Action of pyrethroids on a nerve-muscle preparation of the clawed frog,Xenopus laevis

The effects of a range of pyrethroids on end-plate potentials and muscle action potentials were studied in the pectoralis nerve-muscle preparation of the clawed frog, Xenopus laevis. The noncyano pyrethroids allethrin, cismethrin, bioresmethrin, and IR-cisphenothrin caused moderate presynaptic repetitive activity only, resulting in the occurrence of multiple end-plate potentials (epps). Trains of repetitive muscle action potentials without presynaptic repetitive activity were observed after the α-ethynyl pyrethroid S-5655 and after the α-cyano pyrethroids cypermethrin, deltamethrin, FCR 1272, and FCR 2769. An intermediate group of pyrethroids consisting of the non-cyano compounds 1R-permethrin, des-cyano-deltamethrin, NAK 1901 and NAK 1963, and the α-cyano pyrethroids cyphenothrin and fenvalerate caused both types of effect. The insecticidally inactive S-enantiomers of permethrin had no effect on the nerve-muscle preparation. Trains of repetitive action potentials in pyrethroid-treated muscle fibers were followed by a depolarizing afterpotential which in general decayed more rapidly for the non-cyano pyrethroids than for the α-cyano pyrethroids. The rate of decay of the depolarizing afterpotential decreased gradually as the temperature was lowered, whereas the pre- and postsynaptic repetitive activity remained largely unaffected over a large temperature range. It is concluded that in muscle membrane like in nerve membrane the pyrethroid-induced repetitive activity is due to a prolongation of the sodium current and that a clear distinction between non-cyano pyrethroids on the one hand and α-cyano compounds on the other cannot be made on the basis of the present results.     

Structure-related effects of pyrethroid insecticides on the lateral-line sense organ and on peripheral nerves of the clawed frog, Xenopus laevis

The effects of seven different pyrethroid insecticides on the lateral-line sense organ and on peripheral nerves of the clawed frog, Xenopus laevis, were investigated by means of electrophysiological methods. The results show that two classes of pyrethroid can be clearly distinguished. (i) Pyrethroids without an α-cyano group (permethrin, cismethrin, and bioresmethrin). These noncyano pyrethroids induce short trains of nerve impulses in the lateral-line sense organ. In peripheral nerve branches they induce a depolarizing afterpotential and repetitive firing. These effects are very similar to those previously reported for allethrin. (ii) Pyrethroids with an α-cyano-3-phenoxybenzyl alcohol (cypermethrin, fenpropathrin, deltamethrin, and fenvalerate). In the lateral-line sense organ these α-cyano pyrethroids induce very long trains of nerve impulses which may last for seconds and may contain hundreds or even thousands of impulses. The α-cyano compounds do not cause repetitive activity in peripheral nerves. Instead they induce a quickly reversible, stimulus frequency-dependent suppression of the action potential. Since the chemical structure of cypermethrin differs from that of permethrin only in the α-cyano group and because all four α-cyano compounds act in a very similar way, it is concluded that the α-cyano substituent is responsible for the large differences in neurotoxic effects. In the lateral-line sense organ the duration of nerve impulse trains induced by the noncyano as well as the α-cyano pyrethroids increases dramatically when the temperature is lowered. Further, in sensory fibers the effects of both classes of pyrethroid on the nerve action potential are more pronounced compared to their effects on motor fibers. It is argued that the different neurotoxic effects reported here originate from a common mechanism of action of pyrethroids, which is a prolongation of the transient increase of sodium permeability of the nerve membrane associated with excitation.It is concluded that the sodium channel in the nerve membrane is the major target site of noncyano and α-cyano pyrethroids.     

