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.

Effects of idazoxan, tolazoline, and yohimbine on xylazine-induced respiratory changes and central nervous system depression in ewes.

We compared the ability of 3 alpha 2-adrenoreceptor antagonists, idazoxan (0.05 mg/kg), tolazoline (2 mg/kg), and yohimbine (0.2 mg/kg) to reverse xylazine (0.3 mg/kg)-induced respiratory changes and CNS depression in 6 ewes. Once weekly, each ewe was given a random IV treatment of xylazine, followed in 5 minutes by either an antagonist or 0.9% NaCl solution. Xylazine alone caused recumbency for 54.2 +/- 5.3 minutes (mean +/- SEM). Xylazine also increased respiratory rate and decreased PaCO2 for at least 45 minutes, but did not significantly change arterial pH or PaCO2. Idazoxan and tolazoline were equally effective in reversing the respiratory actions of xylazine; however, yohimbine was less effective in reducing the respiratory rate and was ineffective in antagonizing the decreased PaO2. Idazoxan and tolazoline decreased the duration of xylazine-induced recumbency to 6.3 +/- 0.6 and 9.5 +/- 2.3 minutes, respectively, whereas yohimbine did not significantly change this effect of xylazine. Thus, at the dosages studied, idazoxan and tolazoline appeared to be more effective than yohimbine in reversing the respiratory and CNS depressant actions of xylazine in sheep.

Effects of topical application of amitraz on plasma glucose and insulin concentrations in dogs.

Amitraz, a formamidine insecticide, is used topically in the treatment of demodicosis and other ectoparasitic infestations. When 3.78 L (containing 2.1 g) of amitraz (twice the recommended concentration) was applied to 5 dogs 4 hours before glucose (0.6 g/kg of body weight) was administered IV, plasma glucose concentration increased, but the increase in plasma insulin concentration, which usually follows IV administered glucose, was suppressed. The results suggested that amitraz induced hyperglycemia at least partly by inhibiting insulin release.

Further evidence to support the alpha 2-adrenergic nature of amitraz-induced decrease in intestinal motility.

The effect of amitraz, a formamidine insecticide, on in vitro intestinal contractions was studied in teh transmurally-stimulated guinea-pig ileum. An electrical stimulation (with 80 V/0.5 msec/0.1 Hz shown on the dial of the stimulator) caused the ileum to contract presumably via the release of acetylcholine. Amitraz (10(-7) to 10(-6) M) produced a dose-dependent inhibition of these transmurally-stimulated contractions. This effect of amitraz was blocked and reversed by idazoxan (10(-6) M), an alpha 2-adrenoceptor antagonist, but was not prevented by prazosin (10(-6) M), an alpha 1-adrenoceptor antagonist. These results suggest that alpha 2-adrenoceptors mediate the effects of amitraz on the transmurally-stimulated guinea-pig ileum. The results also suggest that amitraz decreases intestinal contraction by activating the alpha 2-adrenoceptors in the myenteric (Auerbach's) plexus, thus inhibiting parasympathetic tone.

Yohimbine increases plasma insulin concentrations of dogs.

Recent evidence suggests that catecholamines inhibit insulin release by stimulating alpha 2-adrenoreceptors in beta-cells of the pancreatic islets. In the present study, iv injections of 0.1 and 0.3 mg/kg of yohimbine, an alpha 2-adrenoreceptor antagonist, resulted in increased plasma insulin and decreased plasma glucose concentrations in the dog. The use of alpha 2-adrenoreceptor antagonists may be of value in non-insulin-dependent diabetic patients by counteracting the inhibitory influence of endogenous catecholamines.

Effects of tolazoline and yohimbine on xylazine-induced central nervous system depression, bradycardia, and tachypnea in sheep.

We compared the ability of tolazoline and yohimbine to antagonize xylazine-induced central nervous system depression, bradycardia, and tachypnea in 9 ewes and 5 rams. Once a week for 3 weeks, each sheep received one IV treatment of 0.4 mg xylazine/kg, 0.4 mg xylazine/kg followed in 10 minutes by 2 mg tolazoline/kg, or 0.4 mg xylazine/kg followed in 10 minutes by 0.2 mg yohimbine/kg. The order of the 3 treatments in each sheep was randomized. Xylazine alone caused recumbency for 41.0 +/- 3.7 minutes (mean +/- SEM). Tolazoline and yohimbine shortened the xylazine-induced recumbency to 12.1 +/- 0.9 minutes and 18.1 +/- 1.5 minutes, respectively. Sheep given xylazine alone had head droop for 34.0 +/- 5.4 minutes after rising. Head drooping of sheep given tolazoline or yohimbine was reduced to 10.1 +/- 1.7 minutes and 14.2 +/- 1.7 minutes, respectively. Both tolazoline and yohimbine reversed the bradycardia and tachypnea that followed xylazine administration. No statistical differences in the rate and magnitude of the reversal were observed between the 2 drugs.

