EFFICACY OF TOLAZOLINE AND VATINOXAN IN REDUCING ADVERSE EFFECTS OF BUTORPHANOL-AZAPERONE-MEDETOMIDINE IMMOBILIZATION IN ROCKY MOUNTAIN ELK (CERVUS CANADENSIS).

A mixture of butorphanol, azaperone, and medetomidine (BAM) is frequently used for immobilization of North American hoofstock. Common adverse effects include respiratory depression, hypoxemia, and bradycardia. In this nonblinded crossover study the efficacy of two a-2 adrenergic antagonists, tolazoline and vatinoxan, were evaluated in alleviating adverse effects of BAM in Rocky Mountain elk (Cervus canadensis). Early administration of these antagonists was hypothesized to cause an increase in heart rate, respiratory rate, partial pressure of oxygen (PaO2) and hemoglobin oxygen saturation (SpO2), as well as reduction in mean arterial blood pressure without affecting sedation levels. Eight captive adult female elk were immobilized on three separate occasions at least 14 d apart with 0.15 mg/kg butorphanol, 0.05 mg/kg azaperone, and 0.06 mg/kg medetomidine. Tolazoline (2 mg/kg IM), vatinoxan (3 mg/mg medetomidine IV) or sterile saline (2 ml IM) were administered 20 min postinduction. The BAM caused hypoxemia, bradycardia, and moderate hypertension, and because of the severe hypoxemia observed, all animals received intratracheal oxygen throughout immobilization. Heart rate, respiratory rate, rectal temperature, SpO2, PaO2, and systolic, diastolic, and mean arterial blood pressure were monitored every 5 min throughout the immobilization. Intramuscular tolazoline caused a brief but significant drop in mean arterial pressure compared with controls and a brief but nonsignificant increase in heart rate. Vatinoxan caused a significant drop in blood pressure and a brief significant increase in heart rate. Changes in respiratory rates and PaO2 were not observed with either antagonist; however, all animals received oxygen, which may have influenced this result. The depth of sedation was unchanged after administration of either drug.

Tissue Residue Levels of the Tranquilizer Combination of Butorphanol, Azaperone, and Medetomidine, and the Antagonists, Naltrexone, Atipamezole, and Tolazoline, in Black Bears (Ursus americanus) Postimmobilization.

The tranquilizer combination of butorphanol, azaperone, and medetomidine (BAM) has shown good efficacy for immobilization of wildlife, including black bears (Ursus americanus). BAM is antagonized with a combination of naltrexone and atipamezole. We immobilized 19 adult captive wild caught black bears and, except for three bears that were euthanized immediately, bears were recovered with naltrexone and atipamezole. Tissue residues (≥0.01 ppm) for the tranquilizers butorphanol, azaperone, and medetomidine were detected in liver and muscle of all three bears euthanized on day 0 postinjection (PI). Azaperone was not detected after 1 d PI. Residue for medetomidine was detected in two bears: in the liver 3 d PI and in the kidney 6 d PI. Butorphanol was reported in three bears: in fat 5 d PI, in kidney 6 d PI, and, surprisingly, in kidney, muscle, and fat 7 d PI. No tissue residues were detected in the three bears euthanized at 8 d PI. Tissue residues for the antagonists, naltrexone and atipamezole, were detected in bears euthanized 2 and 6 d PI, but not in tissues from animals euthanized at 7 or 8 d PI.

Tissue Residue Levels after Immobilization of Rocky Mountain Elk ( Cervus elaphus nelsoni) using a Combination of Nalbuphine, Medetomidine, and Azaperone Antagonized with Naltrexone, Atipamezole, and Tolazoline.

Previous studies demonstrated that nalbuphine, medetomidine, and azaperone (NalMed-A) can effectively immobilize adult elk ( Cervus elaphus nelsoni), and be antagonized using naltrexone and atipamezole, with or without tolazoline. To assess duration of tissue residues for this immobilization package, we immobilized 14 captive adult elk with NalMed-A, then euthanized animals and collected tissues 0, 3, 6, 14, 21, or 28 d later. Except for two animals euthanized immediately, all elk were recovered using naltrexone, atipamezole, and tolazoline. Tissue residues (≥0.01 parts per million) for the tranquilizers nalbuphine, medetomidine, and azaperone were detected in liver and muscle tissue samples from elk euthanized within 40 min postinjection (PI) and one animal that died 12-24 h PI, but not in tissues from any of the animals euthanized at 3, 6, 14, 21, or 28 d PI. Tissue residues for the antagonists naltrexone, atipamezole, and tolazoline were detected in liver and muscle of the animal that died 12-24 h PI. Only naltrexone was detected in liver from the two elk euthanized at day 3, and no antagonist residues were detected thereafter.

