The effects of yohimbine and four other antagonists on amitraz-induced depression of shuttle avoidance responses in dogs

The ability of five antagonists to prevent the central nervous system's depressant effects of amitraz in dogs was evaluated using a shuttle avoidance paradigm. All drugs were injected iv into six male dogs trained to avoid a 1-mA shock by jumping over a hurdle within 10 sec of the start of a tone. Dogs were given an antagonist or saline followed in 5 min by 3 mg/kg amitraz dissolved in dimethyl sulfoxide (DMSO) or DMSO alone. After pretreatment with saline, amitraz decreased significantly the means number of avoidance responses and increased significantly the means latencies of avoidance responses. After pretreatment with the alpha 2-adrenoreceptor antagonist yohimbine (0.1 mg/kg), amitraz no longer decreased the means number of avoidance responses or lengthened the means latencies of avoidance responses. The nonselective alpha-adrenoreceptor antagonist tolazoline (3.3 mg/kg) prevented amitraz-induced increases in means latencies, but did not prevent the decreases in the means number of avoidances. The alpha 1-adrenoreceptor antagonist prazosin (1 mg/kg), the muscarinic receptor antagonist atropine (0.04 mg/kg), and the opioid receptor antagonist naloxone (1 mg/kg) did not prevent either of amitraz's effects. The data suggest that the amitraz-induced suppression of avoidance responding is mediated by alpha 2-adrenoreceptors rather than by alpha 1-adrenergic, muscarinic, or opioid receptors.     

Effect of amitraz and chlordimeform on heart rate and pupil diameter in rats: mediated by alpha 2-adrenoreceptors

Pupillary and cardiac responses to the insecticide/acaricide amitraz (0.03 to 1.0 mg/kg, iv) and chlordimeform (0.03 to 10.0 mg/kg, iv), as well as the alpha 2-adrenergic agonists clonidine (1 to 30 micrograms/kg, iv) and xylazine (10 to 300 micrograms/kg, iv), were investigated in rats anesthetized with an ether and pentobarbital combination. Amitraz, clonidine, and xylazine caused a dose-dependent mydriasis and bradycardia. The order of potency of the mydriatic and bradycardic effects was: clonidine greater than xylazine greater than amitraz. Chlordimeform did not cause mydriasis or bradycardia at the dosages studied. Amitraz-induced mydriasis and bradycardia were blocked by antagonists with alpha 2-adrenoreceptor blocking activity: yohimbine and phentolamine (2.5 mg/kg each, iv). In contrast, these effects of amitraz were not affected by prazosin (2.5 mg/kg, iv), an alpha 1-adrenoreceptor antagonist. In rats pretreated with reserpine (7.5 mg/kg, sc, 20 hr) and alpha-methyl-p-tyrosine (250 mg/kg, ip, 5 hr) to deplete catecholamine, amitraz (0.03-1.0 mg/kg, iv) produced mydriasis of similar magnitude as in the control animals. However, amitraz did not lower the heart rate in the pretreated animals as it did in the control animals. The results demonstrated that amitraz, a formamidine, induced mydriasis and bradycardia which were not observed with administration of another formamidine, chlordimeform. The data also suggest that amitraz-induced mydriasis is mediated by postsynaptic alpha 2-adrenoreceptors while amitraz-induced bradycardia is mediated by presynaptic alpha 2-adrenoreceptors.     

Amitraz-induced prolongation of gastrointestinal transit and bradycardia in dogs and their antagonism by yohimbine: preliminary study

The effect of IV amitraz on the transit of barium sulfate through the stomach and duodenum as well as amitraz-induced bradycardia was studied in 4 dogs. Control transit time and heart rates were determined after IV injection of dimethyl sulfoxide (0.1 ml/kg), which was subsequently used as the vehicle for amitraz administration. The time for barium sulfate to move from the stomach to the duodenojejunal junction was 6.1 +/- 1.3 minutes (mean +/- SEM). An IV injection of amitraz (1 mg/kg) prolonged the transit time to 251.2 +/- 27.0 minutes, and induced marked bradycardia for at least 60 minutes. During the amitraz-induced prolongation of gastrointestinal transit, there were no vigorous gastric contractions for at least 180 minutes. Yohimbine, an alpha 2-adrenergic blocking agent, given IV 20 minutes after amitraz administration, at a dosage of 0.1 mg/kg, reversed both the gastrointestinal and bradycardic effects of amitraz. It was concluded that 1) amitraz causes decreased gastrointestinal motility and bradycardia, and 2) yohimbine may be useful in the control of the untoward reactions caused by amitraz administration.     

