Single-interface bioelectronic medicines-concept, clinical applications and preclinical data.

Presently, large groups of patients with various diseases are either intolerant, or irresponsive to drug therapies and also intractable by surgery. For several diseases, one option which is available for such patients is the implantable neurostimulation therapy. However, lacking closed-loop control and selective stimulation capabilities, the present neurostimulation therapies are not optimal and are therefore used as only 'third' therapeutic options when a disease cannot be treated by drugs or surgery. Addressing those limitations, a next generation class of closed-loop controlled and selective neurostimulators generically named bioelectronic medicines seems within reach. A sub-class of such devices is meant to monitor and treat impaired functions by intercepting, analyzing and modulating neural signals involved in the regulation of such functions using just one neural interface for those purposes. The primary objective of this review is to provide a first broad perspective on this type of single-interface devices for bioelectronic therapies. For this purpose, the concept, clinical applications and preclinical studies for further developments with such devices are here analyzed in a narrative manner.

An Intraneural Electrode for Bioelectronic Medicines for Treatment of Hypertension.

OBJECTIVES: As the left vagus nerve (LVN) mediates a baroreflex blood pressure (BP) decrease, LVN stimulation (LVNS) could be a therapy for hypertension. Moreover, LVNS could elegantly be adjusted to the patient's actual BP and physical activity by using the neural information about BP and respiration extractable from LVN. However, unselective LVNS will trigger undesirable side-effects and therefore we here investigated the feasibility of using an intraneural electrode for extracting BP and respiration markers from the LVN and for selective LVNS. MATERIALS AND METHODS: Experiments were performed on six anesthetized pigs from which the BP was recorded using arterial catheters and the respiratory cycles by recording the airway pressure. An electrode comprising four tripolar channels was inserted longitudinally in the LVN of the animals to extract BP and respiration markers from the LVN and for selective LVNS. RESULTS: BP-related and respiratory-related neural profiles (BPnPs and RnPs, respectively) were derived from at least two electrode channels in all pigs. The BPnPs accurately resembled the BP waves and the RnPs accurately resembled the respiratory cycles, which suggests that those profiles could serve as BP and respiration markers, respectively. The BP was decreased by intraneural LVNS in all pigs and in four of those pigs such an effect was induced without major cardiac changes through a channel-selective stimulation. CONCLUSION: This study shows that it is feasible to extract BP and respiratory markers from the LVN with the tested intraneural electrode and suggests that this electrode could also be used for selective LVNS.

A New Rat Model of Seizures Suitable for Screening Antiepileptic Electrical Stimulation Therapies.

The antiepileptic effects of the electrical stimulation therapies developed for patients with intractable epilepsies depend critically on the stimulation parameters, including the pulse duration, current, and frequency. Consequently, optimization of such therapies requires many animals for testing each of the stimulation parameters alone or in combination, which is costly and time consuming. This drawback could be reduced by testing several stimulation paradigms in each animal, but this requires an animal model of long-lasting seizures allowing such repetitive tests. This study was performed to validate such a model of long-lasting seizures. The present analysis was performed on electrocorticogram and intracortical signals collected from the somatosensory cortex of 11 Sprague Dawley rats. A protocol of controlled intravenous infusion of pentylenetetrazol (PTZ) was developed to induce spike-and-wave (SW) seizures and maintain stable those seizures for the whole experimental time. SW discharges were induced and maintained stable for 2 h in all rats through a two-stage infusion of PTZ. During the first stage, the SW discharges were induced by 2.5 min infusion of 10 mg/kg/min PTZ. During the second stage, the SW discharges were maintained at a stable level of frequency and power for 2 h via a 0.21 mg/kg/min PTZ infusion rate. The proposed animal model of seizures is characterized by SW discharges which remain stable for 2 h. This 2-h long time interval allows repetitive tests with different stimulation parameters in each animal, which may lead to a significant reduction of the number of animals necessary for optimizing electrical stimulation therapies developed to inhibit seizures.

