Effects of chlordimeform on rectus abdominis muscle of frog

The effects of chlordimeform on rectus abdominis muscle of frog were investigated. Chlordimeform (10^?3M) caused a slow contraction, and at lower concentration (10^?5–10^?3M) it inhibited the acetylcholine-induced contraction in noncompetitive manner. When chlordimeform was applied to the muscle of Rana catesbiana, K⁺-induced contraction was also inhibited in noncompetitive manner. Whereas it had no effect on caffeine-induced contraction.Chlordimeform-induced contraction was not affected by respective addition of d-tubocurarine (10^?4M), procaine (10^?3M), or eserine (0.3 mM), which results were same as that of K⁺-induced contraction. Chlordimeform, at lower concentration (10^?5–10^?3M), inhibits the acetylcholine- and K⁺-induced contractions probably owing to depression of not only the sensitivity of endplate but also the excitability of cell membrane.     

Effects of chlordimeform on vascular smooth muscle

The effects of chlordimeform on agonist-induced contractions of rabbit aortic strips and on calcium flux in the deadventitiated strips have been studied. Chlordimeform antagonizes contractions induced by several vasoactive agents, with the order of antagonism being potassium . histamine > serotonin > norepinephrine, and decreases the rate of contraction of strips exposed to each of the four agonists. Muscles contracted by each of the agonists are rapidly relaxed by application of chlordimeform, although in the case of norepinephrine the relaxation only proceeds to approximately one-half of the maximal tension. The rate of washout of ⁴⁵Ca from the media-intimal layer of the rabbit aorta was increased by chlordimeform, but the norepinephrine-induced decrease in the rate of washout of ⁴⁵Ca was not affected by chlordimeform. Chlordimeform did not affect ⁴⁵Ca uptake by the media-intimal strips. The results of this study indicate that chlordimeform probably interferes with loosely bound calcium to a greater extent than it does with more tightly bound stores.     

Mechanism of neuromuscular block by chlordimeform

The mechanism of action of chlordimeform on the frog sciatic nerve-sartorius muscle preparation has been studied by means of microelectrodes. Chlordimeform (0.1 mM) suppresses the amplitude of spontaneous miniature end-plate potentials without much changing their frequency. At 1 mM, it completely blocks the miniature end-plate potentials. The resting membrane potential is not affected. The end-plate potential evoked by nerve stimulation is also suppressed, while the action potential from the nerve terminal is not impaired. The sensitivity of the end-plate membrane to the transmitter substance as examined by iontophoretic applications of acetylcholine is effectively decreased by chlordimeform. The quantal content of transmitter release is not affected. It is concluded that the block of neuromuscular transmission by chlordimeform is due primarily to a depression of the end-plate sensitivity to the transmitter.     

Similar pharmacological actions of chlordimeform and local anesthetics

The toxic symptoms of the pesticide, chlordimeform, resemble those observed following systemic local anesthetic overdose. In view of similarities in the chemical structures of chlordimeform and the local anesthetic agent phenacaine, additional comparisons between the actions of chlordimeform and local anesthetics were made. Chlordimeform had effects on the frog sciatic nerve preparation similar to those of local anesthetics (i.e., blocked conduction, increased threshold, prolonged refractory period). Chlordimeform was 0.6 times as active as procaine, less active in the ionized form, and more active on the desheathed preparation. Chlordimeform lethality was reduced by pretreatment with diazepam or pentobarbital, but not by diphenylhydantoin, trimethadione, or mephenesin pretreatment. These pretreatments have a comparable effect on local anesthetic toxicity. Chlordimeform lethality was slighly increased by agents possessing “local anesthetic activity” such as imipramine, pyribenzamine, and phenoxybenzamine. These and other results indicate that a number of the pharmacological and toxic actions of chlordimeform in mammals may be due to actions that are similar to those of local anesthetic agents.     