Efficacy of a low-dosage combination of butorphanol, azaperone, and medetomidine (BAM) to immobilize Rocky Mountain elk.

We compared dosages of a combination of sedatives, which included butorphanol tartrate, azaperone tartrate, and medetomidine HCl (BAM) in captive adult Rocky Mountain elk (Cervus elaphus nelsoni). All three BAM dosages (low, medium, and high) effectively immobilized elk and produced an adequate level of sedation in all subjects. Induction times were similar among the three groups (mean ± SD: low=6.9 ± 1.1 min; medium=6.3 ± 0.9 min; high=4.7 ± 1.3 min). Most elk became hypoxemic regardless of BAM dosage, but hypoxemia tended to be most severe in the high-BAM group; regardless of BAM dosage, oxygen supplementation improved the percentage of oxygen saturation and stabilized the vital rates. Recovery after administration of antagonists (3 mg atipamezole/mg medetomidine and 2 mg/kg tolazoline) was comparable among groups (range of means=9 ± 1.5-11.7 ± 1 min). Based on the findings from clinical trials and field data from free-ranging elk immobilizations, we recommend low-dose BAM (2 mL dose; equivalent to 46 mg butorphanol, 30 mg azaperone, and 18 mg medetomidine) and supplemental oxygen for adult elk; immobilization should be antagonized using 3-5 mg atipamezole/mg medetomidine and 2 mg/kg tolazoline, with tolazoline injected about 5-10 min before atipamezole to smooth out recovery.

Effects of three antagonists on selected pharmacodynamic effects of sublingually administered detomidine in the horse.

OBJECTIVE: To describe the effects of alpha2 -adrenergic receptor antagonists on the pharmacodynamics of sublingual (SL) detomidine in the horse. STUDY DESIGN: Randomized crossover design. ANIMALS: Nine healthy adult horses with an average age of 7.6 ± 6.5 years. METHODS: Four treatment groups were studied: 1) 0.04 mg kg(-1) detomidine SL; 2) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.075 mg kg(-1) yohimbine intravenously (IV); 3) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 4 mg kg(-1) tolazoline IV; and 4) 0.04 mg kg(-1) detomidine SL followed 1 hour later by 0.12 mg kg(-1) atipamezole IV. Each horse received all treatments with a minimum of 1 week between treatments. Blood samples were obtained and plasma analyzed for yohimbine, atipamezole and tolazoline concentrations by liquid chromatography-mass spectrometry. Behavioral effects, heart rate and rhythm, glucose, packed cell volume (PCV) and plasma proteins were monitored. RESULTS: Chin-to-ground distance increased following administration of the antagonists, however, this effect was transient, with a return to pre-reversal values as early as 1 hour. Detomidine induced bradycardia and increased incidence of atrioventricular blocks were either transiently or incompletely antagonized by all antagonists. PCV and glucose concentrations increased with tolazoline administration, and atipamezole subjectively increased urination frequency but not volume. CONCLUSIONS AND CLINICAL RELEVANCE: At the doses administered in this study, the alpha2 -adrenergic antagonistic effects of tolazoline, yohimbine and atipamezole on cardiac and behavioral effects elicited by SL administration of detomidine are transient and incomplete.

Vasomodulation influences on the transdermal delivery of Ibuprofen.

