Search

Sustained enhancement of the basal tone of ganglionic transmission is expected to result in an enduring increase in peripheral resistance that would lead to elevated blood pressure. Long-term potentiation of sympathetic ganglia is an activity-dependent long-lasting increase in strength of ganglionic transmission. Therefore, ganglionic long-term potentiation might be involved in the manifestation of neurogenic forms of hypertension. Expression of sympathetic ganglionic long-term potentiation is dependent on activation of 5-HT(3) receptor. We examined the possibility that elevated blood pressure in obese Zucker rat, which is reported to be stress-prone, might be partly due to a neurogenic factor resulting from expression of ganglionic long-term potentiation. Chronic treatment with the 5-HT(3) receptor antagonist ondansetron (0.5 mg/kg/day) caused a significant decrease in blood pressure of the obese Zucker rats without affecting that of normotensive lean Zucker rats. Electropysiological procedures to test for long-term potentiation in isolated ganglia suggest that ganglionic long-term potentiation has been previously expressed in vivo in ganglia from obese Zucker rat but not in those from the normotensive lean Zucker rats. The results indicate that expression of ganglionic long-term potentiation in sympathetic ganglia may be responsible for neurogenic increase in blood pressure, which contributes to the moderate hypertension often seen in the obese Zucker rats.

The anti-epileptiform effect of serotonin was characterized in cellular models of epilepsy using electrophysiological recording techniques. In the bicuculline model, both serotonin (20 microM) and its 5-HT1A agonist, 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT, 10 microM) completely blocked the epileptiform discharge and caused membrane hyperpolarization and reduction in input resistance. These effects were completely antagonized by the 5-HT1A receptor antagonist N-t-butyl-3(4-[2-methoxyphenyl]piperazin-1-yl)-2-phenyl-propanamid e(WAY 100135) (10 microM). Epileptiform discharge induced by positive current injection was also blocked by serotonin. The presence of WAY 100135 renders serotonin ineffective in the same model. In the bicuculline model, epileptiform discharge blocked by serotonin reappeared and was also intensified when BaCl2 was added to the medium. To rule out the possibility of serotonin-induced hyperpolarization strengthening the inhibitory effect of endogenous Mg2+ on glutamate N-methyl-D-aspartic acid (NMDA) receptor we studied the antiepileptic effect of serotonin in the 0 Mg2+ model. Spontaneous activity and evoked bursts seen with the 0 Mg2+ model were completely blocked by serotonin. WAY 100135 completely antagonized serotonin effects in this model as well. This study provides evidence suggesting that in rat CA1 pyramidal neurons, serotonin can inhibit epileptiform activity in a variety of accepted epilepsy cellular models and that inhibition of epileptiform bursts by serotonin may be mediated by activation of the 5-HT1A receptor subtype.

The actions of valproic acid (VPA) on neuronal membrane properties and synaptic transmission were studied using intracellular recording techniques in rat basolateral neurons of the amygdala slices. In therapeutically attainable concentrations (10-100 microM), VPA decreased synaptically-induced epileptiform bursting in the presence of bicuculline. Additionally, the frequency of repetitive discharge induced by direct superthreshold depolarizing current pulses was decreased by VPA. However, evoked excitatory and inhibitory postsynaptic potentials were not affected at this level of drug concentration. The current-voltage relationship of untreated neurons revealed rectification of membrane potential when neuronal membrane was depolarized with cathodal current pulses. This depolarizing rectification was blocked by VPA. High medium calcium or addition of the sodium channel blocker tetrodotoxin (TTX) also blocked the depolarizing rectification, whereas the calcium channel antagonist diltiazem had no effect on the rectification. Elevation of medium calcium concentration also blocked the bicuculline-induced bursting. These results indicate that the inhibition by VPA of subthreshold slow sodium current and membrane depolarizing rectification results in suppression of neuronal membrane excitability which is probably a major mechanism for its anticonvulsant action.

Ganglionic effects of the histamine H2 receptor antagonists cimetidine, ranitidine and 1-nitro-2-(2-propynylamino)-2-(2-[dimethylaminomethyl-2-furanyl) methylthiol]-ethylamino)ethylene (ORF 17578) were compared in the isolated superior cervical ganglion of the rat. Extracellular recording of compound action potentials showed that the drugs caused concentration-dependent inhibition of ganglionic transmission, as indicated by depression of the postganglionic compound action potential. Cimetidine-induced inhibition of ganglionic transmission was stimulus frequency-dependent. Increasing the Ca2+ from 2.2 to 4.4 mM in the bathing solution did not significantly affect the inhibitory actions of these agents. In the series with ranitidine, pretreatment with DFP to inhibit acetylcholinesterase similarly had no significant effect on the depression of the compound action potential by ranitidine. All three agents had little or no effect on nerve conduction in isolated vagi of the rat. The results indicate that all three histamine H2 receptor blockers inhibited ganglionic transmission, but only in large concentrations. The results also suggest that the blocking effect of these drugs was unrelated to their reported anticholinesterase action or to blockade of histamine H2 receptors, which are believed to exist on the presynaptic membrane. It is suggested that the ganglion effect may be due to the action of these agents on the acetylcholine receptor-ion channel complex in the postsynaptic membrane.

The effects of potassium channel blockers on synaptic transmission were studied in the isolated superior cervical ganglia of the rat by means of extracellular recordings. The ganglia were exposed to gradual increase in the concentration of calcium in the presence and absence of potassium channel blockers. At all levels of calcium (0.1-2 mM), 4-aminopyridine (4-AP) produced marked potentiation of both amplitude and duration of the compound action potential. At 0.1 mM, 4-AP completely reversed the failure of transmission regularly seen in low calcium (0.1 mM). The increase in duration, measured as time to peak, was more pronounced in low calcium and became less marked as the concentration of calcium was raised. In media containing low concentrations of calcium (0.8 mM), 4-AP induced a massive spontaneous discharge, often with rhythmic bursts. Cesium (6 mM) abolished the action potential in low calcium media, however, increasing levels of calcium in the presence of cesium resulted in recovery and later marked potentiation of both the amplitude and duration of the action potential in a calcium concentration-dependent manner. Guanidine potentiated the amplitude of the compound action potential but had no measurable effect on its duration and was unable to reverse transmission failure in low calcium. No potentiation of the amplitude or duration of the action potential was seen with tetraethylammonium. Neither guanidine nor tetraethylammonium induced a spontaneous discharge. The results suggest that some actions of 4-AP are unrelated to blockade of potassium channels.