Atropine In Rats Research Articles

Comparison of the neuroprotective effects of a novel bispyridinium oxime KR-22934 with the oxime K203 and obidoxime in tabun-poisoned male rats

Summary The neuroprotective effects of a novel oxime KR-22934, the oxime K203 and obidoxime in combination with atropine in rats poisoned with tabun at a sublethal dose (200 μg/kg i.m.; 80% LD 50 ) were studied. The tabun-induced neurotoxicity was monitored at 24 h following tabun challenge using a functional observational battery and an automatic measurement of motor activity. The results indicate that all tabun-poisoned rats treated with oximes in combination with atropine were able to survive within 24 h following tabun poisoning. One tabun-poisoned rat without antidotal treatment died within 24 h. The oximes KR-22934 and K203 combined with atropine showed a similar potency to decrease tabun-induced neurotoxicity at 24 h after tabun administration while the neuroprotective efficacy of obidoxime was slightly higher. However, no oxime was able to eliminate tabun-induced neurotoxicity completely. When atropine was administered alone, negligible neuroprotective efficacy was observed. Based on the results, a novel oxime KR-22934 did not bring any improvement of the neuroprotective efficacy of antidotal treatment of acute tabun poisonings.

A Comparison of the Potency of a Novel Bispyridinium Oxime K203 and currently available Oximes (Obidoxime, HI‐6) to Counteract the Acute Neurotoxicity of Sarin in Rats

The neuroprotective effects of a newly developed oxime K203 and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with sarin were studied. The sarin-induced neurotoxicity was monitored using a functional observatory battery at 2 hr after sarin challenge. The results indicate that the potency of a novel bispyridinium oxime K203 to counteract sarin-induced neurotoxicity is relatively low and roughly corresponds to the neuroprotective efficacy of obidoxime. Among tested oximes, the oxime HI-6 seems to be significanlty more efficacious to counteract acute neurotoxicity of sarin than commonly used obidoxime and a newly developed oxime K203. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with sarin in comparison with the oxime HI-6 that should be considered to be the best oxime for antidotal treatment of acute sarin poisonings.

A comparison of the ability of newly-developed bispyridinium oxime K203 and currently available oximes (trimedoxime, obidoxime, HI-6) to counteract the acute neurotoxicity of soman in rats

The neuroprotective effects of newly-developed oxime K203 and currently available oximes (trimedoxime, obidoxime, HI-6) in combination with atropine in rats poisoned with soman were studied. The soman-induced neurotoxicity was monitored using a functional observational battery at 24 h following soman challenge. The results indicate that the potency of a newly-developed oxime K203 to counteract soman-induced neurotoxicity is very low and roughly corresponds to the neuroprotective efficacy of currently available oximes. Among tested oximes, the oxime HI-6 seems to be the most efficacious to counteract acute neurotoxicity of soman, although the differences in neuroprotective efficacy of chosen oximes are not significant. Thus, the oxime K203 does not provide any beneficial effect for the antidotal treatment of acute poisoning with soman and the oxime HI-6 should be still considered to be the best oxime for antidotal treatment of acute soman poisonings.

A Comparison of Neuroprotective Efficacy of the Oxime K203 and its Fluorinated Analogue (KR‐22836) with Obidoxime in Tabun‐Poisoned Rats

The ability of the newly developed bispyridinium compound K203 and its fluorinated analogue KR-22836 to reduce tabun-induced acute neurotoxic signs and symptoms was compared with the currently available reactivator of acetylcholinesterase-obidoxime. Tabun-induced neurotoxicity and the neuroprotective effects of all tested oximes in combination with atropine in rats poisoned with tabun at a sublethal dose (200 μg/kg intramuscularly (i.m.); 80% of LD(50) value) were monitored by a functional observational battery at 24 hr after tabun challenge. The results indicate that all tested oximes combined with atropine were able to survive tabun-poisoned rats 24 hr after tabun challenge while one non-treated tabun-poisoned rat died within 24 hr after tabun poisoning. All tested oximes combined with atropine were able to decrease tabun-induced neurotoxicity in the case of sublethal poisoning but they did not eliminate all tabun-induced acute neurotoxic signs and symptoms. While the ability to reduce tabun-induced acute neurotoxicity of obidoxime and K203 was similar, the neuroprotective efficacy of KR-22836 was slightly higher compared to other tested oximes. Thus, the newly developed fluorinated analogue of K203, called KR-22836, is able to slightly increase the neuroprotective effectiveness of antidotal treatment of acute tabun poisonings compared to K203 and currently available obidoxime.