The purpose of the study was to evaluate the effect of adding peripheral vasodilators, tolazoline, or papaverine, to transdermal drug delivery vehicles with the goal of improving the tissue bioavailability of transdermally delivered ibuprofen. Ibuprofen (150 mg) formulations with several concentrations of two different vasodilators and/or a penetration enhancer (PE) complex were topically applied to rabbits. Plasma levels of ibuprofen were determined by a validated high-performance liquid chromatography method and evaluated at 0, 0.5, 1, 2, and 3 h. The PE complex enhanced the plasma ibuprofen level approximately sevenfold versus control, and tolazoline (0.005%) added to the PE complex increased the plasma levels of ibuprofen approximately another twofold compared with the PE. Higher concentrations of tolazoline paradoxically did not exhibit vasodilator enhancement to ibuprofen delivery. Papaverine was tested in the same manner. In this set of experiments, PE increased the plasma ibuprofen 3.7-fold versus control, and addition of papaverine (0.0005%) increased plasma ibuprofen an additional 3.3-fold compared with the PE formulation. Transdermal formulations of ibuprofen containing low concentrations of tolazoline or papaverine increased plasma ibuprofen levels in the presence of passive PE components.

Effects of imidazoline and nonimidazoline alpha-adrenergic agents, including xylazine, medetomidine, yohimbine, tolazoline, and atipamezole, on aggregation of bovine and equine platelets.

OBJECTIVE: To investigate effects of various imidazoline and nonimidazoline α-adrenergic agents on aggregation and antiaggregation of bovine and equine platelets. SAMPLE: Blood samples obtained from 8 healthy adult cattle and 16 healthy adult Thoroughbreds. PROCEDURES: Aggregation and antiaggregation effects of various imidazoline and nonimidazoline α-adrenergic agents on bovine and equine platelets were determined via a turbidimetric method. Collagen and ADP were used to initiate aggregation. RESULTS: Adrenaline, noradrenaline, or α-adrenoceptor agents alone did not induce changes in aggregation of bovine or equine platelets or potentiate ADP- or collagen-induced platelet aggregation. Adrenaline and the α(2)-adrenoceptor agonist clonidine had an inhibitory effect on ADP- and collagen-induced aggregation of bovine platelets. The α(2)-adrenoceptor antagonists phentolamine and yohimbine also inhibited collagen-induced aggregation of bovine platelets. Noradrenaline, other α-adrenoceptor agonists (xylazine, oxymetazoline, and medetomidine), and α-adrenoceptor antagonists (atipamezole, idazoxan, tolazoline, and prazosin) were less effective or completely ineffective in inhibiting ADP- and collagen-induced aggregation of bovine platelets. The imidazoline α(2)-adrenoceptor agonist oxymetazoline submaximally inhibited collagen-induced aggregation of equine platelets, and the α(2)-adrenoceptor antagonist idazoxan, along with phentolamine and yohimbine, also inhibited collagen-induced aggregation of equine platelets. The imidazoline compound antazoline inhibited both ADP- and collagen-induced aggregation of equine platelets. CONCLUSIONS AND CLINICAL RELEVANCE: Several drugs had effects on aggregation of platelets of cattle and horses, and effective doses of ADP and collagen also differed between species. The α(2)-adrenoceptor agonists (xylazine and medetomidine) and antagonists (tolazoline and atipamezole) may be used by bovine and equine practitioners without concern for adverse effects on platelet function and hemostasis.

Pharmacokinetics and pharmacodynamic effects of tolazoline following intravenous administration to horses.

Tolazoline is an α2-adrenergic receptor antagonist, used in veterinary medicine to antagonize the central nervous system depressant and cardiovascular effects of α2 receptor agonists. The pharmacokinetics and pharmacodynamic effects of tolazoline when administered subsequent to detomidine in the horse were recently reported, although the reversal of the sedative and cardiovascular effects following detomidine may not be complete. The current study therefore investigated the pharmacokinetics and pharmacodynamic effects of tolazoline when administered as a sole agent. Nine healthy adult horses were administered tolazoline (4mg/kgIV) and blood samples were collected at time 0 (prior to drug administration) and at various times up to 72h post drug administration. Plasma samples were analyzed using liquid chromatography-mass spectrometry and resulting data analyzed using compartmental analysis. Systemic clearance, steady state volume of distribution and terminal elimination half-life were 0.820±0.182L/h/kg, 1.68±0.379L/kg and 2.69±0.212h, respectively. Tolazoline administration had no effect on chin to ground distance, but the heart rate decreased (relative to baseline) and the percentage of atrial-ventricular block increased in all horses within 2min of administration. Packed cell volume and glucose concentrations were also increased throughout the sampling period. While not commonly used as a sole agent, caution is indicated whenever tolazoline is administered since the effects may be unpredictable.

