Inhibition of ethanol and acetate metabolism in mice by chlordimeform and related compounds.
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Interaction of formamidines with the platelet 5-hydroxytryptamine uptake system.
1. The activity of the insecticide/acaricide N'-(4-chloro-o-tolyl)-N,N-dimethylformamidine (chlordimeform), its two formamidine metabolites, N'-(4-chloro-o-tolyl)-N-methylformamidine (demethylchlordimeform) and N'(4-chloro-o-tolyl) formamidine (didemethylchlordimeform), and 116 other formamidines and related compounds as inhibitors of rat platelet 5-hydroxytryptamine (5-HT) uptake was studied. Though several formamidines were more active than chlordimeform (pI50 3.9), none was as potent as imipramine. Didemethylchlordimeform (pI50 4.4) was the most potent formamidine examined. 2. Inhibition of 5-HT uptake by chlordimeform was mixed. Moreover, chlordimeform inhibition of 5-HT uptake by reserpinized platelets was not significantly different from uptake by non-reserpinized platelets. 3. Chlordimeform and its two formamidine metabolites caused release of platelet 5-HT, and their potency as releasers paralleled their activity as uptake inhibitors. 4. Electron microscopy indicated that chlordimeform treatment changed platelet shape and size but apparently did not alter physical integrity of the membrane. 5. It was suggested that platelet 5-HT storage vesicles were the most probable site of formamidine action.
Amidines↗
Formamidine-mediated inhibition of rat platelet aggregation.
The formamidine pesticide chlordimeform (CDF) was a strong inhibitor of aggregation of rat platelets induced by collagen and arachidonic acid and was a weak inhibitor of that induced by ADP. With the exception of 4-chloro-o-formotoluidide which was an inhibitor of arachidonic acid-induced aggregation only, the CDF metabolites were without discernible effect on aggregation induced by these agents. Amitraz, another formamidine pesticide, inhibited arachidonic acid-induced aggregation but was without effect on that induced by collagen or ADP. Inhibition of collagen- and/or arachidonic acid-induced aggregation by formamidines was concentration-dependent. Although platelets underwent shape change, primary aggregation was markedly inhibited, and secondary aggregation was abolished in some cases. CDF, its two N-desmethyl metabolites, and octopamine, but not amitraz, caused significantly elevated levels of cyclic AMP in platelet rich plasma as compared to controls; however, this effect did not fully account for the action of formamidines on aggregation.
Adenosine Diphosphate↗
Inhibition of rat platelet 5-hydroxytryptamine uptake by chlordimeform.
Chlordimeform, a formamidine insecticide and acaricide, and two of its toxic N-demethyl metabolites inhibited rat blood platelet 5-hydroxytryptamine (5-HT) uptake. A direct relationship existed between formamidine uptake inhibitory potency and N-demethylation. Didemethylchlordimeform, the most potent formamidine inhibitor of 5-HT uptake examined, had a pI50 of 4.2. However, it was appreciably less active than the classical inhibitor imipramine, which yielded 86.4% inhibition of 5-HT uptake at a concentration of 1.10(-5) M.
Amidines↗
Effect of acute and repeated chlordimeform treatment on rat hepatic microsomal drug metabolizing enzymes.
The effect of chlordimeform (CDM) treatment on the hepatic microsomal drug metabolizing enzymes was examined in male and female rats following either acute or repeated treatment. After acute administration of chlordimeform (100 mg/kg, i.p., 1 hour before killing) differential effects were observed in various parameters of the hepatic microsomal mixed function oxidase system with significant decreases in ethylmorphine metabolism, cytochrome P-450 content, NADPH cytochrome c reductase, and in the spectral binding of hexobarbital and aniline while no changes were found in the metabolism of aniline or p-nitroanisole. Durations of zoxazolamine-induced paralysis and pentobarbital-induced hypnosis were increased significantly after acute CDM administration. Following repeated administration of CDM (75 mg/kg, i.p., for 4 days) to adult male rats, a decrease was observed in zoxazolamine-induced paralysis time while pentobarbital-induced hypnosis was not altered. Metabolism studies using isolated hepatic microsomal fractions showed a decreased rate of biotransformation of ethylmorphine and aniline while the activity of p-nitroanisole O-demethylase was not changed. No differences were found in cytochrome P-450 levels whereas microsomal spectral binding of hexobarbital was reduced while that of aniline was not affected. Following acute or repeated administration of CDM to adult female rats, decreases in the hepatic microsomal metabolism of aniline, but not ethylmorphine or p-nitroanisole, were observed. Addition of CDM to microsomal suspensions yielded a Type I binding curve.
Amidines↗
Thermoregulation in mice following acute chlordimeform administration.