Electrophysiological identification of site-insensitive mechanisms in knockdown-resistant strains (kdr,super-kdr) of the housefly larva (Musca domestica)

The effects of pyrethroids were studied upon isolated segmental nerves and neuromuscular junctions in both susceptible (Cooper) and knockdown-resistant (kdr; super-kdr) strains of housefly larvae (Musca domestica L.). Isolated segmental nerves contained neither cell bodies nor synaptic contacts; thus, any effects of pyrethroids were attributed solely to their actions upon voltage-dependent Na⁺ channels. Threshold concentrations of the type II pyrethroid, deltamethrin, required to elevate the spontaneous firing rate of these nerves were determined. Both resistant strains were about ten times less sensitive to deltamethrin than the susceptible strain, but insensitivity of super-kdr nerves was no greater than in the less resistant kdr strain. At neuromuscular junctions, the minimum concentrations of pyrethroids needed to trigger massive increases in the frequency of miniature excitatory postsynaptic potentials (mEPSPs) were determined for deltamethrin and the type I pyrethroid, fenfluthrin. With fenfluthrin there was no detectable difference between the junctions of kdr and super-kdr strains, which were both about ten-fold less sensitive than Cooper junctions. With deltamethrin, kdr junctions were about 30 times less sensitive than those of Cooper; super-kdr junctions were dramatically insensitive to deltamethrin, being some 10000- and 300-fold less sensitive than those of Cooper and kdr respectively. Thus, in the synaptic assay, super-kdr conferred an extension in resistance over kdr only against the type II pyrethroid, it being ineffective against fenfluthrin. We suggest that kdr resistance comprises at least two site-insensitive areas within the nervous system. One involves insensitivity of the Na⁺ channel and has similar efficacy in both kdr and super-kdr strains against type I and II pyrethroids; the other is associated with the presynaptic terminal and is particularly effective in super-kdr resistance against type II pyrethroids. The latter could be associated with Ca²⁺-activated phosphorylation of proteins involved with neurotransmitter release. Such phosphorylation reactions are known to be perturbed by pyrethroids, especially by type II compounds.     

Development of resistance to pyrethroids in field populations of danish houseflies

Houseflies (Musca domestica) on Danish farms have developed high multiresistance to organophosphorus compounds, after successive use of several OPs, mainly dimethoate, in recent years. Topical application tests 1971–73 with flies from many farms showed that the high OP-resistance did not involve resistance to pyrethroids (± the synergist piperonyl butoxide (pb)) above a level of 3–7 x, unless field pressure with synergised pyrethrum (py/pb) or other pyrethroids was applied. In 1971–72 moderate to high, often heterogeneous, pyrethroid resistance was found on a few trial farms treated frequently with pyrethroid aerosols (mainly py/pb) and in 1973 on most of 23 trial farms treated intensively with aerosols (or space spray) containing py/pb, bioresmethrin ± pb, tetramethrin/pb or tetramethrin/resmethrin. The effect of field pressure with these different pyrethroids on development of pyrethroid resistance is summarised and discussed. Maximum resistance ratios, R/S at LD₅₀-LD₉₅, were: py/pb (1:5), 40->100; bioresmethrin, 191–770; bioresmethrin/pb (1:5), 55–133; tetramethrin/pb (1:5), 171->200; tetramethrin/resmethrin (1:5), 78->370. The intensity of selection pressure with pyrethroids is believed to be an important factor. Although py/pb has been widely used as a supplementary fly control on Danish non-trial farms, pyrethroid resistance has only been found on a few of them.     

The crayfish stretch receptor organ: A useful model system for investigating the effects of neuroactive substances: II. A pharmacological investigation of pyrethroid mode of action

The crayfish stretch receptor neuron is very sensitive to disruption by pyrethroids. Experiments were therefore carried out on this preparation to investigate whether all observed symptoms of pyrethroid poisoning could be explained in terms of a single action of pyrethroids on the gating mechanism of sodium channels. Other possible mechanisms of pyrethroid action, including effects on potassium channels, inhibitory synapses, and inhibition of calcium ATPases, were also investigated. An effect on sodium channels was clearly demonstrated, but the contribution of other mechanisms was less clear. It appears that the action on the sodium channel could be responsible for the majority, if not all, of the observed effects of pyrethroids on sensory cells.     

Two different types of inhibitory effects of pyrethroids on nerve Ca- and Ca + Mg-ATPase activity in the squid, Loligo pealei

The biochemical process by which various pyrethroid insecticides affect membrane-bound ATPase activities of the squid nervous system was examined. Of the five ATP-hydrolyzing systems tested, only Ca²⁺-stimulated ATPase activities are seen to be clearly affected by pyrethroids. It was found that the “natural type” pyrethroids (e.g., pyrethrin and allethrin) primarily inhibit Ca-ATPase activity whereas the “highly modified type” pyrethroids (e.g., cypermethrin and decamethrin) mainly inhibit Ca + Mg-ATPase. permethrin, which is considered to possess structural similarities to both the natural type and the highly modified type pyrethroids, was found to have an intermediate property in terms of its inhibitory potency to both Ca- and Ca + Mg-ATPase activities. The level of inhibition of Ca²⁺-stimulated ATPase activities was generally high in the retinal axons and optic lobe synaptosomes but lowest in the axoplasmic preparations.     