Importance of the adrenergic nerve system in the response of gases in the arterial blood following the provoked bronchospasm.

INTRODUCTION: This work, partial pressure of the respiratory gases in the capillary blood (pH, PaO2, PaCO2) was studied, following the protective action of the beta2-drenergic stimulator-Hexoprenaline and alpha2-adrenergic blocker-Tolazoline in the bronchoconstriction caused by a beta-blocker-Propranolol. MATERIAL AND METHODS: in patients with increased bronchial reactibility. pH, oxygen partial pressure (PaO2), dioxide carbon partial pressure (PaCO2) in the arterial blood, with the assistance of the analyzer IL, following some minutes of sample taking were defined in all patients. As a standard to verify the accuracy of the measurement, ampoule solutions of pH, PaO2 and PaCO2 were utilized (Acidobasel, Berlin). RESULTS AND DISCUSSION: Following the inhalation of the beta-blocker-Propranolol (20 mg/ml-aerosol), there was an evident decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2. Beta2-adrenergcic stimulator-Hexoprenaline (2 inh x 0.2 mg), shows an protective effect in the decrease of pO2 (p < 0.05) following the bronchoconstriction being provoked by Propranolol. Alpha2-adrenergic blocker-Tolazoline (20 mg/ml-aerosol), has not shown a protective action in the bronchoconstriction caused with propranolol, therefore significant decrease (p < 0.05) of pO2 and a non-significant increase (p > 0.1) of pCO2 appeared. This shows that stimulation of beta2-adrenergic receptor has protective action in changes of the respiratory gases. Meantime, blocker of the alpha2-adrenergic receptor (Tolazoline) has not shown a protective action in changes of the respiratory gases.

Pharmacological characterization of a Bombyx mori alpha-adrenergic-like octopamine receptor stably expressed in a mammalian cell line.

Series of agonists and antagonists were examined for their actions on a Bombyx morialpha-adrenergic-like octopamine receptor (OAR) stably expressed in HEK-293 cells. The rank order of potency of the agonists was clonidine>naphazoline>tolazoline in Ca(2+) mobilization assays, and that of the antagonists was chlorpromazine>yohimbine. These findings suggest that the B. mori OAR is more closely related to the class-1 OAR in the intact tissue than to the other classes. N'-(4-Chloro-o-tolyl)-N-methylformamidine (DMCDM) and 2-(2,6-diethylphenylimino)imidazolidine (NC-5) elevated the intracellular calcium concentration ([Ca(2+)](i)) with EC(50)s of 92.8 microM and 15.2 nM, respectively. DMCDM and NC-5 led to increases in intracellular cAMP concentration ([cAMP](i)) with EC(50)s of 234 nM and 125 nM, respectively. The difference in DMCDM potencies between the cAMP and Ca(2+) assays might be due to "functional selectivity." The Ca(2+) and cAMP assay results for DMCDM suggest that the elevation of [cAMP](i), but not that of [Ca(2+)](i), might account for the insecticidal effect of formamidine insecticides.

Effect of vasoactive agents on the dermatopharmacokinetics and systemic disposition of model compounds, salicylate and FITC-dextran 4 kDa, following intracutaneous injection of the compounds.

The effects of two vasoactive agents, phenylephrine and tolazoline, were determined on the dermatopharmacokinetics and systemic disposition of model compounds, salicylate (SA) and FITC-dextran 4 kDa (FD-4), following their intracutaneous (i.c.) injection. The determined blood flow in skin was lowered and increased by i.c. injection of phenylephrine and tolazoline, respectively. Dermatopharmacokinetics and the systemic disposition of SA and FD-4 with and without vasoactive agents were analyzed using a compartment model. As a result, the rate constant, k(sc), from skin to systemic circulation of SA after i.c. injection with phenylephrine was almost zero, and the rate constant, k(sm), from skin to muscle increased about 2.4-fold compared with the control group (without vasoactive agents). In contrast, the rate constants, k(sc) and k(sm), after i.c. injection of SA with tolazoline were increased about 1.9- and 2.5-fold, respectively, compared with the control. In FD-4 disposition, k(sc) and k(sm) decreased to about 0.3-fold and increased to about 4.0-fold compared with the control after i.c. injection with phenylephrine. The k(sc) and k(sm) of FD-4 increased with tolazoline about 2.2- and 4.3-fold compared with the control, respectively. These data suggest that these vasoactive agents can be used to modify the dermatopharmacokinetics of topically or intracutaneously applied drugs.