CBA/J mice were injected intraperitoneally (i.p.) with the formamidine insecticide chlordimeform (CDM) while colonic temperature, preferred ambient temperature (Ta), and lethality were monitored. In the first experiment there was a dose-dependent decrease in colonic temperature when measured 60 min after administering CDM doses of 0, 15, 30, 60, and 75 mg/kg. The hypothermic effect of CDM was more pronounced at a Ta of 20 degrees C than at 30 degrees C. In the second experiment, CDM at doses greater than 30 mg/kg caused a dose-dependent reduction in preferred Ta from the normal value of approx. 30 degrees C to approx. 22 degrees C. Thus, the CDM-treated mouse lowered body temperature by selecting a cool Ta which accelerated the hypothermic effect. In the final experiment, a 90 mg/kg i.p. injection of CDM (the approximate LD50 dose) caused 10% and 0% mortality at a Ta of 20 and 30 degrees C, respectively, and 80% mortality at a Ta of 35 degrees C. It is concluded that the physiological and behavioral response to CDM administration, i.e., selecting a cool Ta and lowering body temperature, may be beneficial to survival.
Amidines↗
Induction of hepatic drug-metabolising enzymes following treatment of rats and mice with chlordimeform.
We investigated the effects of the formamidine insecticide chlordimeform upon the activities of various hepatic drug metabolising enzymes in rats and mice. Chlordimeform treatment induced several enzyme activities. However, the extent of induction depended upon the activity studied, the sex of the animal and the species selected. Microsomal cytochrome P-450 content was elevated in both male and female rats and mice. Ethoxycoumarin O-deethylase activity was induced in male and female rats but not in mice, whilst ethylmorphine N-demethylase activity was elevated in mice, but not in rats. Benzo(a)pyrene hydroxylase activity was increased in female rats and mice, but not in males. UDP-glucuronyl transferase, glutathione S-transferase and microsomal epoxide hydrolase were induced in a dose-dependent manner in male rats, and female rats and mice, but not in male mice.
Amidines↗
Monitoring the urine of pesticide applicators in California for residues of chlordimeform and its metabolites 1982-1985.
Chlordimeform (Cdf) is readily absorbed through the skin of pesticide applicators. It also enters the body when breathed into the lungs. Cdf can be found in the urine of workers who handle or are involved in applying pesticide products which contain the chemical, even when they are wearing special protective clothing and respirators. Because of the adverse health effects seen in heavily exposed workers and the cancerous tumors seen in mice, special precautions are necessary when handling products containing Cdf to reduce the risk of adverse health effects. Because Cdf is known to enter the body very easily, with serious injury potential, workers handling pesticide products containing Cdf in California are required to have medical supervision including a blood test at the beginning and end of each application season and monthly testing of urine for possible cellular change and pesticide residues during the time Cdf exposure takes place. This program is designed to keep worker exposure as low as possible.
Agriculture↗
Effects of chlordimeform on heart rate and body temperature of unanesthetized, unrestrained rats.
Heart rate (HR) and body core temperature (Tco) were monitored in unanesthetized, unrestrained adult Sprague-Dawley rats following intraperitoneal administration of 0, 10, 30, or 60 mg/kg of the pesticide chlordimeform (CDM). Significant non-dose-related decreases were observed in both HR and Tco in all treated groups. Although similar in character, the HR response observed in the present study was of a lesser magnitude than that which was reported in previous studies from this laboratory using anesthetized animals in which Tco was maintained at control levels. It is proposed that the attenuation of the toxic response seen in the present study may be causally related to the concomitant decrease in Tco.
Amidines↗
Stimulation by octopamine of the sodium efflux in barnacle muscle fibres.
The behaviour of the ouabain-insensitive Na efflux in barnacle muscle fibres towards DL-octopamine has been investigated. It is found that these fibres are quite often sensitive to external application of octopamine. A concentration as low as 10(-9) M is effective. The kinetic results indicate that the stimulatory response develops within 5-10 min of exposure of the fibre to octopamine and is transitory in nature. The response to octopamine is greater in size in the presence of 1-isoamyl-3-isobutylxanthine (IAX) than in the presence of 1-propyl-3-methyl-7-(5-hydroxyhexyl)-xanthine (PMX). But neither IAX nor PMX stops the response from decaying. The response to octopamine is highly dependent on the presence of external Ca2+. The provisional conclusion is that the barnacle muscle fibre may be a useful preparation for studying the hormonal function of octopamine.
1-Methyl-3-isobutylxanthine↗
5-Hydroxytryptamine stimulates fluid secretion in locust malpighian tubules independently of cAMP.
