cismethrin and decamethrin

The Nav1.8 sodium channel isoform, expressed in sensory neurons and implicated in pain responses, is known to be upregulated in Xenopus oocytes by agents that activate protein kinase A. In the absence of exogenous modulators, Nav1.8 channels expressed in oocytes exhibited spontaneous downregulation, so that the amplitudes of peak sodium currents at the end of a 30-min recording period were reduced to 58% of those at the outset of recording with no change in the properties of the expressed channels. Perfusion of oocytes with either cyclosporin A or deltamethrin, considered to be diagnostic inhibitors of the protein phosphatase calcineurin, at 10 microM blocked spontaneous downregulation. These results identify endogenous calcineurin as the mediator of Nav1.8 sodium channel downregulation in oocytes. The use of a calcineurin inhibitor such as cyclosporin A provides an effective means of stabilizing the expression of Nav1.8 sodium channels in oocytes for functional and pharmacological studies.

Topics: Animals; Cyclosporine; Down-Regulation; Drug Interactions; Electric Conductivity; Enzyme Inhibitors; Membrane Potentials; Nitriles; Oocytes; Patch-Clamp Techniques; Pyrethrins; Sodium Channels; Time Factors; Xenopus

Pyrethroids act on mammalian sodium channels, but we have previously shown that low concentrations of the type II pyrethroid deltamethrin also decrease the open channel probability (P(o)) of voltage-gated chloride channels. This effect would be expected to amplify the sodium channel-mediated signs of poisoning produced by pyrethroids. In the present study we evaluated potential chloride channel agonists in vitro, and then tested the most effective of these on pyrethroid-poisoned rats to determine the practical significance of chloride channel effects in vivo. Patch clamp experiments showed that, for voltage-gated maxi chloride channels in excised, inside-out patches from mouse N1E 115 neuroblastoma cells, ivermectin (10(-7) M) and pentobarbitone (10(-6) M) significantly increased open channel probability (p

Topics: Animals; Chloride Channel Agonists; Chloride Channels; Insecticides; Ion Channel Gating; Isoquinolines; Ivermectin; Male; Mice; Motor Activity; Neuromuscular Junction; Nitriles; Patch-Clamp Techniques; Pentobarbital; Phenobarbital; Pyrethrins; Rats; Rats, Inbred F344

The pyrethroids, deltamethrin and cismethrin, were assessed for their ability to change membrane conductance directly in skeletal muscle and indirectly in non-myelinated nerve fibre preparations from the rat. In diaphragm muscle fibres of the rat, input resistance was significantly increased (35%) by deltamethrin but not by cismethrin, compared with solvent alone. In perfused vagus nerve from the rat, the amplitude of the post-tetanic hyperpolarization was significantly increased (100%) by deltamethrin both in vitro and ex vivo but not by cismethrin or solvent. In both test systems the actions of deltamethrin were abolished by changing the perfusate to a low chloride solution. The enhancement of amplitude of post-tetanic hyperpolarization by deltamethrin was reversed by ivermectin, a compound known to increase the resting chloride flux in neuronal preparations. Depolarizing afterpotentials, indicative of a prolongation in sodium conductance, did not develop until 0.5-1.0 hr after the enhancement of the amplitude of post-tetanic hyperpolarization by deltamethrin in the vagus preparations. The amplitude of post-tetanic hyperpolarization was not enhanced by exposure of the vagus to veratrine. These observations reinforce the conclusion that the enhancement of post-tetanic hyperpolarization by deltamethrin is not the result of intracellular accumulation of sodium. In addition, the chloride-dependent nature of the effects of deltamethrin, in both muscle and non-myelinated nerve, suggests that they are in both cases due to a reduction in resting membrane chloride conductance. This novel action of deltamethrin would be expected to amplify the effect of prolonged sodium current and thus influence the actions on excitable membranes both directly and indirectly.