A Respiratory Marker Derived From Left Vagus Nerve Signals Recorded With Implantable Cuff Electrodes.

OBJECTIVE: Left vagus nerve (LVN) stimulation (LVNS) has been tested for lowering the blood pressure (BP) in patients with resistant hypertension (RH). Whereas, closed-loop LVNS (CL-LVNS) driven by a BP marker may be superior to open-loop LVNS, there are situations (e.g., exercising) when hypertension is normal. Therefore, an ideal anti-RH CL-LVNS system requires a variable to avoid stimulation in such conditions, for example, a respiratory marker ideally extracted from the LVN. As the LVN conducts respiratory signals, this study aimed to investigate if such signals can be recorded using implantable means and if a marker to monitor respiration could be derived from such recordings. MATERIALS AND METHODS: The experiments were performed in 14 anesthetized pigs. Five pigs were subjected to changes of the respiratory frequency and nine to changes of the respiratory volume. The LVN electroneurogram (VENG) was recorded using two cuff electrodes and the respiratory cycles (RC) using a pressure transducer. To separate the afferent and efferent VENGs, vagotomy was performed between the cuffs in the first group of pigs. The VENG was squared to derive respiration-related neural profiles (RnPs) and their correlation with the RCs was investigated in regard to timing and magnitude parameters derived from the two waveforms. RESULTS: The RnPs were morphologically similar with the RCs and the average RnPs represented accurate copies of the average RCs. Consequently, the lung inflation/deflation RC and RnP components had the same duration, the respiratory frequency changes affected in the same way both waveforms and the RnP amplitude increased linearly with the lung inflation in all tested pigs (R2 values between 0.85 and 0.99). CONCLUSIONS: The RnPs comprise information regarding the timing and magnitude of the respiratory parameters. As those LVN profiles were derived using implantable means, this study indicates that the RnPs could serve as respiratory markers in implantable systems.

A neural blood pressure marker for bioelectronic medicines for treatment of hypertension.

A novel therapeutic approach for treating resistant hypertension could be the use of bioelectronic medicines to achieve blood pressure (BP) control in implanted patients by closed-loop stimulation of the left vagus nerve (LVN). However, such a technology would require an implantable BP marker, which is not available yet. As it is known that the LVN conducts afferent BP-related signals, this study aimed to investigate if such signals could be recorded with implantable means and used to derive BP markers. The present experiments were performed in anesthetized pigs subjected to a transient or stable BP increase induced by adrenaline administration. The LVN signals recorded with cuff electrodes and the BP waves recorded with carotid catheters were ensemble averaged relative to the R-peaks of the electrocardiogram. Through this procedure, afferent BP-related neural profiles (BPnPs) were derived from the LVN signals. As the BPnPs represented accurate copies of the BP waves, the timing parameters of both waveforms were almost the same and the BPnP amplitude increased linearly with the diastolic, systolic and mean BP. These results indicate that the BPnPs comprise accurate BP information and that the BPnP amplitude could serve as a BP marker in implantable systems.

Recover of peripheral nerve function after prolong hypothermic cardiac arrest in a porcine model with extra corporeal life support.