Chlordimeform: Uncoupling activity against rat liver mitochondria

The pesticide chlordimeform [N′-(4-chloro-o-tolyl)-N,N-dimethylformamidine] at 0.04 μmoles/mg protein uncouples 50% of respiratory-chain phosphorylation of rat liver mitochondria. This uncoupling activity depends on mitochondrial protein concentration and can be reversed either by the addition of bovine serum albumin or by washing. The normal inhibition of state 3 respiration by oligomycin and atractylate is completely reversed by chlordimeform. Uncoupling concentrations of chlordimeform elicit high adenosine triphosphatase activity. This activity is blocked by the above inhibitors of mitochondrial energy-transfer reactions. Evidence is presented which shows that unprotonated chlordimeform is the form effective in uncoupling. It is concluded that chlordimeform is an uncoupling agent with a potency and site of action close to but probably not identical to that of the classical uncoupler 2,4-dinitrophenol.     

Formamidine structure and detachment of the cattle tick Boophilus microplus

Evaluation of the effectiveness of topically applied chlordimeform, 14 other formamidines, and 5 sulfur-containing related nonformamidine compounds in causing female Boophilus microplus ticks to detach from mice enabled activity to be related to structure. Five compounds were inactive and 15, including 2 sulfur-containing nonformamidines and 1 sulfur-containing formamidine were active at doses ranging from 0.0005 to 2.0 μg/tick. The most active compounds were the N-monomethyl formamidines, BTS-27271 [N′-(2,4-dimethylphenyl)-N-methylformamidine], and C-8520 (demethylchlordimeform). Among the analogs of chlordimeform tested, those with alkyl substitutions at the amino nitrogen decreased in effectiveness in the order, monomethyl (demethylchlordimeform), monoethyl, mono-n-butyl, mono-i-butyl, mono-i-propyl, dimethyl (chlordimeform), and di-n-propyl. Inactive compounds resulted from the replacement of the chlorine at ring position 4 of the aryl moiety of chlordimeform by bromine or hydrogen or by the conversion of the NCH amidino moiety to the NHCSN < thiourea moiety.Detachment due to chlordimeform was antagonized by piperonyl butoxide but that due to its N-monomethyl analog, a known metabolite of chlordimeform in ticks, was synergized by the same compound. These effects on the detaching response parallel those reported elsewhere concerning synergism and antagonism of toxic responses of B. microplus to formamidines.BTS-27271, which was the most effective formamidine in causing detachment after topical application to ticks was moderately effective when injected into mice but its potency relative to chlordimeform was considerably reduced; when sprayed onto cattle BTS-27271 was somewhat more effective in depressing percentage survival of ticks of all stages than chlordimeform.     

Actions of formamidines,local anesthetics,octopamine and related compounds upon the electrical activity of neurohaemal organs of the stick insect (Carausius morosus) and sense organs of fly larvae (Musca domestica; Calliphora erythrocephala)

The pesticides, chlordimeform and amitraz, and their metabolites, demethylchlordimeform, N¹-(2,4-dimethylphenyl)-N-methylformamidine, and 2,4-dimethylformanilide, are effective at concentrations as low as 3 μM in raising the firing rate of endogenously active neurosecretory fibres in the isolated neurohaemal organs of Carausius morosus. Molecules such as bunamidine and cetrimide, with cationic detergent properties, produced sporadic bursting which did not elevate the overall firing rate to any great extent. Indeed, bunamidine could induce complete block of action potentials at concentrations as low as 30 μM. The local anesthetics, procaine, lidocaine, and benzocaine, do not induce block of activity at least up to a level of 1 mM. They have no effect at concentrations lower than 100 μM. Between 100 μM and 1 mM lidocaine and benzocaine produce a small increase in firing rate. Procaine produced a pronounced increase in the frequency of firing. The phenolic amines, octopamine, synephrine, and tyramine, markedly increased electrical activity. The catecholamines, dopamine, noradrenaline, and adrenaline, by contrast, only produced a weak excitation. Neither α- nor β-adrenergic blocking agents were effective in antagonizing the electrical activity induced by chlordimeform or phenolic amines until relatively high concentrations of about 1 mM were used. Chlordimeform was able to induce high-frequency bursts from sense organs associated with the epidermis and body-wall musculature in larvae of Musca domestica and Calliphora erythocephala. Octopamine did not induce any similar bursting activity in these sense organs. These results are discussed in relationship to current views on the mode of action of the N-aryl amidines. It is concluded that the excitatory effects of these compounds upon neurohaemal organs and sense organs are more likely to result from a direct action upon voltage sensitive channels of the nerve membranes, rather than by an effect mediated by interactions with octopamine receptors.     