Effects of pyrethroids on the activity of a purified (Ca2+-Mg2+)-ATPase

We report the effects of pyrethroids on the activity of the (Ca²⁺Mg²⁺)-ATPase purified from rabbit muscle sarcoplasmic reticulum. Deltamethrin causes a small increase in the activity of the native ATPase but a large stimulation for the ATPase reconstituted into bilayers of the short-chain phospholipid dimyristoleoylphosphatidylcholine. The extent of stimulation depends on the structure of the pyrethroid. Stimulation occurs at lower concentrations for the pyrethroid than for the constituent acid or alcohol. Stimulation shows a negative temperature coefficient. Pyrethroids have no effect on the fluidity of lipid bilayers. Effects are therefore discussed in terms of binding of pyrethroids to the ATPase.     

Efficacy of various pyrethroid structures against a highly metabolically resistant isogenic strain of Helicoverpa armigera (Lepidoptera: Noctuidae) from China

BACKGROUND: Resistance to pyrethroids and other types of insecticides in Helicoverpa armigera (Hübner) has been documented in many countries. The isolation of specific resistance mechanisms in isogenic strains is an optimal approach to investigate cross-resistance pattern, and to validate resistance breaking pyrethroids. In this study an isogenic metabolic resistance CMR strain was successfully isolated from a field pyrethroid-resistant population of H. armigera. With this strain, cross-resistance among 19 pyrethroid insecticides with varying chemical structures was analysed. RESULTS: Resistance to pyrethroids in the CMR strain was likely to be due to enhanced oxidative metabolism. The most significant cross-resistance in the CMR strain was between pyrethroids such as fenvalerate, tau-fluvalinate and flumethrin characterised by having both phenoxybenzyl and aromatic acid moieties. Substitution of the phenoxybenzyl group with a polyfluorobenzyl group, as in tefluthrin, benfluthrin and transfluthrin, overcame most of this resistance. CONCLUSION: The findings in this study support the assertion that it is possible to find pyrethroids that are active against resistant populations. Such pyrethroids could be considered as possible partners or resistance breaking pyrethroids in a pyrethroid resistance management programme for H. armigera in China and in other Asian countries where the oxidative metabolism resistance is a dominant mechanism.     

Alkyl aryl ketone oxime O-ethers: A novel group of pyrethroids

The alkyl phenyl ketone oxime O-benzyl ethers are a new group of insecticidal compounds. Although they lack the ester linkage, they resemble the pyrethroids in general, and the esters of 2-phenylalkanoic acids, in particular fenvalerate, because they show similar physiological effects on isolated nerve preparations and on whole insects; they also show a similar pattern of change of biological activity in response to structural change. The compounds may exist as two geometric isomers, of which only the (E) series shows significant biological activity; this observation appears to have some bearing on the relationship between conformation and activity in the pyrethroid series as a whole.     

Characteristics of pyrethroids for insect pest control in agriculture

Pyrethroid insecticides are characterised by high knockdown and lethal activity, a wide spectrum, good residual activity, together with repellent and antifeeding activity. With these characteristics, pyrethroid insecticides have become widely used for plant protection. Their major use has been for the control of bollworms and leafworms in cotton but they have also achieved widespread use for controlling various species of lepidopterous pests in fruits and vegetables, aphids in cereals, and many other minor outlets. Although the early synthetic pyrethroids suffered from a lack of activity against mites and soil pests, later additions, such as fenpropathrin, have combined high acaricidal activity with insecticidal activity and further pyrethroids are being introduced for use in soil. The extent of pyrethroid use has increased progressively since the first of the ‘photostable’ pyrethroids was registered. In 1986, the market share of pyrethroids reached 25 % of the total insecticide market for plant protection; this figure can be increased in the future.     