OBJECTIVES: Surviving long lasting cardiac arrest following accidental hypothermia has been reported after treatment with extra corporeal life support (ECLS), but there is a risk of neurologic injury. Most surviving hypothermia patients have a prolonged stay in the intensive care unit, where most patients experience polyneuropathy. Theoretically, accidental hypothermic cardiac arrest may in itself contribute to polyneuropathy. This study was designed to examine the impact of three hours of cardiac arrest at a core temperature of 20°C followed by reanimation of peripheral nerve function. METHODS: Seven pigs were cannulated for ECLS and cooled to a core temperature of 20°C followed by three hours of circulatory arrest where the extremities were packed with ice. After three hours, ECLS was started and rewarming was performed. During the process, neural testing of the ulnar nerve (a somatic nerve) and of the vagus nerve (an autonomic nerve) were performed and blood was drawn for analysis of p-potassium, serum-neuron-specific enolase, and S100b protein. RESULTS: The ulnar nerve was cooled from 34.9±1.6°C to 12.8±3.8°C and the vagus nerve from 36.2±1.2°C to 15.4±1.4°C. Physiologic function of both somatic and autonomic nerves were strongly affected by cooling, but recovered to almost normal levels during rewarming, even after three hours of hypothermic cardiac arrest. P-potassium rose from 3.9 (3.6-4.6)mmol/l to 8.1 (7.2-9.1)mmol/l after three hours of cardiac arrest, but normalized after recirculation. There was no rise in serum-neuron-specific enolase, but a slight rise in S100b protein during three hours of hypothermic cardiac arrest was observed. All pigs obtained return of spontaneous circulation (ROSC). CONCLUSIONS: Reanimation after three hours of hypothermic cardiac arrest using ECLS was possible with no or, if present, minor damage to the two nerves tested.

Changes in vagus nerve activity associated with ictal tachycardia in pigs.

OBJECTIVE: Ictal tachycardia (IT) is common and may pave the way towards cardiac conditions with high risk potential. However, the mechanisms of IT remain obscure and therefore difficult to control. For example, whereas IT is associated with a sympathetic surge, it is unclear why the IT effects are not opposed by baroreflex cardiac inhibition during seizures. As the vagus nerves (VN) are main mediators for such baroreflexes, this study was performed to investigate the VN activity in IT. METHODS: The present experiments were performed in ten pigs where IT seizures were induced by controlled infusion of pentylenetetrazole. The electrocorticogram was recorded using a cranial electrode, the electrocardiogram (ECG) using surface electrodes and the blood pressure (BP) using a catheter inserted in the right carotid artery. The VN activity was recorded from both nerves using cuff electrodes and further analyzed in correlation with the cortical seizures and the associated heart rate (HR), BP and HR variability (HRV) changes. RESULTS: The cortical seizures progressed from spike-and-wave (SW) to tonic-clonic (TC) discharges associated with ECG, HR and BP changes proportional with this progression and comparable to the IT effects reported in humans. Those IT effects were accompanied by parasympathetic HRV changes, a 20% VN activation (p=0.004) before the onset of TC seizures, a suppression of this VN activation during the TC episode and a rebound VN activation by 79% (left VN, p=0.02) and 57% (right VN, p=0.03) after the TC offset. Further analysis of an afferent BP-related VN component and a mixed VN component showed normal BP-related afferent input and a suppressed efferent output through both nerves during the TC episode. CONCLUSIONS: This study indicates a suppressed ictal VN activation and a rebound postictal VN activation, which may account for the absence of baroreflexes during seizures and the postictal cardiac inhibition, respectively.

The Influence of Vagus Nerve and Spinal Cord Stimulation on the Ictal Fast Ripple Activity in a Spike-and-Wave Rat Model of Seizures.

OBJECTIVES: Fast ripple (FR) activity has received increasing attention as a potential epileptic marker. The current knowledge on how neurostimulation affects FRs is, however, very limited. In this study, we assess the influence of the vagus nerve stimulation (VNS) and spinal cord stimulation (SCS) frequency on ictal FRs associated with spike-and-wave (SW) seizures. METHODS: SW discharges were induced and maintained by an infusion of pentylenetetrazol in rat. During ongoing SW seizures, SCS was conducted at 30, 80, 130, and 180 Hz and VNS at 10, 30, 80, 130, and 180 Hz. The FRs were derived from intracortical recordings and the FR rate was used for quantifying the level of FR activity. RESULTS: The FR rate was significantly correlated (r = 0.81) with the level of total pentylenetetrazol dose. Compared with no stimulation intervals, SCS conducted at 80, 130, and 180 Hz significantly reduced the normalized FR rate by 24, 38, and 44%, respectively. Similarly, VNS conducted at 30, 80, 130, and 180 Hz significantly reduced the normalized FR rate by 23, 40, 61, and 65%, respectively. CONCLUSIONS: In the present model of sustained SW seizures, the FR rate was proportional with the severity of the SW seizures. Both SCS and VNS attenuated the FR rate and this attenuation was consistently strongest at the higher stimulation frequencies. Our results suggest that SCS may induce some of the same antiepileptic effects as VNS.

