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PubMed2006

Rapid and precise release from nano-tracted poly(N-isopropylacrylamide) hydrogels containing linear poly(acrylic acid).

We investigated the rapid and precise molecular release from hydrogels in response to dual stimuli. To achieve precise on/off drug release using thermoresponsive poly(N-isopropylacrylamide) hydrogels, we prepared nano-structured semi-IPNs, which consisted of thermosensitive PNIPAAm networks penetrated by pH-responsive poly(acrylic acid) (PAAc) linear chains and perforated to create nano-tracts as a molecular pathway. The present nano-tracted semi-IPNs show a rapid deswelling response to both temperature and pH. Model drug releases were investigated when simultaneous changes in temperature and pH were applied. We observed that the cationic drug was rapidly released and then abruptly discontinued from the nano-tracted semi-IPNs in response to the dual stimuli, and clear release and stopping cycles were repeatedly observed on successive steps. Moreover, the release rates and amount of drug released were controllable by the deswelling speed of the gels and the PAAc content inside the gels. This novel release system using the nano-tracted semi-IPNs may be useful for the high performance, pulsed release of molecules.

Acrylamides↗
PubMed1994

Divergence of hippocampal mossy fibers.

By connecting the fascia dentata with the hippocampus proper, the axons of the granule cells, the mossy fibers, represent an important element of the main excitatory, trisynaptic pathway of the hippocampal formation. In this review the various synaptic connections of the mossy fibers are discussed. It turns out that the mossy fibers do not only establish synapses with the pyramidal neurons of regio inferior as traditionally assumed, but a variety of local circuit neurons as well as projection cells are also contacted by the mossy fibers. Thus there is an underestimated divergence of the impulse flow within the "trisynaptic" pathway at the level of the mossy fibers. Similarly, the pattern of afferent input to the granule cells, especially that of GABAergic neurons, is more complex than previously assumed. In this respect the concept of a unidirectional "trisynaptic" pathway certainly is an oversimplification. In particular, the hilus of the fascia dentata, that the mossy fibers traverse on their way to regio inferior, is often neglected in this concept. The hilar region comprises a large variety of morphologically and functionally distinct neuronal types that, to a large extent, are targets of hilar mossy fiber collaterals. By focusing on the mossy fiber system, an attempt is made in this review to summarize new data on hippocampal circuitries that have been accumulated since the original description of the trisynaptic pathway. This concept, which originally comprised the synapses of the perforant path fibers on dentate granule cells, the mossy fiber synapses on CA3 pyramidal neurons, and the synapses of the Schaffer collaterals on CA1 pyramidal cells, has been of great heuristic value but needs to be modified in view of recent morphological and physiological data.

Animals↗
PubMed1991

Synthesis of the 2-amino-4-phosphonobutanoic acid analogues (E)- and (Z)-2-amino-2,3-methano-4-phosphonobutanoic acid and their evaluation as inhibitors of hippocampal excitatory neurotransmission.

The cyclopropyl compounds (Z)- and (E)-2-amino-2,3-methano-4-phosphonobutanoic acid, 5 and 6, respectively, were prepared as constrained analogues of 2-amino-4-phosphonobutanoic acid (AP4), a selective glutamate receptor ligand. A Horner-Emmons reaction of trimethyl N-(benzyloxycarbonyl)phosphonoglycinate with 2-(diethoxyphosphinyl)acetaldehyde gave the protected dehydroamino acids 9 and 10, which were individually subjected to the following sequence of reactions: cycloaddition of diazomethane, photoelimination of N2, and acid hydrolysis, to give 5 and 6, respectively. Extracellular recording techniques were used to evaluate the abilities of 5 and 6 to block evoked synaptic transmission in specific neuronal pathways of the rat hippocampal slice. In the lateral perforant path (LPP) 5 and 6 were equipotent and possessed IC50 values of 18 and 17 microM, respectively. In the medial perforant path (MPP), 6 (IC50 = 81 microM) was much more potent than 5 (IC50 = 1580 microM). In paired pulse experiments which differentiate presynaptic and postsynaptic inhibition, 5 and 6 enhanced the second response to the same extent as L-AP4, suggesting a presynaptic site of action for these compounds. In contrast, the cyclopentyl AP4 analogues 3 and 4 enhanced the second response to a lesser extent. It was concluded that the biologically active conformation of AP4 in the LPP is different than in the MPP. In order to explain the same potency of 5 and 6 in the LPP, it was postulated that the two analogues assume a conformation that allows their functional groups to occupy the same relative place in space. Molecular modeling showed that the best overlap was achieved when the alpha C-beta C-gamma C-P dihedral angle for 5 was in the range of 130 degrees to 180 degrees and that of 6 was in the range of -130 degrees to -180 degrees. The results suggest that the bioactive conformation of AP4 in the LPP is an extended one.