Experiences in controlling resistant pollen beetle by type I ether pyrethroid Trebon 30 EC in Germany

Oil seed rape (OSR) is an important crop in Germany with a long growing history. Due to the prevalence of various springtime pests an average of two pyrethroid applications are made. Pyrethroid resistance in Germany was found locally in 2003, widespread distribution of resistance was observed in 2006, a year of very strong pest pressure. Field trials in 2005 and the following years and laboratory analysis showed good control of resistant pollen beetle ( Meligethes aeneus ) by type I ether pyrethroid etofenprox, the active substance of Trebon 30 EC. Etofenprox differs significantly from common pyrethroids, which are usually ester pyrethroids including an α-amino-group and halogen substitutions. Trebon 30 EC has comparable efficacy on all important OSR pests but it has superior efficacy on resistant pollen beetle compared to common pyrethroids. To cope with pyrethroid resistance of pollen beetle, three different modes of action (MOA)s are postulated, which may be type I pyrethroids, neonicotinoids and organophosphates (OPs). Because type I pyrethroids, such as Trebon 30 EC, perform well at low temperatures, have a broad spectrum of activity, are considered as not to be toxic to bees, and give a high level of control of resistant pollen beetle, they will have an important role in the insecticide spraying regime of OSR.     

昆虫对拟除虫菊酯类杀虫剂的代谢抗性机制研究进展

随着拟除虫菊酯类杀虫剂在卫生和农业害虫防治中的广泛应用,昆虫对此类杀虫剂产生抗性的报道越来越多。目前已明确昆虫对拟除虫菊酯类杀虫剂的抗性机制包括表皮穿透率下降、靶标抗性以及代谢抗性,其中代谢抗性机制较为普遍,而且其与昆虫对多种杀虫剂的交互抗性关系密切。目前,随着基因组、转录组以及蛋白质组学等新技术的发展及应用,昆虫对拟除虫菊酯类杀虫剂的代谢抗性机制研究也取得了很多新进展。昆虫体内细胞色素P450酶（P450s）、羧酸酯酶（CarE）及谷胱甘肽S-转移酶（GSTs）等重要解毒酶系的改变均与昆虫对拟除虫菊酯类杀虫剂的代谢抗性有关,其中这3类解毒酶的活性及相关基因表达量的变化是昆虫对此类杀虫剂产生代谢抗性的主要原因。明确昆虫对拟除虫菊酯类杀虫剂的代谢抗性机制,对合理使用此类杀虫剂及延缓抗药性的产生均具有重要意义。本文在总结拟除虫菊酯类杀虫剂代谢路径及相关生物酶研究概况的基础上,综述了近年来有关昆虫对此类杀虫剂代谢抗性机制研究的主要进展。     

The role of B‐type esterases in conferring insecticide resistance in the tobacco whitefly,Bemisia tabaci (Genn)

Separation of non‐specific esterases on electrophoretic gels has played a key role in distinguishing between races or biotypes of the tobacco whitefly, Bemisia tabaci. One intensively staining esterase in particular (termed E_0.14) has assumed significance as a diagnostic of B‐type whiteflies (aka Bemisia argentifolii), despite any knowledge of its biological function. In this study, a whitefly strain (B‐Null) homozygous for a null allele at the E_0.14 locus that had been isolated from a B‐type population was used to demonstrate a significant role for E_0.14 in resistance of B‐type populations to pyrethroids but not to organophosphates (OPs). Bioassays with pyrethroids, following pre‐treatment with sub‐lethal doses of the OP profenofos (to inhibit esterase activity), coupled with metabolism studies with radiolabelled permethrin, supported the conclusion that pyrethroid resistance in a range of B‐type strains expressing E_0.14 was primarily due to increased ester hydrolysis. In the same strains, OP resistance appeared to be predominantly conferred by a modification to the target‐site enzyme acetylcholinesterase. © 2000 Society of Chemical Industry     

Synergism of pyrethroid — organophosphorus insecticide mixtures in insects and their toxicity againstspodoptera littoralis larvae