The Effect of Spinal Cord Stimulation on Epileptic Seizures.

OBJECTIVE: Spinal cord stimulation (SCS) has been applied to relieve chronic pain for decades. Recent studies suggested that SCS also might alleviate epileptic seizures, but the most effective stimulation parameters are not known. The objective of this work was to investigate the role of SCS frequency in alleviating spike-and-wave (SW) discharges induced in rats by pentylenetetrazole (PTZ) infusion. MATERIALS AND METHODS: The SW discharges were induced in nine rats. An epidural electrode was placed in the spinal canal at the cervical level. SCS was delivered at four frequencies (30, 80, 130 and 180 Hz) and compared with control intervals without stimulation. The effect was evaluated by analyzing electrocorticographic and intracortical (IC) signals. The means of normalized SW spike power (mSP) and frequency (mSF) were derived from the IC recordings and used to estimate the seizure severity. RESULTS: Compared with the control intervals, SCS conducted at 30 Hz significantly increased the mSP and mSF indicating an increase of the SW spiking activity; 80 Hz did not induce significant changes of the features. In contrast, 130- and 180-Hz SCS reduced both mSP and mSF significantly indicating a reduction of the SW spiking activity. CONCLUSIONS: The present results showed that 130-Hz and 180-Hz SCS reduced the SWs power and frequency which may indicate an anticonvulsive effect of these SCS frequencies, whereas 30-Hz SCS induced the opposite effects and, therefore, may be proconvulsive.

Optimal Vagus Nerve Stimulation Frequency for Suppression of Spike-and-Wave Seizures in Rats.

Vagus nerve stimulation (VNS) is used as an adjunctive therapy for drug-resistant epilepsy and results in a 50% seizure reduction in up to 50% of treated patients. The VNS frequency used in the clinic today is in the range of 10-30 Hz. The evidence for choosing the stimulation frequency is limited, and little knowledge is available on the effect of other VNS frequencies. Deep brain, trigeminal nerve, or spinal cord stimulation studies have suggested the use of stimulation frequencies above 80 Hz for seizure control. Therefore, our objective for the present study was to investigate if VNS using frequencies higher than those currently used in the clinic could be more effective in attenuating seizures. Spike-and-wave (SW) discharges were induced in 11 rats, which then were subjected to VNS sessions applied at the frequencies of 10, 30, 80, 130, and 180 Hz combined with control intervals without stimulation. The anticonvulsive effect of VNS was evaluated by comparing the normalized mean power (nMP) and frequency (nMSF) of the SW discharges derived from intracortical recordings collected during the stimulation and control intervals. Compared with the control intervals, all the tested VNS frequencies significantly reduced the nMP (in the range of 9-21%). However, we found that 130 and 180 Hz VNS induced a 50% larger attenuation of seizures than that achieved by 30 Hz VNS. In addition, we found that 80, 130, and 180 Hz VNS induced a significant reduction of the nMSF, that is by 5, 7, and 8%, respectively. These results suggest that a VNS stimulation frequency in the range of 130-180 Hz may be more effective in inhibiting seizures than the 30 Hz VNS applied in the clinic today.

Differential effects of thioridazine enantiomers on action potential duration in rabbit papillary muscle.