5-Hydroxytryptamine (5-HT) stimulates fluid secretion by semi-isolated Malpighian tubules of Locusta in a dose-dependent manner. The threshold of stimulation is between 10(-8) and 10(-7) M 5-HT; maximal activation occurs at doses greater than 10(-6) M. Relative to the activation induced by diuretic hormone (storage lobe extracts), 5-HT increases the rate of fluid secretion by only 65%. Phentolamine, the alpha-adrenergic blocker, failed to inhibit either DH or 5-HT stimulated secretion. Diuretic hormone raises the levels of intracellular of cAMP, and activates adenylate cyclase in plasma membrane preparations of Locusta Malpighian tubules. 5-HT (10(-4) M) has no effect in either assay system. Thus 5-HT can stimulate fluid secretion independently of cAMP. A hypothetical model for hormone stimulated fluid secretion by Locusta Malpighian tubules, involving dual-receptor activation, is proposed. Other biogenic amines, including octopamine, adrenalin, dopamine, synephrine and the formamidine chlordimeform were tested for their ability to stimulate fluid secretion. Only dopamine showed a weakly stimulatory effect.
Animals↗
Octopamine receptors in the molluscan aortic bulb: effects of clozapine and chlordimeform.
The presence of specific, stereo-selective octopamine receptors has been demonstrated in the non-spontaneously beating accessory ventricle (aortic bulb) of the clam Tapes watlingi. Analogues of octopamine with a single chloro group in either the para or meta positions of the benzene ring were 10 times less potent than octopamine in their agonist activity. In low concentrations (less than 200 microM), phentolamine, chlordimeform and clozapine were octopamine antagonists. In high concentrations (greater than 200 microM), clozapine, clonidine and chlordimeform induced changes in aortic tone similar to that produced by p-octopamine. This activity may result from the chloro-substituted phenamidine skeleton in both clozapine and chlordimeform.
Action Potentials↗
Modulation of dopamine receptors in the Tapes clam by dextroamphetamine and phenylethanolamine.
The mechanism underlying the modulation, by dextroamphetamine and compounds related to phenylethanolamine, of responses to dopamine and serotonin has been studied in the isolated ventricle and aortic bulb of the clam Tapes watlingi. Dextroamphetamine and phenylethanolamine but not cocaine and benztropine have the ability to unmask inhibitory responses to both dopamine and serotonin in the ventricle. Chlordimeform but not clozapine attenuates the inhibitory response to both dextroamphetamine and phenylethanolamine in concentrations which have little or no effect on the inhibitory response to dopamine in the ventricle. Phenylethanolamine, dextroamphetamine, phenylpropylolamine and p-chloro-phenylethanolamine but not octopamine or noradrenaline attenuate the contractile responses to both dopamine and serotonin in preparations of the quiescent aortic bulb. These data show that there are specific receptors for phenylethanolamine in the Tapes heart capable of modulating responses to dopamine and serotonin, and suggests that this biogenic phenethylamine can act as an environmental and physiological factor which may determine how the mollusc heart responds to dopamine.
Adenosine Monophosphate↗
Behavioral and autonomic thermoregulation in the rat following chlordimeform administration.
This study was designed to assess the effects of a single acute injection of chlordimeform (CDM) on some behavioral and autonomic effectors of the thermoregulatory system of the Sprague-Dawley rat. In one experiment rats injected intraperitoneally with 60 mg/kg CDM were placed in an environmental chamber set at an ambient temperature (Ta) of 5, 10, 15, 20, 25 or 30 degrees C for 60 min. Exposure to CDM resulted in hypothermia at Ta's of 5 to 25 degrees C and had no effect on body temperature at a Ta of 30 degrees C. In a second experiment, rats injected with 60 mg/kg CDM were placed in a temperature gradient which permitted the continuous recording of preferred Ta (i.e., behavioral thermoregulation), oxygen consumption (i.e., metabolic rate), and total activity. CDM-treated rats preferred Ta's of 20 degrees C after 60 min in the temperature gradient in spite of a hypothermic body temperature (35.3 degrees C). That is, the animals could have moved to the warm end of the gradient and thereby prevented a fall in body temperature. CDM also led to a significant reduction in oxygen consumption. In a third experiment, foot and tail skin temperature, and heart rate were recorded in anesthetized rats maintained under normothermia while treated with CDM. Tail and foot skin temperature rapidly increased following CDM administration which was indicative of peripheral vasodilation and increased heat loss. The changes in temperature were concomitant with an abrupt drop in heart rate.(ABSTRACT TRUNCATED AT 250 WORDS)
Amidines↗
Formamidine pesticides enhance susceptibility to kindled seizures in amygdala and hippocampus of the rat.