Synergism of mixtures of pyrethroids with organophosphorus (OP) compounds in insects is reviewed, and the toxicity of such combinations againstSpodoptera littoralis (Boisd.) larvae is reported. Mixtures of one of the pyrethroids cypermethrin, fenvalerate or deltamethrin with one of the OP compounds monocrotophos, profenofos, azinphos-methyl or acephate were assayed at different ratios as 24-h-old dipping residues on alfalfa, which was fed toS. littoralis larvae for 48 h. With most of the binary mixtures containing various OP concentrations in excess of those of the pyrethroids, synergism was demonstrated. In the pairs fenvalerate — azinphos-methyl, deltamethrin — azinphos-methyl and deltamethrin — profenofos, however, no synergism was found. In a detailed investigation with pyrethroid concentrations causing 20% mortality and OP concentrations giving a kill of no higher than ;10%, the above findings on synergism were amply confirmed. A cypermethrinmonocrotophos mixture showed synergism also on cotton leaves sprayed in the field. Synergism could not be demonstrated by topical application of pyrethroid — OP mixtures.     

Promotion of norepinephrine release and inhibition of calcium uptake by pyrethroids in rat brain synaptosomes

A series of 25 pyrethroids were assessed for their effects on Na⁺-dependent norepinephrine release and on Ca²⁺ uptake in vitro using a crude rat brain synaptosomal preparation. The most effective pyrethroids required a concentration of 3–10 μM to promote norepinephrine release. Plotting release data versus lipophilicity (as log P) for each compound resulted in a parabolic curve with log P_opt being 5.4 for maximal release. The release promoted by most of the compounds assessed at 30 μM could not be or was only partially reversed by either tetrodotoxin or substituting choline for Na⁺ conditions which readily reversed the release promoting effects of veratridine. Thus, many pyrethroids, particularly those without the α-cyano group, did not display their expected effects on the Na⁺ channel in rat brain. When assessed at 5 μM, pyrethroids inhibited, had no effect, or caused increases in the amount of Ca²⁺ incorporated in the presence of ATP. The effectiveness of the various pyrethroids to inhibit Ca²⁺ uptake again displayed a parabolic relationship with log P_opt being 6.4. It was concluded that the variations in pyrethroid effects on norepinephrine release and Ca²⁺ uptake are not solely related to their particular chemical structures, but to lipophilicity. The effects of many pyrethroids on Ca²⁺ metabolism, particularly displacement of bound Ca²⁺, better explain the transmitter release promoting properties in vitro rather than a direct effect on the Na⁺ channel. No direct relationship between known toxicity to mammals and Ca²⁺ inhibition by pyrethroids was established.     

Control of air-borne field spread of tulip breaking virus,lily symptomless virus and lily virus X in lilies by mineral oils,synthetic pyrethroids,and a nematicide in the Netherlands

The inhibitory effect on the spread of viruses in lilies viz., tulip breaking virus (TBV; nonpersistently aphid-borne, potyvirus,) lily symptomless virus (LSV; non-persistently alphidborne, carlavirus), and lily virus X (LVX; potexvirus of unknown etiology), was studied of brands of mineral oil (Luxan oil H and Duphar-7E oil) and synthetic pyrethroid insecticides (l-cyhalothrin and deltamethrin), and a nematicide (aldicarb) in crops in which virus-infected plants were present as virus sources. The spread of TBV and LSV were controlled by sprays of mineral oil and insecticide, while that of LSV was also limited by the soil-applied nematicide. The spread of LVX was reduced by the insecticides and, not effectively by the mineral-oil spraying, by which data the mode of transmission may be presumed to be by an insect in the persistent or semi-persistent manner.Mixtures of mineral oil and pyrethroid were more effective in the reduction of spread of TBV and LSV than either components tested alone. The mineral oil was the most effective component in the mixtures in which pyrethroid added a slight extra effect. The addition of pyrethroid did not mask either the lower efficacy of the oil brand Duphar-7E oil, or the diminished inhibitory effect of low dosages of oil. The normal rate of mineral oil gave similar control to that of a mixture of mineral oil at half rate plus the pyrethroid at full dosage. Low rates of oil, or even synthetic pyrethroids alone may be used on cultivars which suffer of the loss of bulb weight by the use of normal or decreased rates of oil. Weekly sprays were more effective than fortnightly sprays. The rate of control by the weekly sprays ranged between 90 and 95% for Luxan oil H at half dosage plus the full rate of pyrethroid. Weekly sprayed synthetic pyrethroids alone onto the virus sources and the plants to be infected gave 60–70% control. The weight ratios tended to be slightly reduced if the half dosage of the efficient Luxan oil H was used. Factors which affect the control of the air-borne field spread of viruses by mineral oils and synthetic pyrethroid insecticides in lilies are discussed.     