A Comparison of neuroprotective efficacy of newly developed oximes (K203, K206) and commonly used oximes (obidoxime, HI-6) in tabun-poisoned rats

The neuroprotective effects of newly developed oximes (K203, K206) and commonly used oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (180 μg/kg i.m.; 80% LD50) were studied. The tabun-induced neurotoxicity was monitored by using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 hours and 7 days following tabun challenge. The results indicate that K203 and obidoxime in combination with atropine allow all tabun-poisoned rats to survive within 7 days following tabun challenge, while 2 nontreated tabun-poisoned rats and 1 tabun-poisoned rat treated with K206 or HI-6 in combination with atropine died within 7 days. Only one of the newly developed oximes (K203) combined with atropine seems to be effective for a decrease in tabun-induced neurotoxicity within 24 hours after tabun sublethal poisoning, although it is not able to eliminate tabun-induced neurotoxicity completely. On the other hand, the neuroprotective efficacy of commonly used oximes (obidoxime and HI-6), as well as one of the new synthesized oximes (K206), is significantly lower in comparison with K203, according to the number of eliminated tabun-induced neurotoxic signs at 24 hours after tabun challenge. Due to its neuroprotective effects, K203 appears to be a suitable oxime for the antidotal treatment of acute tabun poisonings.

Evaluation of the Neuroprotective Efficacy of Newly Developed Oximes (K206, K269) and Currently Available Oximes (Obidoxime, HI‐6) in Cyclosarin‐Poisoned Rats

The neuroprotective effects of newly developed oximes (K206, K269) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with cyclosarin were studied. The cyclosarin-induced neurotoxicity was monitored using a functional observational battery at 24 hr following cyclosarin challenge. The results indicate that a newly developed oxime K206 is able to counteract cyclosarin-induced neurotoxicity while the neuroprotective potency of another newly developed oxime (K269) is negligible. The neuroprotective efficacy of K206 is markedly higher than commonly used obidoxime; nevertheless, its potency to eliminate cyclosarin-induced neurotoxicity is slightly lower compared to the oxime HI-6. Thus, a newly developed oxime K206 seems to be a better oxime for the antidotal treatment of cyclosarin poisonings than obidoxime due to higher neuroprotective potency although the oxime HI-6 is still the most suitable oxime for the antidotal treatment of acute poisonings with cyclosarin.

A Comparison of the Neuroprotective Efficacy of Newly Developed Oximes (K156, K203) and Currently Available Oximes (Obidoxime, HI-6) in Cyclosarin-poisoned Rats

The neuroprotective effects of newly developed oximes (K156, K203) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with cyclosarin were studied. The cyclosarin-induced neurotoxicity was monitored using a functional observational battery 24 hours after cyclosarin challenge. The results indicate that a newly developed oxime K156 is able to counteract slightly cyclosarin-induced neurotoxicity while another newly developed oxime K203 is completely ineffective in reducing cyclosarin-induced neurotoxic signs and symptoms. The neuroprotective efficacy of K156 is comparable with commonly used obidoxime and oxime HI-6. Thus, none of the newly developed oximes achieves better neuroprotective efficacy than both commonly used oximes. They are therefore not suitable replacements for antidotal treatment of acute poisonings with cyclosarin.

The evaluation of neuroprotective efficacy of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI‐6) in cyclosarin‐poisoned rats

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with cyclosarin were studied. The cyclosarin-induced neurotoxicity was monitored using a functional observational battery at 24 h and 7 days following cyclosarin challenge. The results indicate that the oxime HI-6 combined with atropine seems to be the most effective antidote for a decrease in cyclosarin-induced neurotoxicity. Both newly developed oximes (K074, K075) as well as obidoxime are also able to counteract cyclosarin-induced acute neurotoxicity, but their neuroprotective potency is significantly lower compared with the oxime HI-6. Therefore, the oxime HI-6 is still the most suitable oxime for the antidotal treatment of acute poisonings with cyclosarin due to its neuroprotective as well as reactivating efficacy.

A Comparison of the Potency of Newly Developed Oximes (K074, K075) and Currently Available Oximes (Obidoxime, HI-6) to Counteract Soman-Induced Neurotoxicity in Rats

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with soman were studied. The soman-induced neurotoxicity was monitored using a functional observational battery at 24 h and 7 days after soman challenge. The results indicate that the oxime HI-6 combined with atropine seems to be an effective antidote for a decrease in soman-induced neurotoxicity, whereas the ability of both newly developed oximes (K074, K075) as well as obidoxime to counteract soman-induced acute neurotoxicity is negligible. Due to the absence of their neuroprotective potency, both newly developed oximes are not suitable oximes for antidotal treatment after exposure to soman. The oxime HI-6 is still the best acetylcholinesterase reactivator for the antidotal treatment of acute poisonings with soman.