A comparison of two combinations of xylazine-ketamine administered intramuscularly to alpacas and of reversal with tolazoline.

OBJECTIVE: To evaluate the anesthetic and cardiorespiratory effects of two doses of intramuscular (IM) xylazine/ketamine in alpacas, and to determine if tolazoline would reduce the anesthetic recovery time. STUDY DESIGN: Prospective randomized crossover study. ANIMALS: Six castrated male alpacas. METHODS: Each alpaca received a low dose (LD) (0.8 mg kg(-1) xylazine and 8 mg kg(-1) ketamine IM) and high dose (HD) (1.2 mg kg(-1) xylazine and 12 mg kg(-1) ketamine IM) with a minimum of one week between trials. Time to sedation, duration of lateral recumbency and analgesia, pulse rate, respiratory rate, hemoglobin oxygen saturation, arterial blood pressure, blood-gases, and the electrocardiogram were monitored and recorded during anesthesia. With each treatment three alpacas were randomly selected to receive tolazoline (2 mg kg(-1) IM) after 30 minutes of lateral recumbency. RESULTS: Onset of sedation, lateral recumbency and analgesia was rapid with both treatments. The HD was able to provide > or =30 minutes of anesthesia in five of six alpacas. The LD provided > or =30 minutes of anesthesia in three of six alpacas. Respiratory depression and hypoxemia occurred with the HD treatment during the first 10 minutes of lateral recumbency: two animals were severely hypoxemic and received nasal oxygen for 5 minutes. Heart rate decreased, but there were no significant changes in arterial blood pressure. Tolazoline significantly shortened the duration of recumbency with the HD. CONCLUSIONS: The HD provided more consistent clinical effects in alpacas than the LD. Intramuscular tolazoline shortened the duration of lateral recumbency in alpacas anesthetized with the HD combination. CLINICAL RELEVANCE: Both doses of the combination were effective in providing restraint in alpacas and the duration of restraint was dose dependent. Supplemental oxygen should be available if using the HD and IM administration of tolazoline will shorten the recovery time.

Antagonism of detomidine sedation in the horse using intravenous tolazoline or atipamezole.

REASONS FOR PERFORMING STUDY: The ability to shorten the duration of sedation would potentially improve safety and utility of detomidine. OBJECTIVES: To determine the effects of tolazoline and atipamezole after detomidine sedation. HYPOTHESIS: Administration of tolazoline or atipamezole would not affect detomidine sedation. METHODS: In a randomised, placebo-controlled, double-blind, descriptive study, detomidine (0.02 mg/kg bwt i.v.) was administered to 6 mature horses on 4 separate occasions. Twenty-five mins later, each horse received one of 4 treatments: Group 1 saline (0.9% i.v.) as a placebo control; Group 2 atipamezole (0.05 mg/kg bwt i.v.); Group 3 atipamezole (0.1 mg/kg bwt i.v.); and Group 4 tolazoline (4.0 mg/kg bwt i.v.). Sedation, muscle relaxation and ataxia were scored by 3 independent observers at 9 time points. Horses were led through an obstacle course at 7 time points. Course completion time was recorded and the ability of the horse to traverse the course was scored by 3 independent observers. Horses were videotaped before, during and after each trip through the obstacle course. RESULTS: Atipamezole and tolazoline administration incompletely antagonised the effects of detomidine, but the time course to recovery was shortened. CONCLUSIONS AND POTENTIAL RELEVANCE: Single bolus administration of atipamezole or tolazoline produced partial reversal of detomidine sedation and may be useful for minimising detomidine sedation.

Comparative effects of tolazoline and nitroprusside on human isolated radial artery.