Amitraz-Induced Prolongation of Gastrointestinal Transit and Bradycardia in Dogs and their Antagonism by Yohimbine: Preliminary Study

ABSTRACT

The effect of IV amitraz on the transit of barium sulfate through the stomach and duodenum as well as amitraz-induced bradycardia was studied in 4 dogs. Control transit time and heart rates were determined after IV injection of dimethyl sulfoxide (0.1 ml/kg), which was subsequently used as the vehicle for amitraz administration. The time for barium sulfate to move from the stomach to the duodenojejunal junction was 6.1 ± 1.3 minutes (mean ± SEM). An IV injection of amitraz (1 mg/kg) prolonged the transit time to 251.2 ± 27.0 minutes, and induced marked bradycardia for at least 60 minutes. During the amitraz-induced prolongation of gastrointestinal transit, there were no vigorous gastric contractions for at least 180 minutes. Yohimbine, an α₂-adrenergic blocking agent, given IV 20 minutes after amitraz administration, at a dosage of 0.1 mg/kg, reversed both the gastrointestinal and bradycardic effects of amitraz. It was concluded that 1) amitraz causes decreased gastrointestinal motility and bradycardia, and 2) yohimbine may be useful in the control of the untoward reactions caused by amitraz administration.     

The comparative efficacy of yohimbine and atipamezole to treat amitraz intoxication in dogs

This study compared the efficacy of yohimbine with atipamezole, a new alpha2 adrenergic antagonist, to treat canine amitraz intoxication. Thirty dogs were divided equally into 3 groups (A, AY, and AA). Group A received 2.5% amitraz iv at 1 mg/kg; Group AY received the same dose of amitraz followed 30 min later by 0.1 mg/kg (2 mg/mL) yohimbine iv; and Group AA received the same dose of amitraz followed 30 min later by 0.2 mg/kg (5 mg/ mL) atipamezole iv. Temperature, heart rate, respiratory frequency, mean arterial pressure, degree of sedation, mean time of tranquilization and diameter of pupils were monitored for 360 min. Sedation, loss of reflexes, hypothermia, bradycardia, hypotension, bradypnea and mydriasis were observed in Group A, with 3rd eyelid prolapse, increased diuresis and vomiting in some animals. Yohimbine reversed all alterations induced by amitraz, but induced significant cardiorespiratory effects such as tachycardia and tachypnea. Atipamezole was a useful antagonist for amitraz, with less cardiorespiratory effects, suggesting its potential role as an alternative treatment of amitraz intoxication in dogs.     

Effect of yohimbine on amitraz-induced CNS depression and bradycardia in dogs

Yohimbine was studied to examine its effectiveness in preventing central nervous system(CNS) depression and bradycardia induced by amitraz (N'-(2,4-dimethylphenyl)-N-[(2,4-dimethylphenyl-imino)-methyl]-N-methyl- methanimide). In control open-field activity experiments, the dogs showed high numbers of grid-line crossings in the first 5 min (exploratory phase), and subsequently low numbers of grid-line crossings (nonexploratory phase). An iv injection of amitraz (1 mg/kg) abolished both the exploratory and nonexploratory phases and caused bradycardia. Yohimbine alone caused a trend to increase the open-field activity in the nonexploratory phase. In addition, yohimbine prevented the bradycardia and suppression of open-field activity induced by amitraz. The results suggest that yohimbine has a potential to be used as an antidote for amitraz overdose.     