Effects of chlordimeform and lindane on monoamine levels in the central nervous system of the american cockroach, Periplaneta americana L

The effects of chlordimeform and lindane on levels of 5-hydroxytryptamine, tryptophan, and N-acetyl dopamine were studied in the cerebral ganglia of the american cockroach, Periplaneta americana. The effects of chlordimeform on nerve cord levels of 5-hydroxytryptamine, tryptophan, dopamine, and octopamine, and the effect of lindane on cerebral ganglia levels of dopamine were also investigated in this species. Topical applications of chlordimeform deplete 5-hydroxytryptamine and tryptophan from the cerebral ganglia whereas levels of n-acetyl dopamine are elevated. The effect of chlordimeform on these compounds is dose-dependent. Similar chlordimeform-induced effects are observed in the nerve cord, and octopamine levels are also depleted in this tissue following treatment with chlordimeform. A biphasic response to chlordimeform is observed in the nerve cord for dopamine levels with a 40% decrease evident after 2 hr and a 30% increase apparent after 6 hr. In contrast to chlordimeform, lindane does not affect 5-hydroxytryptamine and tryptophan levels in the cebral ganglion but low doses of this insecticide effect increases in brain levels of dopamine and n-acetyl dopamine.     

Inhibition of oviposition in the cattle tick Boophilus microplus by certain acaricides

Doses of ten acaricides, ranging from 2.5 to 10 μg, induced about 10-60% mortality and inhibited oviposition in engorged Boophilus microplus as well as preventing larval hatching from the eggs. The effects of the acaricides were dose dependent. The efficacy of acaricides in reducing the reproductive potential (inhibition of oviposition × inhibition of hatching/100) was in the following order: dimethoate > dioxathion > naled > diazinon > chlordimeform > carbaryl > trichlorphon > phosphamidon > gamma-HCH > fenitrothion. Most of the acaricides also retarded the oviposition cycle, delaying the peak activity by 4-8 days. The ovarian development in control ticks reached its peak between the 5th and 7th days before decreasing gradually and ceasing completely between the 16-20th days after engorgement. The protein content of the ovaries and the rate of incorporation of [¹⁴C]glycine into the tissues followed a similar pattern. Carbaryl, fenitrothion and naled inhibited these activities. Chlordimeform stimulated [¹⁴C]glycine incorporation and increased the ovarian protein content up to the 13th day before resorption of the oocytes. The eggs from treated ticks were mostly non-viable and contained more protein; those from dioxathion, carbaryl and chlordimeform treatments had a higher dry weight than the control.     

Induction of hyperactivity in larvae of the cattle tick Boophilus microplus by formamidines and related compounds

The effect of chlordimeform and 18 related compounds on the aggregation behavior of the negatively geotactic larvae of the cattle tick, Boophilus microplus was investigated. Aggregations were treated and hyperactivity in the forms of immediate dispersal, delayed dispersal, and prolonged leg waving evaluated. A marked structure-activity relationship with delayed dispersal resulted; most active were the N-monomethyl formamidines, N′-(2,4-dimethylphenyl)-N-methylformamidine and demethylchlordimeform. Other compounds, including chlordimeform, with structures compatible with metabolism to N-monomethyl formamidines were also active. Delayed dispersal caused by those possessing the N,N-dimethyl moiety was antagonized after inhibition of oxidative N-demethylation to N-monomethyl analogs by piperonyl butoxide. Since the N-monomethyl moiety had already been reported as important in the killing action of the formamidines in cattle tick larvae, the possibility of a relationship between delayed dispersal and acaricidal effectiveness was examined and percentage mortality at 24 hr found to correlate positively with the rate of onset of dispersal.Delayed dispersal was not characteristic of the responses to other acaricides such as lindane, allethrin, carbaryl, and coumaphos. In addition, the monoamine oxidase inhibitors, tranylcypromine, pargyline, and nialamide, did not induce delayed dispersal and showed no lethal effects.     