BACKGROUND: The radial artery is increasingly being used in coronary revascularization as an alternative conduit to a saphenous vein graft. Its perfect endothelial capacity provides a high patency rate comparable with the internal mammary artery (IMA). However, its spastic characteristics cause difficulties during its intraoperative preparation and may lead to early postoperative graft failure. Thus, treatment and/or prevention of radial artery spasm with an effective vasodilator agent is essential for its longevity. Endogenous vasoconstrictors, including noradrenaline, endothelin-1, and thromboxane A2, are likely to play a role in the pathogenesis of graft spasm. In the present study, we evaluated the vasorelaxant effect of tolazoline, a nonselective alpha-adrenoceptor blocker, against the contractions induced by various spasmogenic agents in an isolated human radial artery. METHODS: Tolazoline (10(-9)-10(-4) M) or sodium nitroprusside (SNP, 10(-9)-10(-4) M) were cumulatively applied on radial artery rings precontracted submaximally with noradrenaline, endothelin-1, thromboxane analogue, U46619, or potassium chloride. In addition, some rings were pretreated with tolazoline (4 x 10(-6) M) for 30 minutes and the contractile response curve to noradrenaline was assessed in its presence. RESULTS: Tolazoline effectively reversed noradrenaline-induced contractions in the radial artery, whereas it failed to produce remarkable relaxations on rings contracted with other spasmogenic agents, while SNP overcame the contractions induced by all spasmogens to a similar extent. In addition, brief pretreatment of radial artery rings with tolazoline significantly inhibited the contractions to noradrenaline. CONCLUSIONS: Tolazoline is not as broadly effective as SNP against all spasmogens investigated; however, it may be effective in counteracting alpha-adrenoceptor-mediated vasospasm in human radial arteries.

Effectiveness of antagonists for tiletamine-zolazepam/xylazine immobilization in female white-tailed deer.

A combination of tiletamine-zolazepam/xylazine (TZ/X) is effective in the chemical immobilization of white-tailed deer (Odocoileus virginianus); however, the lengthy duration of immobilization may limit its usefulness. From October to November 2002, 21 captive female deer were assigned randomly to an alpha(2) antagonist treatment to reverse xylazine-induced sedation (seven does per group). All deer were given 220 mg of TZ (4.5+/-0.4 mg/kg) and 110 mg of X (2.2+/-0.2 mg/kg) intramuscularly (IM). Antagonist treatments were either 200 mg of tolazoline (4.0+/-0.4 mg/kg), 11 mg of atipamezole (0.23+/-0.02 mg/kg), or 15 mg of yohimbine (0.30+/-0.02 mg/kg) injected, half intravenously and half subcutaneously, 45 min after the IM TZ/X injection. In addition, 10 other deer (five per group) were immobilized as before and then given tolazoline (200 mg) after 45 min, with either a carrier (dimethyl sulfoxide [DMSO]) or carrier (DMSO) plus flumazenil (5 mg) to reverse the zolazepam portion of TZ. Mean times from antagonist injection until a deer raised its head were different for alpha(2) antagonist treatments (P=0.02). Times were longer for yohimbine (62.3+/-42.7 min) than for either atipamezole (24.3+/-17.1 min) or tolazoline (21.3+/-14.3 min). Mean times from antagonist injection until standing were not different (P=0.15) among yohimbine (112.0+/-56.4 min), atipamezole (89.7+/-62.8 min), or tolazoline (52.6+/-37.2 min). A sedation score based on behavioral criteria was assigned to each deer every 30 min for 5 hr. On the basis of sedation scores, tolazoline resulted in a faster and more complete reversal of immobilization. Flumazenil treatment did not affect recovery.

A comparison of two intramuscular doses of xylazine-ketamine combination and tolazoline reversal in llamas.