A comparison of the potency of newly developed oximes (K074, K075) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats

The neuroprotective effects of newly developed oximes (K074, K075) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (180μg/kg i.m.; 80% LD50) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24h and 7 days following tabun challenge. The results indicate that all oximes studied in combination with atropine allow all tabun-poisoned rats to survive within 7 days following tabun challenge while two non-treated tabun-poisoned rats died within 2h. Both newly developed oximes combined with atropine seem to be effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The oxime K075 showed a higher neuroprotective efficacy against tabun than K074 according to the number of eliminated tabun-induced neurotoxic signs at 24h as well as 7 days after tabun challenge. The neuroprotective efficacy of obidoxime in combination with atropine is similar to the potency of newly developed oxime K075 but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity is significantly lower at 24h as well as 7 days after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes (especially K075) appear to be more suitable oximes for the antidotal treatment of acute tabun poisonings than the oxime HI-6.

A comparison of the potency of newly developed oximes (K027, K048) and commonly used oximes (obidoxime, HI-6) to counteract tabun-induced neurotoxicity in rats

The neuroprotective effects of newly developed oximes (K027, K048) and currently available oximes (obidoxime, HI-6) in combination with atropine in rats poisoned with tabun at a sublethal dose (170 microg kg(-1) i.m.; 80% of LD(50) value) were studied. The tabun-induced neurotoxicity was monitored using a functional observational battery and an automatic measurement of motor activity. The neurotoxicity of tabun was monitored at 24 h and 7 days following tabun challenge. The results indicate that the oxime HI-6 in combination with atropine was not able to protect the rats from the lethal effects of tabun. Two non-treated tabun-poisoned rats and one tabun-poisoned rat treated with atropine combined with HI-6 died within 2 h. On the other hand, all other tested oximes combined with atropine allowed all the tabun-poisoned rats to survive 7 days following tabun challenge. Both newly developed oximes combined with atropine seem to be sufficiently effective antidotes for a decrease in tabun-induced neurotoxicity in the case of sublethal poisoning although they are not able to eliminate tabun-induced neurotoxicity completely. The neuroprotective efficacy of obidoxime in combination with atropine approached the potency of newly developed oximes but the ability of the oxime HI-6 to counteract tabun-induced acute neurotoxicity was significantly lower, especially at 24 h after tabun poisoning. Due to their neuroprotective effects, both newly developed oximes appear to be suitable oximes for the antidotal treatment of acute tabun poisoning.

A Signal Transduction Pharmacodynamic Model of the Kinetics of the Parasympathomimetic Activity of Low-Dose Scopolamine and Atropine in Rats

We used a novel pharmacokinetic-pharmacodynamic (PK-PD) approach that had been applied for signal transduction kinetics to investigate the kinetics of the parasympathomimetic effect of scopolamine and atropine in rats. The parasympathetic tone was assessed by continuous measurement of the power of the high frequency band (HF) of electrocardiogram (ECG) R-R intervals obtained by power spectral analysis (PSA) of heart rate variability (HRV). To overcome the inherent noise of the HRV-HF data and to quantitatively identify temporal changes in the autonomic tone, a new approach of stepwise regression of the cumulative HF data was applied. The elevation of the parasympathetic tone occurred after a significant lag time (>70 min) following scopolamine administrations [0.25 and 0.5 mg/kg intravenous (iv) bolus or infusion over 100 min], followed by a gradual return to the baseline levels. A similar lag time in parasympathetic stimulation was observed following iv bolus administration of atropine (0.1 mg/kg). The plasma drug concentration versus time data were linked to the response versus time data using a signal transduction pharmacodynamic model that was fitted simultaneously to all four experimental data sets. This PK-PD model resolved the significant discrepancy between the concentration versus time and the response versus time patterns and successfully described the kinetics of the parasympathetic stimulation obtained for different drugs and different rates of administration. This work paves the way for further PK-PD preclinical investigations in this field.

Sleep-wake effects of yohimbine and atropine in rats with a clomipramine-based model of depression.

The present study examined the sleep-wake cycle effects of microinjections of yohimbine, an adrenergic antagonist, and atropine, a cholinergic antagonist, into the cerebral ventricle of clomipramine-induced depressed rats. Yohimbine microinjection caused a significant reduction in the total duration and the number of REM sleep episodes compared to control saline injections. Atropine microinjection caused a significant reduction in the total duration and the number of REM sleep episodes without changing the REM sleep latency compared to control saline microinjection. These results show for the first time that the REM sleep disturbances observed in clomipramine-treatment induced depressed rats can be attenuated by increasing and decreasing the brain noradrenergic and cholinergic activities, respectively.