Aminobutyrates↗
PubMed1995

Endogenous opioids regulate long-term potentiation of synaptic inhibition in the dentate gyrus of rat hippocampus.

Long-term potentiation (LTP) of excitatory transmission in the hippocampus has been extensively studied as a synaptic model of learning and memory. Here we report a new form of LTP in which inhibitory synaptic signals are potentiated following tetanic stimulation of an opioid-containing excitatory pathway in the presence of opioid antagonists. The lateral perforant path (LPP) was stimulated at the dentate outer molecular layer of hippocampal slices. Evoked synaptic currents were recorded from dentate granule cells using whole-cell voltage-clamp techniques. A high-frequency stimulus train (100 Hz, 1 sec) delivered to the LPP in the presence of naloxone (1 microM) was found to induce a long-lasting potentiation (20 min to 2 hr) in the amplitude of gamma-aminobutyric acidA (GABAA) receptor-mediated inhibitory postsynaptic currents (IPSCs) of granule cells. Such a potentiation was not observed when tetanizing the LPP in control medium. Naloxone-revealed LTP of LPP-evoked IPSCs did not depend upon the presence of granule cell discharge, and was not accompanied by potentiation of mossy fiber-evoked IPSCs, indicating that feedforward, but not feedback, inhibitory circuits were involved. Induction of this LTP could be completely blocked by the N-methyl-D-aspartate (NMDA) receptor antagonist D-2-amino-5-phosphonopentanoic acid (D-APV). However, it was not significantly affected by hyperpolarization of granule cells. These results suggest that LTP may occur at the excitatory synapses between LPP terminals and GABAergic interneurons, rather than at the inhibitory synapses between interneurons and granule cells. Further examination using selective opioid antagonists demonstrated that blocking delta, but not mu and kappa, receptors is critical for inducing LTP of IPSCs in granule cells.

2-Amino-5-phosphonovalerate↗
PubMed1993

Receptor-activated Ca influx in human airway smooth muscle: use of Ca imaging and perforated patch-clamp techniques.

Previous studies have demonstrated a dihydropyridine-insensitive, receptor-activated calcium influx pathway in cultured human airway smooth muscle (ASM) cells. To further define the biophysical characteristics of this pathway, the relationship between membrane potential and cytosolic free calcium ([Ca2+]i) was studied with the combined methods of the patch-clamp technique and single cell calcium imaging. The nystatin perforated-patch method was used to maintain normal intracellular calcium buffering and receptor-activated signal transduction processes in voltage-clamped cells. Single voltage-clamped human ASM cells responded to exposure to histamine (200 microM) with an initial transient rise in [Ca2+]i followed by a secondary sustained elevation that was dependent on extracellular calcium. Before agonist activation, step changes in holding potential produced only slight changes in [Ca2+]i, whereas, after activation, cells developed a sustained rise in [Ca2+]i that showed a large variation as a function of membrane potential. Depolarization from -80 to 0 mV caused a fall in the steady-state [Ca2+]i to basal levels or slightly below. Repolarization to -80 mV caused the redevelopment of the sustained phase of the calcium response. When calcium was removed from the extracellular fluid by the addition of a stoichiometric excess of ethylene glycol-bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid (EGTA), the voltage dependence of the sustained phase was abolished. In a series of experiments, agonist addition evoked a 54-fold increase in the voltage dependence of calcium.(ABSTRACT TRUNCATED AT 250 WORDS)

Bronchi↗
PubMed1998

Paired pulse suppression and facilitation in human epileptogenic hippocampal formation.