Acute cardiovascular effects of the alpha2-adrenoceptor antagonist, idazoxan, in rats: influence of the basal sympathetic tone

Intravenous administration of the alpha2-adrenoceptor antagonist, idazoxan, elicits variable cardiovascular effects, depending on experimental conditions. In this study, the effects of idazoxan were investigated in rats with high, low, or no basal sympathetic tone. In a group of conscious Sprague-Dawley rats (n = 9), mean arterial pressure (MAP), heart rate (HR), and renal sympathetic nervous activity (RSNA) were recorded. Idazoxan (250 microg/kg, i.v.) induced a transient decrease in MAP (-12+/-3 mm Hg) that was accompanied by increases in HR (49+/-14 beats/min) and RSNA (53+/-14%). In six of nine rats, a light pentobarbitone anesthesia was given. Basal RSNA was decreased (6.0+/-1.3 microV from 12.8+/-4.1 microV; p<0.05), and the depressor effect of idazoxan was reversed to a pressor effect (21+/-6 mm Hg) associated with bradycardia (-16+/-8 beats/min) and sympathoinhibition (-56+/-15%). In eight conscious intact rats, idazoxan (250 microg/kg, i.v.) attenuated by approximately 40% the pressor response to the selective alpha1-adrenoceptor agonist, cirazoline (0.5 microg/kg, i.v.). In three groups of six to seven ganglion-blocked (chlorisondamine, 2.5 mg/kg, i.v.) conscious rats, idazoxan dose-dependently increased mean arterial pressure (MAP: 39+/-2, 55+/-3, and 69+/-4 mm Hg at 125, 250, and 500 microg/kg, i.v., respectively) with minimal changes in HR. In contrast, the noradrenaline-releasing agent, tyramine (62.5, 125, and 250 microg/kg, i.v.), dose-dependently increased both MAP and HR. The alpha1-adrenoceptor antagonist, prazosin (1 mg/kg, i.v.; n = 8) blunted by approximately 70% (p<0.01) the pressor effect of 250 microg/kg idazoxan. It is concluded that in rats with high sympathetic tone, idazoxan has depressor effects, most likely related to its peripheral alpha-adrenoceptor antagonist properties. In rats with low or no sympathetic tone, idazoxan induced pressor responses mainly secondary to its partial agonist activity at vascular postjunctional alpha1-adrenoceptors.     

Effects of tetramethylpyrazine on heart rate and pupil diameter in rats

The alpha-adrenergic nature of tetramethylpyrazine (TMPZ), a commonly used cardiovascular drug in China, was studied with a combined bradycardia and mydriasis model in the pentobarbital anesthesized rat. Intravenous injections of TMPZ at 1-30 mg/kg failed to change heart rate or pupil size, whereas iv injections of both clonidine (alpha 2-adrenoceptor agonist, 1-30 micrograms/kg) and methoxamine (alpha 1-adrenoceptor agonist, 10-300 micrograms/kg) caused dose-dependent bradycardia and mydriasis. Pretreatment of rats with TMPZ (30 mg/kg) did not significantly change clonidine- or methoxamine-induced bradycardia or mydriasis. However, when TMPZ was injected 2 min after clonidine administration (30 micrograms/kg), while the mydriasis reached a maximum, it slightly but significantly reversed the clonidine-induced mydriasis for 15-20 s. In contrast, the alpha 2-adrenoceptor antagonist idazoxan (6 micrograms/kg) caused the same degree of reduction of the clonidine-induced mydriasis for greater than 2 min. Our results suggested that TMPZ at the doses studied did not have alpha-adrenoceptor agonistic activities, but may have slight alpha 2-adrenoceptor antagonistic activities.     

Effect of scorpion Leiurus quinquestriatus (H&E) venom on rat's heart rate and blood pressure.

The effects of scorpion Leiurus quinquestriatus (H&E) venom collected from the South Sinai region, Egypt, on heart rate (HR) and mean arterial pressure (MAP) were studied after intramuscular administration of 3 different doses (100, 200 and 400 micrograms/kg) to anesthetized rats. The effects of adrenergic and cholinergic blocking agents on the venom-induced HR and MAP changes were also evaluated. In two groups of rats, propranolol or atropine were given before the venom administration. In the third group the venom was given before the injection of propranolol and atropine in combination. HR was measured by using a cardiotachometer coupler connected to an ECG coupler. MAP was calculated from the recorded arterial blood pressure (ABP) after catheterization of the left common carotid artery. Venom doses of 100 and 200 micrograms/kg produced tachycardia with a dose-response relationship, whereas 400 micrograms/kg evoked sinus tachycardia followed by bradycardia then tachycardia. MAP was elevated after the administration of each dose and reached its maximum value after 60 min with a dose-response relationship. Sinus, atrial and ventricular arrhythmias were observed from the recorded ECG during the time studied. This study revealed that the venom has pressor and depressor effects which are mediated through the autonomic nervous system. Propranolol reduced the stimulatory effects of the highest dose of the venom while atropine was effective in eliminating the depressor effect of the venom on HR. The arrhythmias induced by the venom were blocked by the injection of the two blockers and are assumed to be due to the release of catecholamines and acetylcholine.     