Antagonism of xylazine-induced depression of shuttle-avoidance responses in dogs by administration of 4-aminopyridine, doxapram, or yohimbine.

The effectiveness of 4-aminopyridine, doxapram, or yohimbine as antagonists against xylazine-induced CNS depression in dogs was evaluated and compared, using the 2-way shuttle-avoidance paradigm. All drugs were given IV to 5 male dogs trained to avoid mild shock by jumping over a hurdle within 10 s after initiation of an audible tone. At dosages of 1 and 2 mg/kg of body weight, xylazine abolished or significantly decreased the mean number of avoidance responses and significantly increased the mean latency of avoidance responses. The analeptic 4-aminopyridine (0.5 mg/kg) did not significantly antagonize xylazine in all dogs. One dog convulsed both times it was given xylazine followed by 4-aminopyridine, but did not convulse when given either drug alone. Doxapram (5.5 mg/kg), a short-acting analeptic and respiratory stimulant, was only partially effective in antagonizing xylazine, and its antagonistic actions were brief. Yohimbine (0.1 mg/kg), an alpha 2-adrenoreceptor-blocking agent, was superior to 4-aminopyridine and doxapram in its ability to antagonize xylazine-induced CNS depression. Yohimbine consistently increased the mean number of avoidance responses to the maximum of 8 and consistently decreased the mean latency of avoidance responses to control values in dogs given 1 or 2 mg of xylazine/kg. In dogs given 2 mg of xylazine/kg, yohimbine was significantly more effective than 4-aminopyridine or doxapram in its ability to increase the mean number of avoidance responses and decrease the mean latency of avoidance responses.(ABSTRACT TRUNCATED AT 250 WORDS)

The emetic effect of B-HT 920 and apomorphine in the dog: antagonism by haloperidol.

Recent investigations have suggested that the alpha 2-adrenoreceptor agonist B-HT 920 is also a dopamine (DA) agonist with a selectivity for presynaptic receptors. In the present study, the emetic effect of B-HT 920 was investigated. Intravenous injections of B-HT 920 (0.32-10.0 micrograms/kg) and a DA2-agonist apomorphine (3.2-100.0 micrograms/kg) caused dose-dependent emesis. The ED50 of B-HT 920 and apomorphine were 3.2 and 12.3 micrograms/kg, respectively. When haloperidol (10.0-24.5 micrograms/kg i.v.), a DA2-antagonist, was given 5 minutes before B-HT 920 (10 micrograms/kg) or apomorphine (32 micrograms/kg), it caused a dose-dependent prevention of B-HT 920- and apomorphine-induced emesis. The ED50 of haloperidol in preventing the emetic effect of both drugs was identical (13.5 micrograms/kg). In contrast, haloperidol (32 micrograms/kg i.v.) did not prevent the emetic effect of ouabain (40 micrograms/kg i.v.). Neither did yohimbine (0.1 mg/kg i.v.), an alpha 2-adrenoreceptor antagonist, prevent the emetic effect of B-HT 920 (10 micrograms/kg). These results suggest that B-HT 920, acting like apomorphine, induces emesis by activating DA2-receptors probably in the chemoreceptor trigger zone of the area postrema.

The caffeine CO2 breath test: dose response and route of N-demethylation in smokers and nonsmokers.

The optimal conditions for performing the caffeine CO2 breath test (CBT) were investigated in smokers and nonsmokers. Caffeine labeled with 13C or 14C in all three (1, 3, and 7) methyl groups or specifically in the 1-, 3-, or 7-methyl groups were orally administered to healthy adults and the expiration of labeled CO2 was measured for 8 or 24 hr. The absolute rate of labeled CO2 excretion from trilabeled caffeine was proportional to the dose up to 3 mg/kg in all subjects. In smokers, the rate of labeled CO2 excretion averaged twice that in nonsmokers at all doses. A correlation was observed between the 2-hr cumulative CO2 excretion from trilabeled caffeine and the apparent oral metabolic clearance rate (MCR) of caffeine (R = 0.90). Monolabeled CBTs in smokers and nonsmokers demonstrated that 80% +/- 4% of labeled CO2 expired in the breath during the first 2 hr of a trilabeled CBT was derived from the 3 position; at 6 to 8 hr equal amounts were derived from the 3 and 7 positions. Little N-demethylation was observed from the 1 position at any time during the 8-hr test. The results indicate that the 2-hr cumulative excretion of labeled CO2 could be used to accurately predict the metabolic clearance rate of caffeine is the best CBT parameter for detecting the effect of smoking on caffeine N-demethylation. The data suggest that the primary routes of caffeine metabolism are 3-N-demethylation and ring hydroxylation and confirm that caffeine metabolites are N-demethylated primarily in the 3 and 7 positions.