The antipsychotic drug thioridazine has potential for treatment of multidrug-resistant microbes including tuberculosis but also causes cardiotoxic QT interval prolongation. Both thioridazine enantiomers have potent antimicrobial effects, but the neuroleptic effect primarily resides with (+)-thioridazine. In this study we for the first time investigate the cardiotoxicity of the isolated thioridazine enantiomers and show their effects on ventricular repolarization. The effects of (+)-thioridazine, (-)-thioridazine, and racemate on the rabbit ventricular action potential duration (APD) were investigated in a randomized controlled blinded experiment. Action potentials were measured in papillary muscles isolated from 21 female rabbits, and the drug effect on 90% APD in comparison with control (ΔΔ-APD90) was evaluated. Increasing concentrations of (+)-thioridazine and the racemate caused significant dose-dependent ΔΔ-APD90 prolongation, while (-)-thioridazine did not. At 0.5 and 2Hz pacing, (+)-thioridazine caused 19.5% and 20.1% ΔΔ-APD90 prolongation, the racemate caused 8.0% and 12.9%, and (-)-thioridazine caused 1.5% and 1.1%. The effect of (-)-thioridazine on APD90 was significantly less than that of the other drugs at both pacing rates (P<0.01 in all cases), and there was no significant difference between (-)-thioridazine and control. The results of this study indicate that the APD prolonging effect of thioridazine is primarily due to the (+)-thioridazine enantiomer. If these results are valid in humans, (-)-thioridazine may be a safer drug for treatment of multidrug-resistant tuberculosis and other microbes.

Comparison of Mono-, Bi-, and Tripolar Configurations for Stimulation and Recording With an Interfascicular Interface.

Previous studies have indicated that electrodes placed between fascicles can provide nerve recruitment with high topological selectivity if the areas of interest in the nerve are separated with passive elements. In this study, we investigated if this separation of fascicles also can provide topologically selective nerve recordings and compared the performance of mono-, bi-, and tripolar configurations for stimulation and recording with an intra-neural interface. The interface was implanted in the sciatic nerve of 10 rabbits and achieved a median selectivity of S=0.98-0.99 for all stimulation configurations, while recording selectivity configurations was in the range of S=0.70-0.80 with the monopolar configuration providing the lowest and the average reference configuration the highest recording selectivity. Interfascicular electrodes could provide an interesting addition to the bulk of peripheral nerve interfaces available for neural prosthetic devices. The separation of the nerve into chambers by the passive elements of the electrode could ensure a higher selectivity than comparable cuff electrodes and the intra-neural location could provide an option of targeting mainly central fascicles. Further studies are, however, still required to develop biocompatible electrodes and test their stability and safety in chronic experiments.

Fascicle-selectivity of an intraneural stimulation electrode in the rabbit sciatic nerve.

The current literature contains extensive research on peripheral nerve interfaces, including both extraneural and intrafascicular electrodes. Interfascicular electrodes, which are in-between these two with respect to nerve fiber proximity have, however, received little interest. In this proof-of-concept study, an interfascicular electrode was designed to be implanted in the sciatic nerve and activate the tibial and peroneal nerves selectively of each other, and it was tested in acute experiments on nine anaesthetized rabbits. The electrode was inserted without difficulty between the fascicles using blunt glass tools, which could easily penetrate the epineurium but not the perineurium. Selective activation of all tibial and peroneal nerves in the nine animals was achieved with high selectivity (S = 0.98 ± 0.02). Interfascicular electrodes could provide an interesting addition to the bulk of peripheral nerve interfaces available for neural prosthetic devices. Since interfascicular electrodes can be inserted without fully freeing the nerve and have the advantage of not confining the nerve to a limited space, they could, e.g., be an alternative to extraneural electrodes in locations where such surgery is complicated due to blood vessels or fatty tissue. Further studies are, however, necessary to develop biocompatible electrodes and test their stability and safety in chronic experiments.

The effect of spinal cord stimulation on seizure susceptibility in rats.