Characterization of the peripheral action of neuropeptide K on the rat cardiovascular system.

The effects of neuropeptide K (NPK) were measured on mean arterial pressure (MAP) and heart rate (HR) after i.v. injection in urethane-anesthetized rats. NPK (6.5 and 32.5 nmol/kg) produced sustained decreases in MAP and elicited increases in HR. Whereas the NPK-induced tachycardia lasted more than 30 min at 32.5 nmol/kg, a latent and long-lasting bradycardia appeared from 20 min after injection of 6.5 nmol/kg. The initial tachycardia was converted to bradycardia by metoprolol but remained unaffected by hexamethonium, atropine and naloxone. These four treatments, however, prevented the bradycardiac response to NPK at 30 min. Whereas phentolamine, idazoxan, bilateral adrenalectomy and chemical sympathectomy with 6-hydroxydopamine (6-OHDA) preserved the initial tachycardia induced by NPK, they converted the decrease in HR to a tachycardiac response at 30 min. The vasodepressor response to NPK was significantly enhanced by bilateral adrenalectomy, chemical sympathectomy and metoprolol but remained unaffected by all other treatments. Neither the MAP nor the HR responses to NPK were affected by indomethacin. These results suggest that NPK can accelerate HR through non-reflex activation of the sympathoadrenal system. The secondary bradycardia induced by NPK may be due to a vagal reflex while the vasodepressor response to NPK is probably attributable to a direct action mediated by specific receptors on arterial blood vessels. Thus, NPK is considered as the most potent biologically active tachykinin so far described on the rat cardiovascular system.     

Amitraz-induced delay of gastrointestinal transit in mice: Mediated by α2-adrenergic receptors

Subcutaneous injection of amitraz (0.3–3.0 mg/kg) produced a dose-dependent delay of gastrointestinal transit in conscious mice. This effect of amitraz was antagonized by α₂-adrenergic blocking agents, e.g., yohimbine, piperoxan, and tolazoline. Other adrenergic antagonists without α₂-blocking activity (thymoxamine, prazosin, phenoxybenzamine, and propranolol) did not reduce the depressant effect of amitraz on gastrointestinal transit at the dosages studied. Furthermore, this effect of amitraz was not altered by a dopaminergic antagonist (haloperidol), a serotonergic antagonist (methysergide), a histamine H₁-antagonist (chlorpheniramine), a histamine H₂-antagonist (cimetidine), cholinergic antagonists (atropine and hexamethonium), a GABAergic antagonist (bicuculline), and an opioid antagonist (naloxone). Pretreatment of mice with 6-hydroxydopamine failed to antagonize the effect of amitraz. These results suggest that amitraz-induced delay of gastrointestinal transit is mediated by postjunctional α₂-adrenergic receptors and appears not to involve the activation of β-adrenergic, dopaminergic, serotonergic, histaminergic, cholinergic, GABAergic, or opioid receptors.     