Monoamine oxidase inhibition and brain catecholamine levels in the rat following treatment with chlordimeform

Norepinephrine and dopamine levels in rat brain increase by 51.7 and 70.3%, respectively, within 14 hr of intraperitoneal injection of 24 mg chlordimeform/kg wet wt. An inhibition of monoamine oxidase (MAO) activity in mitochondrial extracts from brains and livers of chlordimeform-treated rats occurred concomitantly with the elevation of catecholamine levels. In the brain extract the oxidative deamination of tyramine was inhibited by 8.1% and that of 2-phenylethylamine by 54.5%, whereas in the liver preparation the extent of inhibition using these substrates was 23.8 and 31.1%, respectively. The results suggest specific inhibition of type B MAO, and the conclusion was substantiated by use of clorgyline, a specific inhibitor of type A MAO. The results are discussed in light of the observation that rats which are exposed to sublethal concentrations of chlordimeform display pronounced behavioral changes.     

Insecticides and electrophysiological symptoms: A comparative study on a tarsal motor nerve of Locusta migratoria

Spontaneous discharges of a tarsal motor nerve preparation of the jumping leg of Locusta migratoria were recorded extracellularly under the influence of various insecticides applied to the in situ metathoracic ganglion of the insect. Insecticides from different chemical classes were found to exhibit rather specific electrophysiological symptoms: cholinesterase inhibitors produced groups of action potentials with highly increased frequencies, and led to the appearance of new units which were not present in untreated control insects. They also caused transitory phases of conduction blocks, the length of which increased as intoxication proceeded. The DDT analog tested could be characterized by pronounced repetitive dischanges, whereas the neuroactivity of pyrethroids was typically associated with a very regular spike pattern in continuous phases of extremely high frequencies. Also chlordimeform, a formamidine insecticide, was found to increase the spike frequency, but to a much lesser extent than that observed for the other insecticides tested.     

The effect of single and combined doses of chlordimeform and permethrin on cAMP and cGMP levels in the moth,Mamestra configurata Wlk

Treatment of adult males of the moth, Mamestra configurata, with chlordimeform caused large increases (up to 27-fold) in the concentration of cAMP in the head, thorax, and abdomen but had little effect on cGMP. This pesticidal effect, termed A⁺G⁰, likely results from the interaction of chlordimeform (or a metabolite) with an octopamine-sensitive adenylate cyclase present in the brain and other tissues. Treatment of moths with permethrin caused substantial increases (up to 3.4-fold) in the concentration of cGMP in the head and thorax but had little effect on cAMP. This effect, termed A⁰G⁺, may result from a disturbance of cholinergic function. Treatment of moths with a combined dose of chlordimeform and permethrin caused increases in the concentration of both cAMP and cGMP (A⁺G⁺ effect) in the head and thorax and had a synergistic effect on mortality. The synergistic effect on mortality appears to be caused by the disruption of distinct and different physiological systems by the A⁺G⁰ and A⁰G⁺ pesticides. The hypothesis that A⁺G⁰ and A⁰G⁺ pesticides, when combined, will exhibit synergism is supported by examples from the literature.     

Effects of chlordimeform on mitochondria from eggs of Spodoptera littoralis

Mitochondria were isolated from eggs of Spodoptera littoralis. With succinate (+pyruvate) as substrate, respiratory control ratios between 1.70 and 2.54 were obtained. Uncouplers and the energy transfer inhibitor oligomycin influenced these mitochondria in the well-known manner. The uncoupling activity of chlordimeform in vitro was very weak and decreased with increasing age of the eggs. Electron transport in mitochondria from chlordimeform-treated eggs was not uncoupled. Therefore, it is concluded that the ovicidal effect of this pesticide is not due to its uncoupling effect.     