Inhibition of gastric emptying and secretion by pirenzepine and atropine in rats

The effects of pirenzepine and atropine on gastric emptying, gastric secretion and heart rate were studied in rats. Both drugs inhibited gastric emptying and secretion dose depedently and increased pulse rate. In the gastric secretory studies both compounds displayed potencies which were not very dissimilar (ID50 were 8.1 μmol·kg−1 and 1.4 μmol·kg−1 for pirenzepine and atropine respectively, potency ratio 6); pirenzepine was however decidedly less potent than atropine in inhibiting gastric emptying (potency ratio 36 on a molar basis) and in increasing heart rate (potency ratio 125). These data, in accordance with results of clinical trials, indicate that pirenzepine — unlike atropine — can inhibit acid secretion without appreciably affecting gastric motility and cardiac function.

DEVELOPMENTAL CHANGE IN REARING RESPONSE TO ATROPINE IN RATS TREATED WITH 6-HYDROXYDOPA

DEVELOPMENTAL CHANGE IN REARING RESPONSE TO ATROPINE IN RATS TREATED WITH 6-HYDROXYDOPA

Role of gastrin in mucosal DNA synthesis after vagotomy and atropine in the rat.

The purpose of this study was to examine 1) the influence of the cholinergic innervation of the stomach on the rate of DNA synthesis in the fundic mucosa of the rat and 2) the possibility that hypergastrinemia might be involved in the response. Repeated injections of atropine in fasting rats increased by 40% the rate of DNA synthesis in the oxyntic gland mucosa. Two weeks after truncal vagotomy, the DNA synthesis rate in oxyntic gland mucosa was increased 64% compared to sham-operated control animals. In the rat colon, atropine administration produced a 56% increase in DNA synthesis compared to saline-injected controls. The injection of pentagastrin in fasting rats also increased the DNA synthesis rate in both stomach and colon, but pentagastrin combined with either atropine or vagotomy stimulated DNA synthesis no more than pentagastrin alone. Cholinergic interruption by atropine or vagotomy elevated endogenous serum gastrin concentrations, indicating that the observed DNA stimulation may be mediated by hypergastrinemia.

Locomotor activity increases produced by intrahippocampal and intraseptal atropine in rats

Increases in locomotor activity were produced by intrahippocampal and intraseptal application of crystalline atropine sulfate. The correlation of positive effects with anatomical location suggested that the activity increases were not due to widespread diffusion of the drug. Cannulas that opened into the lateral ventricle produced less activity increase than cannulas well placed in the hippocampus or medial septal area. The data support the suggestion of a septo-hippocampal site of action of atropine and are consistent with the hypothesis of a cholinergic inhibitory system anatomically located in the septo-hippocampal complex.

Atropine antagonism of carbachol-induced hyperglycemia

Hyperglycemia was induced with carbachol in rats, rabbits, and dogs, and the effect in rabbits was shown to be dose related. In albino rabbits with negligible plasma esterase activity, atropine sulfate effectively prevented hyperglycemia following 25 mcg./Kg. of carbachol, and the effect appeared to be dose dependent. In rabbits with moderate esterase levels, atropine sulfate dosage as high as 0.8 mg./Kg. had little inhibitory effect on carbachol hyperglycemic or cholinomimetic responses. This plasma esterase was not effectively blocked in vivo with 20 mg./Kg. of 2-(diethylamino)ethyl-2,2-diphenylvalerate (proadifen) HCl (SKF 525-A). However, this dose of proadifen HCl did block carbachol hyperglycemia in rabbits with negligible esterase activity. Carbachol hyperglycemia was similarly prevented by atropine in rats and dogs. Hyperglycemia was induced with carbachol in rats, rabbits, and dogs, and the effect in rabbits was shown to be dose related. In albino rabbits with negligible plasma esterase activity, atropine sulfate effectively prevented hyperglycemia following 25 mcg./Kg. of carbachol, and the effect appeared to be dose dependent. In rabbits with moderate esterase levels, atropine sulfate dosage as high as 0.8 mg./Kg. had little inhibitory effect on carbachol hyperglycemic or cholinomimetic responses. This plasma esterase was not effectively blocked in vivo with 20 mg./Kg. of 2-(diethylamino)ethyl-2,2-diphenylvalerate (proadifen) HCl (SKF 525-A). However, this dose of proadifen HCl did block carbachol hyperglycemia in rabbits with negligible esterase activity. Carbachol hyperglycemia was similarly prevented by atropine in rats and dogs.

The Absorption and Distribution of Atropine in Rats.

The Absorption and Distribution of Atropine in Rats.