OBJECTIVES: Spinal cord stimulation (SCS) activates the thalamus, which may be involved in generation of seizures. SCS may therefore influence seizure susceptibility. We investigated the effect of SCS on seizure susceptibility when performed at low frequency (4 Hz) and a frequency in the typical range of SCS treatment (54 Hz). MATERIALS AND METHODS: Rats were divided in three groups: control (N = 8), 4 Hz SCS (N = 6), and 54 Hz SCS (N = 8). Tonic-clonic seizures were induced by 10-min intravenous infusion of pentylenetetrazole (PTZ). SCS was started 5 min prior to PTZ infusion and continued for 5 min after infusion offset. Seizure susceptibility was accessed via the latency, number, and total duration of seizures. RESULTS: Four Hz SCS significantly increased seizure susceptibility. Fifty-four Hz SCS produced a nonsignificant trend toward decreased seizure susceptibility. CONCLUSIONS: Low-frequency SCS is proconvulsive in rats. Further research needs to investigate if this also applies to humans.

Ictal and peri-ictal changes in cervical vagus nerve activity associated with cardiac effects.

The vagus nerves convey both afferent and efferent information about autonomic activity related to cardiovascular functions. Those functions have been shown to change due to epileptic seizures, which suggests that ictal events might be detected via the vagus electroneurogram (VENG). In this study, we characterize the association of ictal and peri-ictal VENG with cardiac parameters. The electrocorticogram (ECoG), electrocardiogram, and the VENG were recorded in anesthetized rats, which were intravenously infused with either a pentylenetetrazole (PTZ) solution (PTZ-lot, n = 11) or saline (control-lot, n = 6). Control animals were subsequently vagotomized and also infused with a PTZ solution (n = 5, V-PTZ-lot). Cardiac and VENG parameters were assessed during different ECoG stages of ictal activity. None of the parameters changed in the control-lot. PTZ infusion induced seizures in all rats. Cardiac-related VENG showed distinctive firing patterns for the left and right vagus nerves. Significant ictal and post-ictal changes were seen in both the left and the right VENG in association with cardiac changes and increased parasympathetic influence on the heart. Changes in VENG parameters might provide a new way to assess the ictal state of patients, which could be suitable for triggering on-demand vagus nerve stimulation.

Early seizure detection in rats based on vagus nerve activity.

Continuous, scheduled vagus nerve stimulation (VNS) is used for the treatment of refractory epilepsy. On-demand VNS, started prior to or at the onset of a seizure may improve the effect of the treatment, however, this requires seizures to be predicted or detected early. This study investigates the possibility of early seizure detection based on the cervical vagus electroneurogram (VENG). Fourteen anesthetized rats received an intravenous infusion (IV) of either saline (control, n = 6) or pentylenetetrazol (PTZ) diluted in saline (PTZ-treated, n = 8). A cardiac-related VENG profile (CrVENG) was derived by using R-peak triggered averaging of the VENG energy. Following, changes in this profile were evaluated as a seizure predictor. Using left nerve VENG, seizures were detected in all PTZ-treated rats 103 ± 51 s (mean ± SD) before they developed tonic seizures. Control rats did not develop seizures and our method did also not detected seizures in these rats. Seizures can be early detecting based on left nerve VENG in anesthetized rats. Preictal CrVENG changes may reflect central-mediated changes and/or changes in the relation between the respiration and the cardiac cycle. Further research is needed to evaluate the method in awake and freely moving animals and eventually in humans.

Autonomic alterations and cardiac changes in epilepsy.

Studies with heart rate variability have revealed interictal autonomic alterations in patients with epilepsy. In addition, epilepsy is frequently associated with ictal tachycardia or bradycardia, which sometimes precedes the onset of seizures. Ictal tachycardia is sometimes associated with electrocardiography (ECG) morphologic changes and ictal bradycardia often progresses to asystole. Such cardiac manifestations of seizures have been hypothesized as possible causes for sudden unexplained death in epilepsy (SUPEP). The present review relates to interictal and ictal cardiac manifestations of epilepsy with focus on heart rate, heart rate variability, and ECG changes. Aspects of the supporting mechanisms are discussed and attention is drawn to the interaction between central and peripheral effects, interictal autonomic conditions, ictal autonomic discharges, and administration of antiepileptic drugs in shaping the ictal cardiac changes. Because these interactions are complex and not totally understood, closer surveillance of patients and more experimental work is necessary to elucidate the mechanistic support of autonomic and cardiac changes in epilepsy, and to design better strategies to avoid their undesirable effects. It is also suggested that some of these changes could be used as predictors or markers for the onset of seizures.