Topics: Animals; Diaphragm; In Vitro Techniques; Male; Membranes; Myelin Sheath; Neurons; Nitriles; Pyrethrins; Rats; Respiratory Muscles; Vagus Nerve

Pyrethroid insecticides have recently been purported to possess strong proconvulsant potential. The seizure-inducing properties of two pyrethroids were assessed by pentylenetetrazol (PTZ) seizure models (repeated ip, suprathreshold ip, and iv), and electrical kindling of the amygdala. The efficacy of po versus ip routes of deltamethrin administration was compared using iv-PTZ administration and tests of locomotor activity in a figure-eight maze. Both po and ip deltamethrin produced comparable decreases in motor activity indicating the effectiveness of both of these exposure routes on biological activity. The Type I pyrethroid, cismethrin (15 mg/kg, po), produced a 17% reduction in the threshold dosage of ip-PTZ required to induce a seizure, while delaying the onset of generalized seizure activity. The Type II pyrethroid, deltamethrin (10 mg/kg, po), failed to alter threshold or latency to seizure onset, but did increase seizure duration. No differences were revealed between po (0, 10, 15 mg/kg) or ip (0, 1, 10 mg/kg) administered deltamethrin on seizure thresholds or durations following iv-PTZ. Seizure severity, however, was enhanced by pyrethroids administered po in the iv-PTZ and suprathreshold-ip PTZ tests, ip deltamethrin was without effect. Cismethrin (0, 8, 15 mg/kg) and deltamethrin (0, 6, 10 mg/kg) administered po daily, 2 hours prior to electrical kindling stimulation facilitated amygdala kindling to a minimal but equivalent degree at the highest dosage. This dosage also evoked strong behavioral signs of toxicity. Deltamethrin also induced spontaneous seizures in partially kindled animals in the absence of stimulation. Thus strong evidence of proconvulsant activity of pyrethroids was not evident. The primary effects were limited to an enhancement of seizure severity in response to PTZ (tonic seizures) and the provocation of spontaneous seizures in partially kindled animals.

Topics: Amygdala; Animals; Convulsants; Disease Models, Animal; Injections, Intraperitoneal; Injections, Intravenous; Insecticides; Kindling, Neurologic; Male; Motor Activity; Nitriles; Pentylenetetrazole; Pyrethrins; Rats; Salivation; Tremor

The pyrethroid insecticides have been divided into two classes on the basis of their biochemical actions and behavioral indices of toxicity. Both types of pyrethroids have effects on sodium conductance, and Type II pyrethroids have been reported to antagonize gamma-aminobutyric acid (GABA) by interacting with the t-butyl-bicyclophosphorothionate (TBPS)/picrotoxinin binding site. The dentate gyrus of the hippocampus is equipped with GABAergic recurrent inhibitory circuits. The present experiment was designed to demonstrate dissociation in the biochemistry of pyrethroids by activating the perforant path with pairs of stimulus pulses and monitoring the recurrent inhibition in this circuit. Antagonism of GABA leads to a reduction in inhibition, measured as an increase in the size of the population spike in response to the second pulse of the pair. The GABAergic properties of the pyrethroids were assessed by examining paired pulse inhibition before and after oral treatment with 20 mg/kg of cismethrin (Type I), 20 mg/kg of fenvalerate, or 10 mg/kg of deltamethrin (Type IIs). Input/output (I/O) functions revealed a reduction in excitatory postsynaptic potential (EPSP) following cismethrin and deltamethrin. Population spike height was unaffected. Fenvalerate had no effect on I/O functions. In contrast to the prediction of reduced inhibition following treatment with Type II pyrethroids, deltamethrin and fenvalerate increased inhibition up to 500 and 150 ms interpulse intervals, respectively. Cismethrin was without effect on paired pulse inhibition. These findings fail to provide evidence of GABA antagonistic properties of Type II pyrethroids and may be best explained by a differential effect of these three pyrethroids on sodium channel kinetics.

Topics: Animals; Evoked Potentials; Hippocampus; Insecticides; Male; Nitriles; Pyrethrins; Rats; Reference Values; Structure-Activity Relationship; Synapses

Phenobarbital-induced rat liver homogenate and microsomes were used to study covalent binding of 14C-labelled (at the alcohol moiety) cismethrin, 14C-labelled (at the alcohol and acid moieties) cypermethrin, and 14C-labelled (at the alcohol and acid moieties) deltamethrin. Covalent binding was dependent on pyrethroid concentration. With liver homogenate, inhibition of esterases by tetraethylpyrophosphate and of mitochondrial respiration by rotenone or potassium cyanide only slightly altered the covalent binding level. With microsomes, inhibition of cytochrome P-450 and mixed function oxidases by carbon monoxide and piperonyl butoxide reduced the covalent binding so far as to be nearly absent. Eighty percent inhibition of epoxide hydrolase decreased the covalent binding by 50%. The comparison of data between alcohol and acid labelling of the same pyrethroid suggested that, in vitro, the whole molecule is bound to proteins and that hydrolysis can occur afterwards. The experiments stress the role of cytochrome P-450-dependent monoxygenases in the covalent binding process.