Electrical kindling of the amygdala and hippocampus was used to evaluate the effects of two formamidines, chlordimeform (CDF) and amitraz (AMZ), upon seizures susceptibility in the rat. Male Long-Evans rats were implanted with electrodes in the amygdala or dorsal dentate gyrus, and injected IP daily with 40 mg/kg CDF, 50 mg/kg AMZ, or equal volumes of their respective vehicles. Afterdischarge (AD) thresholds were determined after the first injection. Animals were then stimulated twice daily, 2 and 4 hours postinjeciton, at a standard 200 microA stimulus intensity until three stage 5 generalized seizures ensued. Both CDF and AMZ significantly facilitated amygdaloid kindling rate, and CDF also facilitated hippocampal kindling rate. The effects of AMZ on hippocampal kindling were not assessed. AD durations were prolonged in the formamidine-treated groups, but there was no effect on AD thresholds. The alpha-2 adrenergic agonist and/or local anesthetic-like properties of these compounds may be responsible for these seizure enhancing effects.
Amidines↗
Formamidine pesticides and alpha 2-adrenoceptors: studies with amitraz and chlordimeform in rats and development of a radioreceptor binding assay.
The interaction of the formamidine pesticides chlordimeform (CDM) and amitraz (AMZ) with rat brain alpha2-adrenoceptors was investigated. Both compounds inhibited the binding of 3H-clonidine and 3H-yohimbine in vitro with IC50 values of 62-68 microM (CDM) and 95-110 nM (AMZ). In vivo administration of AMZ and CDM caused a dose-dependent inhibition of 3H-clonidine binding in rat forebrain. The inhibition was short-lasting (24 hr) following CDM administration, while after AMZ recovery of 3H-clonidine binding occurred only after 72 hr. Good correlations were found between inhibition of brain 3H-clonidine binding by the formamidines and "plasma equivalents" of these compounds and/or their biologically active metabolites, as measured by a new radioreceptor assay. These results suggest that 1) formamidines can interact in vivo with brain alpha 2-adrenoceptors when administered at doses previously shown to cause toxic effects on the central nervous system: and 2) this effect is reversible, both in vivo and in vitro, and appears to be linked to the presence of the formamidines and/or their active metabolites at the receptor sites.
Amidines↗
Octopamine is the synaptic transmitter between identified neurons in the buccal feeding network of the pond snail lymnaea stagnalis.
We report the pharmacological properties of synaptic connections from the three octopamine-containing OC interneurons to identified buccal feeding neurons in the pond snail, Lymnaea stagnalis. Intracellular stimulation of an OC interneuron evokes inhibitory postsynaptic potentials in the B3 motoneurons and N2 (d) interneurons, while the synapse between OC and N3 (phasic) interneurons has two components: an initial electrical excitation followed by chemical inhibition. All synaptic responses persist in a saline with elevated calcium and magnesium suggesting that the connections are monosynaptic. Local perfusion of 10(-4) M octopamine produces the same inhibitory membrane responses from these buccal neurons as OC stimulation. These responses also persist in high Mg(2+)/Ca(2+) saline indicating direct membrane effects. The similarities in reversal potentials for the synaptic hyperpolarization evoked on B3 neurons after OC stimulation (-89.0 mV, S.E.M.=14.1, n=10) and the octopamine response of the B3 neurons (-84.7 mV, S.E.M.=6.6, n=6) indicate that increased K(+)-conductance underlies both responses. Bath application of the octopaminergic drugs phentolamine (10(-6) M), epinastine (10(-6) M) or DCDM (10(-4) M) blocks the inhibitory synapse onto B3 or N2 neurons and the chemical component of the N3 response. They also block the octopamine-evoked inhibition of B3, N2 and N3 neurons. NC-7 (2x10(-5) M) has a hyperpolarizing agonist effect (like octopamine) on these neurons and also blocks their chemical synaptic input from the OC interneurons. These results provide pharmacological evidence that the neurotransmitter between the octopamine-immunopositive OC interneurons and its followers is octopamine. This is the first example of identified octopaminergic synaptic connections within the snail CNS.
Action Potentials↗
Capillary gas chromatography with mass spectrometric and atomic emission detection for characterization and monitoring chlordimeform degradation in honey.
Capillary gas chromatography-mass spectrometry and capillary gas chromatography-atomic emission detection have been successfully used to identify and monitor the main degradation products of chlordimeform when this compound is initially present in honey. The analysis of laboratory-spiked honey samples over 28 weeks revealed the occurrence of two degradation products: 4-chloro-o-toluidine (I) and N-formyl-4-chloro-o-toluidine (III). During this period the concentration of chlordimeform decreased to 7.5% of its initial value; the concentration of compound I increased gradually whereas compound III was present in a larger proportion and reached a maximum around the 14th week.
Chlorphenamidine↗