Paired pulse stimulation has commonly been employed to investigate changes in excitability in epileptic hippocampal tissue employing the in vitro slice preparation. We used paired pulse stimulation in the intact temporal lobe of patients with temporal lobe seizures to compare the excitability of pathways in the epileptogenic hippocampus (located in the temporal lobe in which seizures arise) with those in the non-epileptogenic hippocampus of the contralateral temporal lobe (in the hemisphere to which seizures spread). A total of 20 patients with temporal lobe seizure onsets were studied during chronic depth electrode monitoring for seizure localization. Intracranial in vivo stimulation and recording sites included the hippocampus, entorhinal cortex, subicular cortex and parahippocampal gyrus. A comparison of all hippocampal pathways located in the temporal lobe where seizures typically started (n = 37) with those in temporal lobes contralateral to seizure onset (n = 53) showed significantly greater paired pulse suppression of population post-synaptic potentials on the epileptogenic side (F(1,87) = 6.1, P < 0.01). Similarly, mean paired pulse suppression was significantly greater for epileptogenic perforant path responses than for contralateral perforant path responses (F(1,13) = 7.5, P < 0.01). In contrast, local stimulation activating intrinsic associational pathways of the epileptogenic hippocampus showed decreased paired pulse suppression in comparison to the epileptogenic perforant path. These results may be a functional consequence of the formation of abnormal recurrent inhibitory and recurrent excitatory pathways in the sclerotic hippocampus. Enhanced inhibition may be adaptive in suppressing seizures during interictal periods, while abnormal recurrent excitatory circuits in the presence of enhanced inhibition may drive the hypersynchronization of principal neurons necessary for seizure genesis.

Action Potentials↗
PubMed1996

Low-frequency trains of paired stimuli induce long-term depression in area CA1 but not in dentate gyrus of the intact rat.

We have examined the efficacy of a recently introduced protocol for inducing homosynaptic long-term depression (LTD) in area CA1 of the anesthetized rat (Thiels et al. [1994] J Neurophysiol 72:3009-3116.). In area CA1 of the awake animal, this protocol, consisting of 200 pairs of pulses delivered at 0.5 Hz, with an interpulse interval of 25 ms, consistently produced LTD, provided the initial pulse was sufficiently strong to produce significant paired-pulse depression of the evoked response. We extended these experiments to the dentate gyrus, using either paired pulses given to the perforant path in the awake adult rat, or, in the anesthetized adult, a two-pathway pairing procedure, in which the first pulse was delivered to the commissural input to the dentate gyrus and the second to the perforant path. In both cases, the first pulse led to substantial suppression of the response evoked by the second pulse. With neither protocol, however, was there any evidence for LTD or depotentiation. Paired-pulse stimulation of the perforant path of young rats (10-11 days) also failed to induce LTD or depotentiation of the population excitatory postsynaptic potential (EPSP). Thus, the dentate gyrus in the intact animal appears to be less susceptible to LTD and depotentiation than area CA1, a conclusion consistent with previous experiments in which we found that stimulation at 1-5 Hz produced LTD/depotentiation in area CA1 of young (but not adult) rats in vivo but was ineffective at any age in the dentate gyrus. Our results do not rule out the possibility that other, untested protocols may produce homosynaptic LTD and/or depotentiation in the dentate gyrus in vivo.

Anesthesia↗
PubMed2006

Fornix lesions decouple the induction of hippocampal arc transcription from behavior but not plasticity.

The immediate-early gene (IEG) Arc is transcribed after behavioral and physiological treatments that induce synaptic plasticity and is implicated in memory consolidation. The relative contributions of neuronal activity and learning-related plasticity to the behavioral induction of Arc remain to be defined. To differentiate the contributions of each, we assessed the induction of Arc transcription in rats with fornix lesions that impair hippocampal learning yet leave cortical connectivity and neuronal firing essentially intact. Arc expression was assessed after exploration of novel environments and performance of a novel water maze task during which normal rats learned the spatial location of an escape platform. During the same task, rats with fornix lesions learned to approach a visible platform but did not learn its spatial location. Rats with fornix lesions had normal baseline levels of hippocampal Arc mRNA, but unlike normal rats, expression was not increased in response to water maze training. The integrity of signaling pathways controlling Arc expression was demonstrated by stimulation of the medial perforant path, which induced normal synaptic potentiation and Arc in rats with fornix lesions. Together, the results demonstrate that Arc induction can be decoupled from behavior and is more likely to indicate the engagement of synaptic plasticity mechanisms than synaptic or neuronal activity per se. The results further imply that fornix lesions may impair memory in part by decoupling neuronal activity from signaling pathways required for long-lasting hippocampal synaptic plasticity.