Topics: Animals; Enzyme Inhibitors; Female; In Vitro Techniques; Insecticides; Liver; Microsomes, Liver; Nitriles; Protein Binding; Pyrethrins; Rats; Rats, Inbred Strains

The effects of saturating concentrations of DDT [1,1,1-trichloro-2,2-bis(p-chlorophenyl)ethane] and the pyrethroid insecticides cismethrin and deltamethrin on alkaloid-dependent activation of the voltage-sensitive sodium channel were studied using measurements of 22Na+ uptake into mouse brain synaptosomes. In survey experiments, these compounds enhanced sodium uptake stimulated by veratridine and batrachotoxin, but inhibited uptake stimulated by aconitine. Concentration response curves for aconitine run in the absence and presence of 10 microM cismethrin demonstrated that the inhibition was noncompetitive. This unanticipated inhibitory effect of insecticides on aconitine-dependent sodium uptake suggests a possible overlap or negative allosteric coupling between the binding sites for insecticides and aconitine and reveals unique characteristics of the action of aconitine that are not shared by veratridine and batrachotoxin. More detailed studies of the effects of insecticides on veratridine- or batrachotoxin-stimulated uptake found small insecticide-dependent increases in the potency of these activators. In addition to this effect, DDT and deltamethrin also enhanced maximal uptake stimulated by veratridine. Possible mechanisms underlying these effects of insecticides on alkaloid-dependent uptake are discussed in light of a qualitative model formulated from these results and previous biochemical and electrophysiological studies. Additional experiments were designed to assess the interactions of insecticides and toxin II of the sea anemone Anemonia sulcata (ATX II) as modifiers of alkaloid-dependent uptake. DDT and ATX II acted synergistically to increase uptake stimulated by veratridine. Moreover, DDT shifted the potency of ATX II for enhancing veratridine-dependent uptake to 5-fold lower concentrations. In contrast, DDT and subsaturating concentrations of ATX II acted independently in their enhancement of sodium channel activation by batrachotoxin. Mutually exclusive effects on veratridine-dependent uptake were observed when cismethrin was co-applied with ATX II. However, independent effects of cismethrin and ATX II were found with aconitine-modified channels, in that cismethrin was able to inhibit ATX II-enhanced aconitine-dependent sodium flux. Thus, the interactions between insecticides and ATX II as modifiers of alkaloid-dependent uptake are complex and depend on the insecticide-activator combination under study.

Topics: Aconitine; Animals; Batrachotoxins; Cnidarian Venoms; DDT; In Vitro Techniques; Ion Channels; Kinetics; Mice; Nitriles; Pyrethrins; Sodium; Synaptosomes; Veratridine

Two behavioral tests, motor activity and the acoustic startle response (ASR), were used to test for dose-addition of cismethrin, a Type I, or deltamethrin, a Type II pyrethroid, with compounds active at the gamma-aminobutyric acid (GABAA) receptor complex (picrotoxin, muscimol and chlordiazepoxide). Additivity was assessed using a simplified version of isobolographic analysis using chlorpromazine and haloperidol as positive controls for dose-additivity. Dosage-effect functions for all compounds were determined for both motor activity and the ASR. The effects of various combinations of chlorpromazine (0.5-4.0 mg/kg) and haloperidol (0.05-0.2 mg/kg) on motor activity indicate dose-addition. To test for dose-addition of pyrethroids and GABAergic compounds, cismethrin (3-18 mg/kg) or deltamethrin (2-6 mg/kg) were administered 90 min before testing, either alone, or before treatment with picrotoxin (0.25-2.0 mg/kg), muscimol (0.6-2.5 mg/kg) or chlordiazepoxide (2.5-10 mg/kg) administered 20 to 30 min before testing. All compounds produced dosage-dependent decreases in motor activity. Muscimol and picrotoxin decreased ASR amplitude, increased ASR latency and reduced ASR sensitization to increasing background noise levels. Chlordiazepoxide had no effect on any measure of the ASR. Results from the interaction studies indicate dose-addition of the effects of picrotoxin and deltamethrin on motor activity and the ASR. Additivity of dose was not seen with any other combination. These data suggest that the in vivo effects of the Type II pyrethroid deltamethrin may be due in part to interaction with the picrotoxinin binding site of the GABAA receptor-ionophore complex. In addition, these results are consistent with reported differential effects of the two classes of pyrethroids on the GABAA receptor complex.

