinus.

This study examined the transduction pathways activated by epinephrine in the pacemaker region of the toad heart. Recordings of membrane potential, force, and intracellular Ca(2+) concentration ([Ca(2+)](i)) were made from arrested toad sinus venosus. Sympathetic nerve stimulation activated non-alpha-, non-beta-adrenoceptors to evoke a membrane depolarization and a transient increase in [Ca(2+)](i). In contrast, the beta-adrenoceptor agonist isoprenaline (10 microM) caused membrane hyperpolarization and decreased [Ca(2+)](i). The phosphodiesterase inhibitor 3-isobutyl-1-methylxanthine (0.5 mM) mimicked the isoprenaline-evoked membrane hyperpolarization. Epinephrine (10-50 microM) caused an initial membrane depolarization and an increase in [Ca(2+)](i) followed by membrane hyperpolarization and decreased [Ca(2+)](i). The membrane depolarizations evoked by sympathetic nerve stimulation or epinephrine were abolished either by the phospholipase C inhibitor U-73122 (20 microM) or by the blocker of D-myo-inositol 1,4,5,-trisphosphate-induced Ca(2+) release, 2-aminoethoxydiphenyl borate (2-APB, 60 microM). Neither U-73122 nor 2-APB had an affect on the membrane hyperpolarization evoked by beta-adrenoceptor activation. These results suggest that in the toad sinus venosus, two distinct transduction pathways can be activated by epinephrine to cause an increase in heart rate.

Adrenergic Agonists↗
PubMed2000

Vagal inhibition in the antral region of guinea pig stomach.

The effects of vagal stimulation in the presence of a muscarinic antagonist were examined on three distinct rhythmically active cells located in guinea pig antrum. Vagal stimulation inhibited contractions of the circular muscle layer but did not change their rate of occurrence. With the use of intracellular recording techniques, these stimuli were found to initiate inhibitory junction potentials in the circular layer but produced smaller potential changes in driving and follower cells. Inhibition of the circular muscle layer involved two separate components. The dominant component was independent of changes in membrane potential and was abolished by nitro-L-arginine. After abolishing Ca(2+) entry into smooth muscle cells with a Ca(2+) antagonist, vagal stimulation continued to inhibit the residual contractions associated with each slow wave. When the cyclic changes in intracellular Ca(2+) concentration associated with each slow wave were measured, they were found to be unchanged by vagal stimulation. The observations suggest that vagal inhibition of stomach movements does not alter pacemaker activity in the stomach; rather, it results from a change in the sensitivity of smooth muscle contractile proteins to Ca(2+).

Animals↗
PubMed1999

Unitary nature of regenerative potentials recorded from circular smooth muscle of guinea-pig antrum.

1. When short segments of single bundles of circular muscle of guinea-pig antrum were isolated and impaled with two microelectrodes, the membrane potential recordings displayed an ongoing discharge of noise. 2. Treating the preparations with acetoxymethyl ester form of BAPTA (BAPTA AM) reduced the membrane noise and revealed discrete depolarizing unitary potentials. The spectral densities determined from control preparations and ones loaded with BAPTA had similar shapes but those from control preparations had higher amplitudes, suggesting that membrane noise results from a high frequency discharge of unitary potentials. 3. Depolarization of isolated segments of antrum initiated regenerative responses. These responses, along with membrane noise and unitary potentials, were inhibited by a low concentration of caffeine (1 mM). 4. Loading the preparations with BAPTA decreased the amplitudes of regenerative responses. Depolarization was now seen to increase the frequency and mean amplitude of unitary potentials over a time course similar to that of a regenerative potential. 5. Noise spectra determined during periods of rest, during regenerative potentials triggered by direct depolarization and during slow waves, recorded from preparations containing interstitial cells of Cajal (ICC), had very similar shapes but different amplitudes. 6. The observations suggest that a regenerative potential, the secondary component of a slow wave, is made up of a cluster of several discrete unitary potentials rather than from the activation of voltage-dependent ion channels.

Animals↗
PubMed1999

Spontaneous and neurally activated depolarizations in smooth muscle cells of the guinea-pig urethra.

1. Membrane potential recordings were made from longitudinal smooth muscle cells of the guinea-pig urethra using conventional microelectrode techniques. 2. Smooth muscle cells of the urethra developed spontaneous transient depolarizations (STDs) and slow waves. Single unit STDs had amplitudes of approximately 5 mV and slow waves seemed to occur as amplitude multiples of single unit STDs. 3. STDs and slow waves were abolished by niflumic acid or low chloride solution and also by cyclopiazonic acid (CPA), BAPTA or high concentrations of caffeine. Lower concentrations of caffeine abolished slow waves but not STDs. Nifedipine inhibited slow waves but not STDs. 4. When stochastic properties of STDs were examined, it was found that the intervals between occurrences were not well modelled by Poisson statistics, instead the STDs appeared to be clustered. 5. Transmural stimulation evoked excitatory junctional potentials (EJPs) and triggered slow waves which were abolished by either alpha,beta-methylene-ATP or tetrodotoxin. Evoked slow waves were also abolished by caffeine, co-application of caffeine and ryanodine or by CPA which left EJPs unaffected. 6. In conclusion, smooth muscle cells of urethra exhibit STDs which are clustered rather than random events, and are the result of spontaneous Ca2+ release from intracellular stores and subsequent activation of Ca2+-activated chloride channels. STDs sum to activate L-type Ca2+ channels which contribute to the sustained phase of slow waves. Stimulation of purinoceptors by neurally released ATP initiates EJPs and also causes the release of Ca2+ from intracellular stores to evoke slow waves.