Animals↗
PubMed1985

[Coronary collaterals in patients with total obstruction of the proximal left anterior descending artery: their pathways and functional significance].

The relationship of patterns of collateral pathways and the functions of collaterals in patients with proximal occlusion of the left anterior descending artery (LAD) was analyzed by coronary arteriography and left ventriculography. Forty-seven patients with dominant right coronary artery (RCA) as anatomic variations had nearly the same filling areas from three major collateral pathways from the RCA to the LAD via conus branches, marginal branches, and septal perforator. The grades of collateral flows were classified as good, fair and poor according to the sizes and numbers of collateral channels, and the filling density of contrast in each collateral and three (basal, mid and apical) segments of the main trunk of the LAD. On left ventriculography in the right anterior oblique projection, the anterior wall was divided into five segments, and the regional ejection fraction in each segment was measured from end-diastolic and end-systolic areas. Three main collateral pathways and connections to the LAD were observed from the RCA. Those were the conus branches to the basal-mid LAD, the marginal branches to the mid-apical LAD, and the posterior descending branches to the basal-mid LAD via the septal perforators. Only seven patients showed normal contraction in all of the segments (Group I). In seven patients with normal contraction in the basal-mid segments and reduced contraction in the apical segment of the anterior wall, the main collateral pathways from the RCA to the LAD were the posterior descending branches via the septal perforators (Group II). In 10 patients with reduced contraction in the basal-mid segments and normal contraction in the apical segment of the anterior wall, the main collateral pathways from the RCA were the conus branches and/or the marginal branches to the LAD (Group III). In the other 23 patients with reduced contraction in entire segments (Group IV), the patterns of segmental contraction were similar to those of either Group II or Group III. These findings indicate that in the majority of cases collateral circulation from the RCA did not preserve wall contraction in all segments perfused by the occluded LAD at rest, and suggest that various patterns of segmental contraction may be influenced by the dominant of collateral pathways.

Collateral Circulation↗
PubMed1975

Pathways of extrapelvic spread of disease: Anatomic-radiologic correlation.

Extrapelvic spread of disease, particularly from gastrointestinal tract perforations which may be clinically occult, may first present in the buttock, hip, thigh, and even lower leg, and the extraperitoneal space of the abdomen itself. Clinical manifestations at these remote sites may be very misleading. Anatomic and roentgenologic observations establish the preferential pathways of extrapelvic spread. These are related to the insertions and fascial investments of the iliopsoas, pyriformis, and obturator internus muscles and the ensheathed penetrations of the superior gluteal arteries. Superiorly, extension from the pelvic tissues seeks out the posterior pararenal compartment of the extraperitoneal region of the abdomen. Roentgenologic signs may first identify the presence, extent, and localization of the primary process.

Adult↗
PubMed1997

Assessment of the penile vascular system with color-coded duplex sonography and pharmacocavernosometry and -graphy in impotent men.