盐酸戊乙奎醚注射液用于全麻术前减少腺体分泌的剂量探索研究

目的研究盐酸戊乙奎醚作为全麻术前用药减少腺体分泌的有效剂量并评价其安全性,并与阿托品和空白对照比较。方法择期在全身麻醉下行外科手术的患者共50例,随机分为5组,分别于术前肌内注射盐酸戊乙奎醚注射液0.0046mg/kg(组1)、0.0091mg/kg(组2)、0.0137mg/kg (组3)、阿托品0.5mg(组4)以及空白对照(组5)。观察并记录给药前后各时点患者唾液分泌量、口干程度视觉模拟评分等变化及循环、呼吸指标的变化。结果各组中仅阿托品组于给药后30min时唾液分泌量显著减少(P<0.01)。盐酸戊乙奎醚不同剂量组患者用药后唾液分泌量于术后1h明显减少。口干程度视觉模拟评分升高。二者均有统计学意义(P<0.05),其中剂量最大的组3效果最为显著,与阿托品组和空白对照组相较也有显著差异(P<0.05)。盐酸戊乙奎醚不同剂量组患者给药后心率均有不同程度的下降。结论盐酸戊乙奎醚是一类新型选择性抗胆碱药,其抗唾液分泌的作用强,起效时间较阿托品慢,药效持续时间长。有可能出现心动过缓,需在心电监护下使用。     

戊乙奎醚与阿托品对幼儿术前用药时心血管稳定性的比较

目的 观察戊乙奎醚和阿托品做为幼儿术前用药时心率(HR)、平均动脉压(MAP)、脉搏血氧饱和度(SpO2)、心电图(ECG)的变化,比较其对心血管稳定性的影响.方法 幼儿择期手术40例随机分为两组,每组20例,戊乙奎醚组(A组)给予戊乙奎醚0.015 mg/kg,阿托品组(B组)给予阿托品0.015 mg/kg,均于术前30 min肌内注射,观察记录给药前及给药后10 min、20 min、30 min、40 min时患儿HR、MAP、SpO2、ECG的变化.结果 A组用药后HR、MAP、SpO2变化不明显,B组HR、MAP明显变化,SpO2变化不明显,两组均无其他心律失常.结论 戊乙奎醚做为幼儿术前用药,有利于心血管稳定性的维护.     

戊乙奎醚与阿托品对幼儿术前用药时心血管稳定性的比较

目的 观察戊乙奎醚和阿托品做为幼儿术前用药时心率(HR)、平均动脉压(MAP)、脉搏血氧饱和度(SpO2)、心电图(ECG)的变化,比较其对心血管稳定性的影响.方法 幼儿择期手术40例随机分为两组,每组20例,戊乙奎醚组(A组)给予戊乙奎醚0.015 mg/kg,阿托品组(B组)给予阿托品0.015 mg/kg,均于术前30 min肌内注射,观察记录给药前及给药后10 min、20 min、30 min、40 min时患儿HR、MAP、SpO2、ECG的变化.结果 A组用药后HR、MAP、SpO2变化不明显,B组HR、MAP明显变化,SpO2变化不明显,两组均无其他心律失常.结论 戊乙奎醚做为幼儿术前用药,有利于心血管稳定性的维护.     

戊乙奎醚与阿托品对幼儿术前用药时心血管稳定性的比较

目的观察戊乙奎醚和阿托品做为幼儿术前用药时心率（HR）、平均动脉压（MAP）、脉搏血氧饱和度（SpO2）、心电图（ECG）的变化,比较其对心血管稳定性的影响。方法幼儿择期手术40例随机分为两组,每组20例,戊乙奎醚组（A组）给予戊乙奎醚0．015mg／kg,阿托品组（B组）给予阿托品0．015ms／ks,均于术前30min肌内注射,观察记录给药前及给药后10min、20min、30min、40min时患儿HR、MAP、SpO2、ECG的变化。结果A组用药后HR、MAP、SpO2变化不明显,B组HR、MAP明显变化,SpO2变化不明显,两组均无其他心律失常。结论戊乙奎醚做为幼儿术前用药,有利于心血管稳定性的维护。     

Acute cardiovascular effects of (+)-nantenine, an alkaloid isolated from Platycapnos spicata, in anaesthetised normotensive rats