OBJECTIVE: To evaluate the anesthetic and cardiorespiratory effects of two doses of intramuscular xylazine/ketamine in llamas, and to determine if an intramuscular injection of tolazoline would shorten the anesthesia recovery time. STUDY DESIGN: Prospective randomized study. ANIMALS: Six castrated male llamas. METHODS: Each llama received a low dose (LD) (0.4 mg kg(-1) xylazine and 4 mg kg(-1) ketamine) and high dose (HD) (0.8 mg kg(-1) xylazine and 8 mg kg(-1) ketamine). Time to sedation, duration of lateral recumbency and analgesia, pulse, respiratory rate, hemoglobin oxygen saturation, arterial blood pressure, blood gases, and the electrocardiogram were monitored and recorded during anesthesia. Three llamas in each treatment were randomized to receive intramuscular tolazoline (2 mg kg(-1)) after 30 minutes of lateral recumbency. RESULTS: Onset of sedation, lateral recumbency, and analgesia was rapid with both treatments. The HD was able to provide at least 30 minutes of anesthesia in all six llamas. The LD provided only 30 minutes of anesthesia in two out of six llamas. Respiratory depression and hypoxemia were seen in the HD treatment during the first 10 minutes of lateral recumbency. Two llamas were severely hypoxemic during this period and were given nasal oxygen for five minutes. Heart rate decreased, but there were no significant changes in blood pressure. Tolazoline significantly shortened the duration of recumbency in the HD treatment. CONCLUSIONS: The HD provided more consistent clinical effects in llamas than did the LD. Intramuscular tolazoline shortens the duration of lateral recumbency in llamas anesthetized with this combination. CLINICAL RELEVANCE: Both doses appear to be very effective in providing restraint in llamas. The LD may be used for procedures requiring a short period of anesthesia or restraint. The HD could be used when a longer duration of anesthesia is desired. Supplemental oxygen should be available if using the HD. Tolazoline (IM) shortened the recovery time with this combination in llamas.

Comparison of the vasodilating effect of nitroglycerin, verapamil, and tolazoline in hand angiography.

PURPOSE: To compare the vasodilating effect and safety of intraarterial verapamil with the long-accepted standard vasodilators nitroglycerin and tolazoline in hand angiography. MATERIALS AND METHODS: The authors studied 25 patients who underwent brachial artery angiography. In 22 cases, there was poor or moderate visualization of the forearm and hand vasculature. To improve blood flow to the periphery, subsequent angiograms with intraarterial vasodilating agents were obtained. First, nitroglycerin was administered (n = 22). In cases of continuous poor or moderate visualization of the forearm and hand vasculature, another angiogram was obtained with verapamil (n = 21). If opacification remained poor or moderate, eventually tolazoline was injected (n = 20). To avoid pharmacologic interactions of the different vasodilating drugs, a minimum 15-minute interval between series was observed. The degree of opacification of the forearm and hand arteries was graded on a scale from 1 to 5: visualization of the forearm arteries only was defined as 1, of the forearm arteries and superficial/deep palmar arch as 2, of the forearm arteries, superficial/deep palmar arch, and digital arteries to the level of the metacarpophalangeal joints as 3, to the level of the proximal interphalangeal joints as 4, and to the distal interphalangeal joints as 5. RESULTS: All three vasodilating agents demonstrated highly significant improvement in blood flow; verapamil and tolazoline showed statistically greater effects than nitroglycerin. Verapamil caused the fewest and least severe adverse effects. CONCLUSION: Intraarterial verapamil and tolazoline are comparable in terms of vasodilatory efficacy in hand arteries. However, because of its favorable adverse effect profile, verapamil is recommended for optimizing visualization of the peripheral arterial vascular system.

Octopaminergic modulation of synaptic transmission between an identified sensory afferent and flight motoneuron in the locust.

The role of the biogenic amine octopamine in modulating cholinergic synaptic transmission between the locust forewing stretch receptor neuron (fSR) and the first basalar motoneuron (BA1) was investigated. The amines 5-hydroxytryptamine (5-HT, serotonin) and dopamine were also studied. Bath application of octopamine, 5-HT, and dopamine at concentrations of 10(-4) M reversibly decreased the amplitude of monosynaptic excitatory postsynaptic potentials (EPSPs) evoked in BA1 by electrically stimulating the fSR axon. These effects occurred without any detectable change in either input resistance or membrane potential of BA1. The amines also reversibly decreased the amplitude of responses to acetylcholine (ACh) pressure-applied to the soma of BA1. The muscarinic antagonist scopolamine (10(-6) M) had no significant effect on the octopamine-induced decrease in ACh responses. These observations suggest that these amines potentially could physiologically depress cholinergic transmission between fSR and BA1, at least in part, by altering nicotinic rather than muscarinic cholinergic receptor function. Although the octopaminergic agonists naphazoline and tolazoline both mimicked the actions of octopamine, the receptor responsible for octopamine-mediated modulation could not be characterized since amine receptor antagonists tested on the preparation had complex actions. Confocal immunocytochemistry revealed intense octopamine immunoreactivity in the anterior lateral association center, thus confirming the presence of octopamine in neuropil regions containing fSR/BA1 synapses and therefore supporting a role for this amine in the modulation of synaptic transmission between the fSR and BA1. 5-HT-immunoreactivity, conversely, was concentrated within the ventral association centers; very little staining was observed in the dorsal neuropil regions in which fSR/BA1 synapses are located.