OBJECTIVE: To examine the extent to which color-coded duplex sonography permits complete clarification of vessel-dependent erectile dysfunction (ED). MATERIAL AND METHODS: A total of 215 patients with ED were examined. All patients underwent pharmacocolor-coded duplex sonography (PHCCDS; 20 micrograms of prostaglandin E1, PGE1, intracavernosally) as well as pharmacocavernosometry and -graphy (PHCM and PHCG; 20 micrograms of PGE1 intracavernosally). The penile vessels were visualized, i.e. the dorsal arteries, the cavernosal arteries, and the anastomoses between them, as well as the venous pathways. Peak flow and end-diastolic flow in all arteries and, when present, anastomoses were determined after stimulation. Induction flow to achieve maximal tumescence/rigidity as well as maintenance flow were determined during PHCM. Finally, for the morphological visualization of the cavenous body and possible venous insufficiencies, a radiography in 2 planes was produced with infusion of a water-soluble contrast medium. RESULTS: In 145 patients with a grade 0-III tumescence after stimulation with 20 micrograms of PGE1, PHCCDS revealed an end-diastolic flow of > 5 cm/s, with a peak flow velocity > 25 cm/s in the 2 cavernosal and 2 dorsal arteries. The deep dorsal vein of the penis was visualized in 110 of these 145 patients with a blood flow > 5 cm/s, and in 35 cases with a blood flow < 5 cm/s. Venous drainage to the corpus spongiosum was visualized in 80 patients with a blood flow > 10 cm/s. All patients had a pathologically increased induction (normal value < 100 ml/min) and maintenance venous flow (normal value < 10 ml/min) in the PHCM as well as venous drainage in the PHCG. Sixty patients with a tumescence grade of IV-V (rigidity) had a peak flow velocity clearly > 25 cm/s, an end-diastolic flow < 5 cm/s in the 2 cavernosal and 2 dorsal arteries in the PHCCDS, as well as induction values < 100 ml/min and maintenance flow values < 10 ml/min in the PHCM, without visible insufficient efferent venous pathways on the PHCG. In 29 patients (13.5%) hemodynamically active anastomoses perforating the tunica albuginea could be detected. Ten patients with a tumescence grade of III had a peak flow velocity < 25 cm/s and an end-diastolic flow < 5 cm/s without venous leakage in PHCM and PHCG. CONCLUSION: PHCCDS allows for the assessment of arterial flow disorder as well as of venous leakage in ED. PHCM and PHCG should only be carried out in patients in whom surgical or radiological interventional procedures at the efferent venous pathways are planned.

Alprostadil↗
PubMed2004

Hypothyroidism impairs late LTP in CA1 region but not in dentate gyrus of the intact rat hippocampus: MAPK involvement.

Thyroid hormone activates extracellular signal-regulated kinases (ERK1 and ERK2), which are important in late long-term potentiation (L-LTP). The aim of this study was to determine the possible mechanism underlying the impairment of L-LTP as a result of hypothyroidism. We investigated the effect of hypothyroidism on L-LTP of the two associative pathways in the hippocampus: the Schaffer collateral synapses and the perforant path synapses. We also examined the effect of hypothyroidism on ERK1 and ERK2 levels in both the CA1 and dentate gyrus (DG) regions of the hippocampus. Electrophysiological recordings from hippocampi of anesthetized rats show that hypothyroidism impairs L-LTP in CA1 region, but not in the DG. Western blot analysis of the CA1 region shows that hypothyroidism decreases phosphorylated ERK1 and ERK2 levels without affecting their total levels. In the DG of the hypothyroid rat, however, there was no significant change in the levels of phosphorylated or total ERKs. The correlation between the effect of hypothyroidism on L-LTP and enzyme levels suggests that hypothyroidism-induced impairment of L-LTP in CA1 may be due to decreased levels of phosphorylated ERK1 and ERK2.

Action Potentials↗
PubMed2006

Structural insights from high-resolution diffusion tensor imaging and tractography of the isolated rat hippocampus.

The hippocampus is a critical structure for learning and memory formation injured by diverse neuropathologies such as epilepsy or Alzheimer's disease. Recently, clinical investigations have attempted to use diffusion tensor MRI as a more specific surrogate marker for hippocampal damage. To first better understand the tissue architecture of healthy hippocampal regions, this study characterized 10 rat hippocampi with diffusion tensor imaging (DTI) at 50-microm in-plane image resolution using a 14.1-T magnet. Chemical fixation of the dissected and straightened rat hippocampus provided a simple, effective way to reduce partial volume effects when segmenting hippocampal regions and improved mean signal-to-noise per unit time (e.g. 50.6+/-4.4 at b=1250 s/mm2 in 27 min). Contrary to previous reports that water diffusion is homogeneous throughout the nervous system, statistically different mean diffusivities were observed (e.g. 0.238+/-0.054 and 0.318+/-0.084 microm2/ms for the molecular and granule cell layers respectively) (ANOVA, P<0.05). Different hippocampal subregions had lower fractional anisotropy than uniformly fibrous structures like corpus callosum because of their complex architecture. DTI-derived color fiber orientation maps and tractography demonstrated most components of the trisynaptic intrahippocampal pathway (e.g. orientations in stratum lacunosum-moleculare were dominated by perforant and Schaffer fibers) and also permitted some assessment of connectivity in the rat hippocampus.