Interaction of formamidine pesticides with insect neural octopamine receptors: Effects on radioligand binding and cyclic AMP production

The formamidines chlordimeform, demethylchlordimeform (DCDM), amitraz and BTS-2727l were tested for their respective abilities to inhibit [³H]mianserin binding in membrane preparations of cockroach brain and, in the same tissue, to stimulate octopamine-sensitive receptors coupled to adenylate cyclase. Analysis of [³H]mianserin binding indicated negative cooperativity between two binding sites with respective K_d and B_max values of 3.82 mM and 0.886 pmol (mg protein)^?1 for a high-affinity site and 218 nM and 13.56pmol (mg protein)^?1 for a low-affinity site. DCDM, BTS-27271 and amitraz inhibit [³H]mianserin binding with IC₅₀ values similar to those obtained with octopamine and the μ-adrenergic antagonist, phentolamine, whereas chlordimeform is a poor competitor for the binding sites. Similarly DCDM, BTS-27271 and amitraz elevate cyclic AMP production in brain membrane preparations in a dose-dependent manner with K_a values of 0.32 uM, 1.5 uM and 3.4 uM respectively, whereas chlordimeform was again without effect. The formamidine-mediated responses were fully additive with the evaluation of cyclic AMP obtained using the maximal concentration of dopamine but not with octopamine-mediated increases; thus the formamidine effects appear to be expressed through partial agonism of octopamine receptors that are coupled to adenylate cyclase.     

Influence of amidines and anilides on biogenic amine regulatory mechanisms in the bulb mite Rhizoglyphus echinopus

Levels of dopamine (DA) and its precursor 3-(3,4-dihydroxyphenyl)alanine (DOPA) in adult bulb mites Rhizoglyphus echinopus (Fumouze and Robin), after exposure for 1 and 24 h in vials precoated with an acetone solution (1.0 mg ml^?1) of the amidines chlordimeform, clenpyrin, or flubenzimine, were measured by high-performance liquid chromatography with electrochemical detection and compared with those of untreated controls. When mites were exposed to the formamidine chlordimeform, there was an initial increase in levels of DA and DOPA; after 24 h, DOPA levels were still increased, but there was a significant decrease in the levels of DA. Exposure of mites to the cyclic amidines clenpyrin and flubenzimine resulted in decreased levels of DA and DOPA at both time intervals. The effects of amidines and anilides on the metabolism of 2-phenylethylamine (PEA) by whole homogenates of bulb mites were also examined. Degradation of PEA was inhibited by chlordimeform and some of the other formamidines, but not by the cyclic amidines clenpyrin and flubenzimine. Formanilides, that are degradation products of certain formamidines, were the most potent inhibitors of PEA metabolism. These studies provide direct evidence for the interaction of amidines with mite biogenic amines and their regulatory mechanisms.     

几种植物油对水稻害虫生物活性及利用方式研究

本文研究了苦楝油和棉籽油对水稻害虫的生物活性及其利用方式,结果表明,植物油单用虽具有生物活性,但防治效果不够理想,但与杀虫脒混用可提高防效。如每亩用50克25％杀虫脒水剂与250克苦楝油或者棉籽油混用,对二化螟可取得较好防治效果,且节省化学农药,降低残留,有利于保护环境,有益生物和人体健康,为杀虫脒的合理使用开辟了一条新途径。     

Transformations of 4-chloro-o-toluidine in soil: Generation of coupling products by one-electron oxidation

Four coupling products formed by one-electron oxidation of 4-chloro-o-toluidine were isolated from soil samples after 90 days of incubation with [¹⁴C]chlordimeform (200 mg/kg). The metabolic compounds were identified as 4,4′-dichloro-2,2′-dimethyl-azobenzene, 4-chloro-6-nitro-o-toluidine, N-(4-chloro-o-tolyl)-2-methyl-p-benzoquin-one monoimine and 2-(4-chloro-o-toluidino)-N-(4-chloro-o-tolyl)-6-methyl-p-benzo-quinone monoimine, respectively. Mechanisms of formation and possible significance of these substances as indicators for metabolic pathways to mineralisation of aniline derivatives are discussed. The chlordimeform soil concentrations (70–100 mg/kg) necessary for the formation of the azobenzene and the benzoquinone monoimines are at least 10 times higher than those occurring after actual field application.