Simultaneous monitoring of cellular depolarization and contraction: a new method to investigate excitability and contractility in isolated smooth muscle cells.

The present experiments were performed to establish a method for simultaneous monitoring of excitation and contraction in isolated smooth muscle cells. The smooth muscle cells were dissociated from the colons of Wistar rats by enzymatic digestion. All the experiments were performed on mixtures of circular and longitudinal cells. In a first set of experiments, focal extracellular potentials (FEPs) and transmembrane action potentials (APs) were simultaneously recorded from the cells by use of extracellular and intracellular pipettes, respectively. In a second set of experiments, cellular contraction induced by chemical stimulation was monitored simultaneous with the FEP recordings. The FEPs had spike and plateau amplitudes of 44.5 +/- 2.3 and 8.9 +/- 0.7 mV, respectively, and reproduced the general morphology of gastrointestinal APs. The parallel mechanical measurements from the rat colonic cells showed that they shortened with an average peak contraction of 8.8 +/- 1.4 microm and an average contraction velocity of 8.2 +/- 0.9 microm/s, to develop an average peak force of 1.2 +/- 0.2 microN, and generated an average peak power of 36 +/- 15 pW. Simultaneous monitoring of FEPs and cellular contraction demonstrates correlations between the electrical and mechanical events taking place in the investigated cells.

Electrical and mechanical effects induced by cold temperatures in the ventricle of isolated Rana ridibunda hearts.

A temperature decrease changes the contractility of the amphibian heart, but the underlying mechanisms are not totally understood. The objectives of the present work were to better understand the intrinsic mechanisms supporting contractility changes induced by a rapid temperature decrease in the ventricle of Rana ridibunda, and to investigate how fast they develop. Ventricular mechanical cycles (VMCs) and monophasic action potentials (MAPs) recorded from 15 isolated hearts were measured at 15, 30, 45, 60, 90, 120 and 150 s after the application of Ringer solutions of 20, 10 and 5 degrees C. Treatment with 10 and 5 degrees C Ringer solutions decreased the heart rate, and increased the magnitude of the ventricular contraction and the duration of the contraction and relaxation periods. The electrical changes included prolongation of the MAP depolarization plateau, which also decreased in amplitude as an effect of perfusion with 5 degrees C Ringer solution. In addition, treatment with 5 degrees C Ringer solution increased the latency of contraction. The block of L-type channels totally abolished the depolarization plateau at all perfusion temperatures, but failed to inhibit ventricular contraction. In conclusion, treatment with cold temperatures changes the electrical activity of the ventricular myocardium in R. ridibunda hearts, which results in modified ventricular contractility. Data suggest that in addition to L-type Ca2+ channels, other components that support calcium elevation are present R. ridibunda ventricular cells.

A review of electrical stimulation to treat motility dysfunctions in the digestive tract: effects and stimulation patterns.

Electrical stimulation of the digestive organs may become a valuable alternative to pharmaceutical and surgical approaches to the treatment of gastrointestinal motor dysfunctions. For more than 40 years, encouraging results with electrical stimulation to activate motility in gastrointestinal organs have been published. The most significant achievements with this work have been either stimulation to attenuate the symptoms of gastroparesis or stimulation to modify the feeding behavior in obese patients. In addition, animal studies have investigated the different stimulation systems and methods to activate or inhibit transit in the small and large intestines. This article presents a review of the published literature on electrical stimulation of the stomach and intestines.