Animals↗
PubMed2001

Propagation of synchronous epileptiform events from subiculum backward into area CA1 of rat brain slices.

The hippocampal trisynaptic pathway is comprised of superficial entorhinal afferents (part of the perforant path) to dentate granule cells, dentate mossy fiber inputs to CA3 pyramidal neurons, and CA3 cell projections to CA1 pyramidal neurons. This CA1 output is among others to the subiculum, and both CA1 and subiculum project to the entorhinal cortex to close the loop. Smaller circuits involving fewer hippocampal and parahippocampal regions have also been described. We present morphological and electrophysiological evidence from rat brain slices for a projection from subiculum back into area CA1. Axons of neurobiotin-labeled subicular pyramidal neurons were visualized in the apical dendritic region of CA1. Spontaneous activity in isolated subiculum--CA1 slices was produced by bathing slices in reduced magnesium media. Events in CA1 always followed events in proximal subiculum. Disruption of this subiculum--CA1 circuit with a radially oriented knife cut in the apical dendritic region between subiculum and CA1 eliminated afterdischarges in subicular and CA1 events, but did not de-synchronize the two regions. Full transections between CA1 and subiculum were necessary to functionally isolate the two regions. Only subiculum remained spontaneously active. We conclude that a subiculum--CA1 circuit supports afterdischarges in both regions and synchronizes their activity. This circuit may serve to maintain a level of depolarization in subicular and CA1 pyramidal neurons well beyond the duration of excitatory synaptic potentials resulting from activation of the trisynaptic circuitry.

Action Potentials↗
PubMed1994

Cysteamine potentiates entorhinal activation of dentate gyrus granule cells in rats.

A dense plexus of somatostatin-positive fibers and varicosities is observed in the outer two-thirds of the dentate gyrus molecular layer where the glutamatergic perforant path afferents from the entorhinal cortex terminate. To test for a functional interaction between these two pathways, we examined the effects of cysteamine, which enhances somatostatin release for a few hours after administration but produces subsequent depletion of somatostatin lasting several days, on perforant path evoked potentials recorded in the dentate gyrus. Cysteamine (50-400 mg/kg, IP) increased the population spike dose-dependently both in anesthetized and in awake rats, but the slope of the population excitatory postsynaptic potential (EPSP) was left unchanged or even decreased. The antidromic population spike evoked by mossy fiber stimulation was not changed by cysteamine. The change is thought to be due to the increase in slope of the EPSP-spike relationship. In the hippocampal slice preparation, a similar effect of the drug (1-5 mM) on dentate evoked potentials was observed, suggesting that cysteamine acts through its effects on somatostatin in the hippocampus itself. In chronically implanted awake animals, the perforant path population spike was increased 1 h after cysteamine but returned to the predrug level by 24 h when somatostatin seemed to be depleted. These results suggest that hippocampal somatostatin released by cysteamine potentiates the response of dentate granule cells to perforant path input, without directly affecting synaptic transmission or general cell excitability.

Anesthesia↗
PubMed1988

Magnesium and cobalt, not nimodipine, protect neurons against anoxic damage in the rat hippocampal slice.