Adenosine Triphosphate↗
PubMed1997

Electrical properties of iridial arterioles of the rat.

When intracellular recordings were made from iridial arterioles, the cells had membrane potentials of about -65 mV and perivascular nerve stimulation evoked a membrane depolarization. When these cells were labeled with lucifer yellow, all cells that responded to perivascular nerve stimulation had the morphological characteristics of smooth muscle cells. Cells with the morphological characteristics of endothelial cells were never stained. When impaled with two separate recording electrodes, the smooth muscle layer was shown to form an electrical syncytium with a membrane time constant of approximately 80 ms and an electrical length constant of approximately 900 microns. At the ultrastructural level, areas of close apposition were frequently observed between adjacent smooth muscle cells and between adjacent endothelial cells. On the other hand, at contacts between smooth muscle and endothelial cells, the membranes characteristically had much larger separations. The observations show that individual smooth muscle cells are electrically coupled to their neighbors, but the morphological studies raise the possibility that in these arterioles the endothelial and muscle layers are electrically separate.

Animals↗
PubMed1995

Different types of ganglion cell in the cardiac plexus of guinea-pigs.

1. Intracellular recordings were made from the parasympathetic ganglion cells that lie in the epicardium of the left atrium of guinea-pig heart near the interatrial septum. 2. Three distinct types of neurone were identified on the basis of their electrophysiological properties. In one group of neurones, S cells, somatic action potentials were followed by brief after-hyperpolarizations. In the other two sets of neurones, somatic action potentials were followed by prolonged after-hyperpolarizations. The neurones with prominent after-hyperpolarization were further subdivided: one group of neurones, P cells, showed inward rectification at membrane potentials near the resting membrane potential whilst neurones in the other group, SAH cells, did so only at more negative potentials. 3. In the group of neurones that displayed inward rectification at potentials near rest, rectification resulted from the activation of an inward current, which resembled the hyperpolarization-activated inward current present in cardiac muscle pacemaker cells. 4. The three different types of neurone received different patterns of synaptic input. Each SAH cell received a synaptic excitatory connection from the vagus which in most cells released sufficient transmitter to initiate an action potential in that cell; several SAH cells also received a separate connection, which could be activated by local stimulation. Although most S cells failed to receive a synaptic input from the vagus, all of those tested received an excitatory synaptic input which could be activated by local stimulation. Virtually all P cells failed to receive a synaptic input from the vagus; in addition, local stimulation failed to initiate synaptic potentials in P cells. 5. When the structure of cardiac ganglion cells was determined, by loading the cells with either biocytin or neurobiotin, it was found that most cells lacked extensive dendritic processes. S cells were invariably monopolar, most P cells were dipolar or pseudodipolar, whereas many SAH cells were multipolar. 6. In many neurones an on-going discharge of action potentials was detected in the absence of obvious stimulation. In S and SAH cells, the action potentials resulted from an on-going discharge of excitatory synaptic potentials. However, when a spontaneous discharge of action potentials was detected in P cells a discharge of excitatory synaptic potentials was not detected. 7. The results are discussed in relation to the idea that the three different types of cell may have different functions and that some of the cells may be organized in such a way as to permit the local handling of neuronal information within the heart.

Animals↗
PubMed1995

Neuronally released and applied acetylcholine on the longitudinal muscle of the guinea-pig ileum.

Brief transmural stimuli, which selectively excited cholinergic fibres, initiated contractions and excitatory junction potentials in preparations of longitudinal muscle isolated from the guinea-pig ileum: these responses were associated with an increase in the internal concentration of calcium ions. When muscle voltage-dependent calcium channels were blocked using the organic calcium antagonist nifedipine, brief stimuli continued to initiate contractions, evoke excitatory junction potentials and cause an increase in the intracellular calcium concentration. Ionophoretically applied acetylcholine caused depolarizations which resembled the excitatory junction potentials evoked by cholinergic nerve stimulation. Both responses had slow time courses and were abolished by muscarinic receptor antagonists. However, the depolarizations produced by ionophoretically applied acetylcholine, unlike those produced by nerve stimulation, were frequently interrupted by transient hyperpolarizations. The transient hyperpolarizations were abolished by barium ions or charybdotoxin. High concentrations of the calcium antagonists nicardipine, verapamil or diltiazem had a tendency to preferentially abolish the excitatory junction potential. When the effects of the cholinesterase inhibitor, eserine, on excitatory junction potentials were examined, it became apparent that when the destruction of acetylcholine was prevented it initiated an additional conductance change to that initiated by acetylcholine in untreated tissues. The results are discussed in relation to the idea that neuronally released acetylcholine and applied acetylcholine might activate different subsets of muscarinic receptors on longitudinal ileal smooth muscle.

Acetylcholine↗