Topics: Animals; Chlordiazepoxide; Chlorides; Dose-Response Relationship, Drug; Haloperidol; Male; Motor Activity; Muscimol; Nitriles; Picrotoxin; Pyrethrins; Rats; Receptors, GABA-A; Reflex, Startle

Radioligand binding displacement studies were conducted to determine the effects of Type I and II pyrethroids on [3H]flunitrazepam (FLU), [3H]muscimol (MUS), and [35S]t-butylbicyclophosphorothionate (TBPS) binding. Competition experiments with [3H]FLU and [3H]MUS indicate a lack of competition for binding by the pyrethroids. Type I pyrethroids failed to compete for the binding of [35S]TBPS at concentrations as high as 50 microM. Type II pyrethroids inhibited [35S]TBPS binding to rat brain synaptosomes with Ki values ranging from 5-10 microM. The data presented here suggest that the interaction of Type II pyrethroids with the gamma-aminobutyric acid (GABA) receptor-ionophore complex is restricted to a site near the TBPS/picrotoxinin binding site.

Topics: Animals; Binding, Competitive; Brain; Bridged Bicyclo Compounds; Bridged Bicyclo Compounds, Heterocyclic; Diazepam; Flunitrazepam; Male; Muscimol; Nitriles; Permethrin; Pyrethrins; Rats; Receptors, GABA-A

Pyrethroids are potent synthetic insecticides which have been increasingly employed in recent years. Such compounds have been shown to bind covalently to hepatic proteins. Covalent binding is often associated with toxic effects. Possible cytotoxic, cytogenotoxic and allergenic effects could be due to covalent binding of these compounds and/or their metabolites to endogenous macromolecules. In the present paper we examine possible cytotoxic effects of certain pyrethroids on human lymphocytes and L 1210 lymphoblastoid mouse cells, cytogenotoxic effects with micronuclei test and allergenic effects with Magnusson and mast cell degranulation tests. Under our experimental conditions, the tested compounds showed neither acute cytotoxic nor cytogenotoxic effects, though, Cismethrin presented slight antimitotic effects statistically different to those with the control. Slight allergenic character of Cismethrin, Bioresmethrin and Deltamethrin was revealed by Magnusson and mast cell degranulation tests.

Topics: Animals; Cell Survival; Humans; Insecticides; Leukemia L1210; Lymphocytes; Mast Cells; Mice; Nitriles; Permethrin; Pyrethrins; Rats; Rats, Inbred Strains; Tumor Cells, Cultured

The mechanical and electrophysiological effects of two synthetic pyrethroids, cismethrin (Type I) and deltamethrin (Type II) have been studied in whole rat gastrocnemius muscle and in isolated perfused rat diaphragm. In both directly or indirectly stimulated preparations deltamethrin but not cismethrin had a positive inotropic effect which in the case of the whole animal could be reversed by increasing the stimulation frequency. In the isolated diaphragm the deltamethrin effect could be prevented by TTX suggesting it is primarily the result of an increased sodium conductance. Deltamethrin also reversed a partial curare blockade in the diaphragm. Electrophysiological studies showed that the inotropic effect of deltamethrin is accompanied by repetitive muscle action potentials. In addition deltamethrin significantly increased muscle fibre input resistance, a novel finding which may underlie the curare reversal effect. It is concluded that the effectiveness of deltamethrin compared with cismethrin in causing repetitive firing in the muscle membrane is attributable to the greater duration of the after-depolarization produced by deltamethrin.

Topics: Action Potentials; Animals; Diaphragm; In Vitro Techniques; Insecticides; Male; Muscle Contraction; Muscles; Nitriles; Pyrethrins; Rats; Tetrodotoxin