This is the first study of the in vivo potential activity of (+)-nantenine (a natural aporphinoid alkaloid) on the rat cardiovascular system. In anaesthetized normotensive rats, acute intravenous ( i. v.) administration of (+)-nantenine (3 - 6 mg/kg) produced a dose-dependent fall in mean arterial pressure (MAP), accompanied by a significant decrease in heart rate (HR). In addition, (+)-nantenine (5 mg/kg i. v.) did not modify the cardiovascular effects induced by angiotensin II (0.2 microg/kg i. v.) and the selective alpha (2)-adrenoceptor agonist B-HT 920 (0.2 mg/kg i. v.) [unlike nifedipine (0.8 mg/kg i. v.) and yohimbine (1 mg/kg i. v.), respectively] but markedly attenuated [like prazosin (0.2 mg/kg i. v.)] the hypertension evoked by phenylephrine (PE, 25 microg/kg, i. v.), a selective alpha (1)-adrenergic receptor agonist and, like ketanserin (1 mg/kg i. v.), the second phase (rise in MAP) of the cardiovascular response caused by 5-hydroxytryptamine (5-HT, 0.3 mg/kg i. v.). On the other hand, pre-treatment of anaesthetised rats with NG-nitro- L-arginine ( L-NOARG, 5 mg/kg i. v.) did not significantly affect the cardiovascular effects of (+)-nantenine. These results indicate that the hypotension and bradycardia elicited by this aporphine alkaloid in anaesthetised normotensive rats seem to be due, at least in part, to a combined alpha (1)-adrenergic and 5-HT (2A) receptor blockade but not to the release of nitric oxide (NO) from vascular endothelium, to an alpha (2)-adrenoceptor antagonism or to a calcium antagonist activity. Abbreviations. BP:blood pressure HR:heart rate 5-HT:5-hydroxytryptamine i. v.:intravenous L-NOARG: NG-nitro- L-arginine MAP:mean arterial pressure NO:nitric oxide PE:phenylephrine     

戊乙奎醚与阿托品对幼儿术前用药时心血管稳定性的比较

目的 观察戊乙奎醚和阿托品做为幼儿术前用药时心率(HR)、平均动脉压(MAP)、脉搏血氧饱和度(SpO2)、心电图(ECG)的变化,比较其对心血管稳定性的影响.方法 幼儿择期手术40例随机分为两组,每组20例,戊乙奎醚组(A组)给予戊乙奎醚0.015 mg/kg,阿托品组(B组)给予阿托品0.015 mg/kg,均于术前30 min肌内注射,观察记录给药前及给药后10 min、20 min、30 min、40 min时患儿HR、MAP、SpO2、ECG的变化.结果 A组用药后HR、MAP、SpO2变化不明显,B组HR、MAP明显变化,SpO2变化不明显,两组均无其他心律失常.结论 戊乙奎醚做为幼儿术前用药,有利于心血管稳定性的维护.     

戊乙奎醚与阿托品对幼儿术前用药时心血管稳定性的比较

目的 观察戊乙奎醚和阿托品做为幼儿术前用药时心率(HR)、平均动脉压(MAP)、脉搏血氧饱和度(SpO2)、心电图(ECG)的变化,比较其对心血管稳定性的影响.方法 幼儿择期手术40例随机分为两组,每组20例,戊乙奎醚组(A组)给予戊乙奎醚0.015 mg/kg,阿托品组(B组)给予阿托品0.015 mg/kg,均于术前30 min肌内注射,观察记录给药前及给药后10 min、20 min、30 min、40 min时患儿HR、MAP、SpO2、ECG的变化.结果 A组用药后HR、MAP、SpO2变化不明显,B组HR、MAP明显变化,SpO2变化不明显,两组均无其他心律失常.结论 戊乙奎醚做为幼儿术前用药,有利于心血管稳定性的维护.     

戊乙奎醚与阿托品对幼儿术前用药时心血管稳定性的比较

目的 观察戊乙奎醚和阿托品做为幼儿术前用药时心率(HR)、平均动脉压(MAP)、脉搏血氧饱和度(SpO2)、心电图(ECG)的变化,比较其对心血管稳定性的影响.方法 幼儿择期手术40例随机分为两组,每组20例,戊乙奎醚组(A组)给予戊乙奎醚0.015 mg/kg,阿托品组(B组)给予阿托品0.015 mg/kg,均于术前30 min肌内注射,观察记录给药前及给药后10 min、20 min、30 min、40 min时患儿HR、MAP、SpO2、ECG的变化.结果 A组用药后HR、MAP、SpO2变化不明显,B组HR、MAP明显变化,SpO2变化不明显,两组均无其他心律失常.结论 戊乙奎醚做为幼儿术前用药,有利于心血管稳定性的维护.