The importance of nerve terminal depolarization in pyrethroid poisoning of insects

The effects of several pyrethroids and DDT were examined on neuromuscular preparations from larvae of Musca domestica, Culex quinquefasciatus, Anopheles stephensi, and Trichoplusia ni, in order to determine the importance of the type I effect (repetitive firing) and the type II effect (increased miniature excitatory postsynaptic potential (mepsp) rate, indicating nerve terminal depolarization) in the poisoning process. α-Cyano pyrethroids were very potent in increasing mepsp rate, and although DDT and non-α-cyano compounds were more potent at inducing repetitive firing, all these compounds increased mepsp rate at higher concentrations. A variety of evidence showed that the mepsp rate-increasing activity could be an important factor in toxicity: among all of the compounds, there was a positive correlation between toxicity and mepsp rate-increasing activity; mepsp rate-increasing activity had a negative temperature dependence; nerves of kdr larvae in vitro were resistant to the mepsp rate-increasing activity, commensurate with resistance level; and finally, increased mepsp rate and neuromuscular block were observed in poisoned insects, associated with paralysis. Among type I compounds, repetitive firing activity was correlated negatively with toxicity, but positively with knockdown activity.     

Cross-resistance to pyrethroids and other insecticides in Aedes aegypti

Two substrains of Aedes aegypti, already resistant to DDT and pyrethroids, were further selected using either DDT or permethrin by mass exposure of the females only. DDT selection over 14 generations raised the resistance to DDT so far that no accurate LC₅₀ values could be determined. Selection with permethrin raised the tolerance to an irregular plateau 7–10 times the original. DDT selection in the adults raised the DDT resistance of the larvae, but this could be partly overcome using a dehydrochlorinase inhibitor. The resistance to pyrethroids was increased but tolerance of dieldrin, malathion and propoxur compounds was little changed. Permethrin selection of the adults raised resistance to pyrethroids more than DDT selection but also increased DDT resistance. Similar patterns were found for the larval insects. A strain from Demerara in Guyana showed both DDT and pyrethroid resistance, including strong resistance to pyrethrins together with dieldrin and propoxur. It was concluded that two major independent resistance mechanisms existed in the selected strains, a dehydrochlorinase affecting DDT alone, and an unknown mechanism, probably nerve insensitivity (kdr) affecting both DDT and pyrethroids.     

Neural and behavioral correlates of pyrethroid and DDT-type poisoning in the house fly, Musca domestica L

Intact house flies were observed during poisoning caused by several pyrethroid and DDT-type insecticides. The two insecticide classes could be generally distinguished from each other based on differences in symptoms and several physiological correlates. Both insecticide types caused motor unit repetitive backfiring, but the temporal development and stability of repetitiveness were distinctly different between the two classes. Repetitive backfiring always disappeared at low temperatures, but DDT-type backfiring disappeared at lower temperatures than the pyrethroids. trans-Tetramethrin caused a threshold increase in flight motor nerve endings which did not occur in DDT or trans-Barthrin poisoning. Pyrethroids caused “uncoupling” of the flight motor pattern, while DDT-types did not. trans-Barthrin, a methylenedioxyphenyl pyrethroid, was unique in causing both symptoms and physiological aberrations which more closely resembled those of the DDT-types than the pyrethroids.     

Pyrethroids, knockdown resistance and sodium channels

Knockdown resistance to DDT and the pyrethrins was first described in 1951 in the housefly (Musca domestica L.). This trait, which confers reduced neuronal sensitivity to these insecticides, was subsequently shown to confer cross-resistance to all synthetic pyrethroid insecticides that have been examined to date. As a consequence, the worldwide commercial development of pyrethroids as a major insecticide class over the past three decades has required constant awareness that pyrethroid overuse has the potential to reselect this powerful resistance mechanism in populations that previously were resistant to DDT. Demonstration of tight genetic linkage between knockdown resistance and the housefly gene encoding voltage-sensitive sodium channels spurred efforts to identify gene mutations associated with knockdown resistance and understand how these mutations confer a reduction in the sensitivity of the pyrethroid target site. This paper summarizes progress in understanding pyrethroid resistance at the molecular level, with particular emphasis on studies in the housefly.