To better characterize the behavioral toxicity of pyrethroid insecticides, comparisons were made of the effects of cismethrin and deltamethrin exposure on motor activity and the acoustic startle response in male Long-Evans rats. Acute dose-effect, acute time course, and 30-day repeated-exposure determinations of 1-hr motor activity were made using figure-eight mazes. The acoustic startle response was measured to a 13-kHz, 120-dB(A), 40-msec tone at each of three background white noise levels (50, 65, and 80 dB). Deltamethrin (0, 2, 6, or 8 mg/kg) or cismethrin (0, 6, 12, 18, or 24 mg/kg) were administered po in 0.2 ml/kg corn oil. Cismethrin and deltamethrin produced similar dosage-dependent decreases in motor activity. The time course of onset and recovery for this decreased activity was rapid (1 to 4 hr) No cumulative effects on motor activity of a 30-day exposure to 2 mg/kg/day deltamethrin or 6 mg/kg/day cismethrin were found. The effects of cismethrin and deltamethrin on the acoustic startle response were dissimilar: deltamethrin produced a dosage-dependent decrease in amplitude and an increase in latency, and cismethrin produced an increase in amplitude and no change in latency. The differential effects of cismethrin and deltamethrin on the acoustic startle response may be related to the contrasting effects previously shown with neurophysiological and/or neurochemical techniques.

Topics: Administration, Oral; Analysis of Variance; Animals; Male; Motor Activity; Nitriles; Pyrethrins; Rats; Reflex, Startle

The cardiovascular actions of two pyrethroids, deltamethrin and cismethrin, were assessed using the pithed rat, the isolated working heart, and perfused mesentery preparations. Deltamethrin but not cismethrin, increased mean arterial pressure and differential pressure in the pithed rat, and the aortic output and mean systolic aortic pressure in the working heart. Reserpine pretreatment reduced, but did not abolish, the pressor response to deltamethrin in the pithed rat and working heart, but did not reduce the increase in aortic output following deltamethrin in the working heart. In the perfused mesentery, deltamethrin did not modify the action of exogenous noradrenaline, but increased the response to 10 Hz stimulation. It is concluded that the cardiovascular effects of deltamethrin are due to both increased catecholamine release in peripheral vascular beds, and to a direct positive inotropic effect on the heart. The results also provide a distinction between the action of the two pyrethroids in terms of their cardiovascular activity.

Topics: Animals; Blood Pressure; Cardiovascular System; Decerebrate State; In Vitro Techniques; Insecticides; Ion Channels; Male; Myocardial Contraction; Nitriles; Pyrethrins; Rats; Sodium

Topics: Animals; Behavior, Animal; Blood Glucose; Cerebrovascular Circulation; Drug Interactions; Electroencephalography; Male; Mephenesin; Nitriles; Pyrethrins; Rats; Spinal Cord; Time Factors

Deltamethrin produced a prolonged period of increased excitability following the passage of a nerve impulse, which was dose-related and lasted up to 400 ms. Excitability changes were detected without neurological signs following a single IV injection of 0.5 mg/kg and feeding 200,100 and 50 ppm in the diet for up to 8 weeks. No changes were detected following 0.3 mg/kg IV or 25 ppm in the diet. No cumulative effects were detected during chronic feeding. Cismethrin produced increased nerve excitability only between 2 and 4 ms after a nerve impulse. Excitability changes after cismethrin were biphasic during the first 20 ms.

Topics: Animals; Dose-Response Relationship, Drug; Electric Stimulation; Evoked Potentials; Male; Neuromuscular Junction; Nitriles; Pyrethrins; Rats; Rats, Inbred Strains; Synaptic Transmission

The administration of very small doses of two synthetic pyrethroids, cismethrin and deltamethrin, into the lateral ventricles of the brain or the subarachnoid space around the spinal cord, produced signs of toxicity in rats that were similar to those observed after iv injection of much larger doses. Intraventricular injection of the radiolabeled pyrethroids demonstrated that the onset of toxicity corresponded to the radiolabel reaching a threshold level in the brain stem, cerebellum or upper spinal cord. The injection of similarly labeled pyrethroid solutions into the lumbar region of the spine indicated that there was very little movement of the pyrethroid up the spinal cord to the brain. This corresponded to the signs of toxicity occurring only caudal to the site of injection. It was concluded that both pyrethroids produce their different syndromes of toxicity predominantly by their action on the spinal cord.

Topics: Animals; Central Nervous System; Female; Injections, Intraventricular; Insecticides; Lumbosacral Region; Nitriles; Pyrethrins; Rats; Salivation; Time Factors; Tissue Distribution

Topics: Animals; Blood Glucose; Catecholamines; Lactates; Lactic Acid; Male; Nitriles; Oxygen Consumption; Propranolol; Pyrethrins; Rats

Topics: Acetylcholine; Animals; Brain; Cerebellum; Cyclic AMP; Cyclic GMP; DDT; Female; Nitriles; Nucleotides, Cyclic; Pyrethrins; Rats