Brain tissue, maintained in vitro, was used to determine whether agents that block calcium entry into neurons can improve the recovery of evoked responses after anoxia. The hippocampus was dissected from a rat brain and sliced perpendicular to its long axis such that its main neuronal circuits remain functional. A pathway in the slice was stimulated electrically, and an extracellular potential, the evoked population spike, recorded from the neurons postsynaptic to that pathway. A bipolar stimulating electrode was placed in either the perforant path or the Schaeffer collaterals and a monopolar metal microelectrode placed, respectively, in either the dentate granule cell layer or the CA1 pyramidal cell layer. The slices were maintained in vitro by superfusing them with oxygenated (95% O2, 5% CO2) artificial cerebrospinal fluid (aCSF). In order to generate anoxia, the tissue was superfused with aCSF bubbled with 95% N2, 5% CO2 for either 5 or 10 min. All drugs examined were present in the aCSF before, during, and immediately after the anoxic period. Percentage recovery was expressed as the amplitude of the evoked population spike 60 min after anoxia divided by its preanoxic amplitude. Protection in this model is defined as a significant (P less than 0.05) improvement in percentage recovery compared with the recovery of untreated slices. There was no recovery of the response recorded from untreated dentate granule cells after 10 min of anoxia (0 +/- 0%, n = 5; mean +/- SE), whereas 5 min of anoxia was sufficient to cause damage to the untreated CA1 pyramidal cells (4 +/- 3%, n = 6).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1983

Anticonvulsant-like actions of baclofen in the rat hippocampal slice.

1 The effects of baclofen were tested on epileptiform discharge in the rat hippocampal slice. Slices were superfused with bicuculline methiodide (100 microM) and maximal periods of afterdischarge were evoked by stimulating the Schaffer collateral-commissural pathway in area CA1, mossy fibres in area CA3 or perforant path fibres in the fascia dentata or by antidromic stimulation of CA1 pyramidal cells. 2 (-)-Baclofen attenuated the afterdischarge evoked by stimulating all three sets of fibres in areas CA1 and CA3. In each case, a threshold effect was observed at a concentration of 0.25 or 0.5 microM, and complete suppression was usually attained with a concentration of 5 microM. EC50 values ranged between 1 and 2 microM. (-)-Baclofen attenuated hippocampal afterdischarge with 120 times the potency of (+)-baclofen. It did not, however, affect the repetitive firing of dentate granule cells in response to stimulation of perforant path fibres. 3 (-)-Baclofen also reduced the amplitude of the initial population spike evoked by stimulation of Schaffer collateral-commissural fibres, but did not affect the antidromic population spike nor the initial population spike evoked by stimulation of the mossy fibres. 4 Recurrent inhibition in area CA1 was abolished by 1 microM (-)-baclofen. Thus baclofen, unlike many anticonvulsants, does not suppress afterdischarge by potentiating GABAergic inhibition. 5 These results suggest that baclofen attenuates hippocampal afterdischarge by a combination of pre- and postsynaptic mechanisms.

Animals↗
PubMed1994

Calcitonin gene-related peptide activated ATP-sensitive K+ currents in rabbit arterial smooth muscle via protein kinase A.

1. Whole-cell K+ currents activated by calcitonin gene-related peptide (CGRP) in smooth muscle cells enzymatically isolated from rabbit mesenteric arteries were measured in the conventional and perforated configurations of the patch clamp technique. The signal transduction pathway from CGRP receptors to activation of potassium currents was investigated. 2. CGRP (10 nM) activated a whole-cell current that was blocked by glibenclamide (10 microM), an inhibitor of ATP-sensitive K+ channels. Elevating intracellular ATP reduced glibenclamide-sensitive currents. CGRP increased the glibenclamide-sensitive currents by 3- to 6-fold in cells dialysed with 0.1 mM ATP, 3.0 mM ATP or in intact cells. The reversal potential of the glibenclamide-sensitive current in the presence of CGRP shifted with the potassium equilibrium potential, while its current-voltage relationship exhibited little voltage dependence. 3. Forskolin (10 microM), an adenylyl cyclase activator, Sp-cAMPS (500 microM) and the catalytic subunit of protein kinase A increased glibenclamide-sensitive K+ currents 2.1-, 3.3- and 8.2-fold, respectively. 4. Nitric oxide and nitroprusside did not activate glibenclamide-sensitive K+ currents. 5. Dialysis of the cell's interior with inhibitors of protein kinase A (synthetic peptide inhibitor, 4.6 microM or H-8, 100 microM) completely blocked activation of K+ currents by CGRP. 6. Our results suggest the following signal transduction scheme for activation of K+ currents by CGRP in arterial smooth muscle: (1) CGRP stimulates adenylyl cyclase, which leads to an elevation of cAMP; (2) cAMP activates protein kinase A, which opens ATP-sensitive K+ channels.

Adenosine Triphosphate↗