Butorphanol/xylazine/ketamine immobilization of free-ranging Baird's tapirs in Costa Rica.

Cardiopulmonary effects and the utility of a butorphanol/xylazine/ketamine combination were evaluated during twenty immobilizations of sixteen Baird's tapirs (Tapirus bairdii) between March 1996 and January of 1998 in Corcovado National Park (Costa Rica). The animals were attracted to a bait site and darted from tree platforms. The tapirs were estimated to weigh between 200 to 300 kg. Actual weights of three tapirs taken at later dates fell within the estimated range. A butorphanol, 48+/-1.84 (x +/- SE) mg/animal IM, and xylazine, 101+/-2.72 mg/animal IM, combination was used to immobilize the animals. In some instances, ketamine was used either IM or IV at 187+/-40.86 mg/animal to prolong the immobilization period in addition to the butorphanol/xylazine combination. Naltrexone was used IM to reverse butorphanol at 257+/-16.19 mg/animal. Either yohimbine, 34+/-0.61 or tolazoline at 12+/-10.27 mg/animal, was used to reverse xylazine. The mean time from dart impact to first visible effect was 4.63+/-0.50 min (x +/- SE). Mean time to sternal recumbency was 12.21+/-1.08 min. Mean time the tapirs were immobilized was 45.63+/-3.6 min. Mean time to return to sternal recumbency and standing in animals that received yohimbine and naltrexone was 3.16+/-1.06 and 5.33+/-1.45 min, respectively. Mean time to return to sternal recumbency and standing in animals that received tolazoline and naltrexone was 1.57+/-0.39 and 3.14+/-0.51 min, respectively. Cardiopulmonary parameters including heart rate, respiratory rate, body temperature, electrocardiogram, percent oxygen satoration, and indirect blood pressure were recorded. Arterial blood gas analysis was performed on four animals. A mild degree of hypoxemia was evidenced by low arterial oxygen saturations. Five of 14 (36%) animals measured had oxygen saturations below 90%. Bradycardia (heart rates <45 BPM) was an expected finding in 11 (55%) immobilizations. Induction, recovery and muscle relaxation of each immobilization was graded. Premature arousal, which occurred in six (30%) animals, was the only problem associated with the immobilizations. Butorphanol/xylazine is a recommended protocol for immobilization of calm, free-ranging tapirs lasting less than 30 min. Supplemental intravenous administration of ketamine is recommended for longer procedures. Nasal insufflation of oxygen is recommended.

Bidirectional allosteric effects of agonists and GTP at alpha(2A/D)-adrenoceptors.

Agonists and GTP exert reciprocal effects on the stability of the G protein-coupled receptor/G protein complex, implying bidirectional control over the receptor/G protein interface. To investigate this relationship, we compared the ability of a series of hydroxyl-substituted phenethylamine and imidazoline agonists to stimulate [(35)S]guanosine 5'-O-(3-thio)triphosphate ([(35)S]GTPgammaS) binding in membranes from alpha(2A/D)-adrenergic receptor-transfected PC12 cells with the magnitude of the GTP-induced reduction in agonist affinity in [(3)H]rauwolscine-binding studies. Agents previously described as full and partial agonists in functional studies showed similar relative efficacies in promoting GTP binding (r = 0.97) as well as similar relative potencies (r = 0.94). Efficacy among agonists for promotion of [(35)S]GTPgammaS binding was closely correlated with the relative influence of GTPgammaS on agonist binding (r = 0.97), consistent with a bidirectional allosteric influence by agonists and GTP on receptor/G protein complexation. In an additional series of tolazoline derivatives, a range in efficacy from full agonism to strong inverse agonism was observed, depending on the presence or absence of hydroxyl substituents. Together these results suggest that agonist-induced repositioning of transmembrane helices via their hydroxyl interactions is a critical determinant of the stability of the receptor/G protein complex and therefore of agonist efficacy.