Cardiopulmonary effects of the alpha2-adrenoceptor agonists medetomidine and ST-91 in anesthetized sheep.
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To test the hypothesis that pulmonary alterations are more important than hemodynamic changes in alpha2-agonist-induced hypoxemia in ruminants, the cardiopulmonary effects of incremental doses of (4-[1-(2,3-dimethylphenyl)ethyl]-1H-imadazole) hydrochloride (medetomidine; 0.5, 1.0, 2.0, and 4 micrograms/kg) and 2-(2, 6-diethylphenylamino)-2-imidazol (ST-91; 1.5, 3.0, 6.0, and 12 micrograms/kg) were compared in five halothane-anesthetized, ventilated sheep using a placebo-controlled randomized crossover design. Pulmonary resistance (RL), dynamic compliance, and tidal volume changes in transpulmonary pressure (DeltaPpl) were determined by pneumotachography, whereas cardiac index (CI), mean pulmonary artery pressure (Ppa), and pulmonary artery wedge pressure (Ppaw) were determined using thermodilution and a Swan-Ganz catheter. The most important finding was the fall in partial pressure of oxygen in arterial blood (PaO2) after administration of medetomidine at a dose (0.5 micrograms/kg) 20 times less than the sedative dose. The PaO2 levels decreased to 214 mm Hg as compared with 510 mm Hg in the placebo-treated group. This decrease in PaO2 was associated with a decrease in dynamic compliance and an increase in RL, DeltaPpl, and the intrapulmonary shunt fraction without changes in heart rate, CI, mean arterial pressure, pulmonary vascular resistance, Ppa, or Ppaw. On the other hand, ST-91 only produced significant changes in PaO2 at the highest dose. After this dose of ST-91, the decrease in PaO2 was accompanied by a 50% decrease in CI and an increase in mean arterial pressure, Ppa, Ppaw, and the intrapulmonary shunt fraction without significant alterations of RL and DeltaPpl. The study suggests that the mechanism(s) by which medetomidine and ST-91 produce lower PaO2 are different and that drug-induced alterations in the pulmonary system are mainly responsible for the oxygen-lowering effect of medetomidine. (+info)
Direct effects of alpha1- and alpha2-adrenergic agonists on spinal and cerebral pial vessels in dogs.
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BACKGROUND: The effects of adrenergic agonists, often used as local anesthetic additives or spinal analgesics, on spinal vessels have not been firmly established. The authors investigated the effects of alpha2- and alpha1-adrenergic agonists on spinal and cerebral pial vessels in vivo. METHODS: Pentobarbital-anesthetized dogs (n = 28) were prepared for measurement of spinal pial-vessel diameter in a spinal-window preparation. The authors applied dexmedetomidine, clonidine, phenylephrine, or epinephrine in three different concentrations (0.5, 5.0, and 50 microg/ml; [2.1, 1.9, 2.5, and 2.3] x [10(-6), 10(-5), and 10(-4)] M, respectively) under the window (one drug in each dog) and measured spinal pial arteriolar and venular diameters in a sequential manner. To enable the comparison of their effects on cerebral vessels, the authors also administered these drugs under a cranial window. RESULTS: On topical administration, each drug constricted spinal pial arterioles in a concentration-dependent manner. Phenylephrine and epinephrine induced a significantly larger arteriolar constriction than dexmedetomidine or clonidine at 5 microg/ml (8%, 11%, 0%, and 1%, respectively). Spinal pial venules tended to be less constricted than arterioles. In cerebral arterioles, greater constrictions were induced by dexmedetomidine and clonidine than those induced by phenylephrine and epinephrine (14%, 8%, 0%, and 1%, respectively). Cerebral pial venules tended to exhibit larger constrictions than cerebral arterioles (unlike in spinal vessels). CONCLUSION: Dexmedetomidine and clonidine constricted spinal vessels in a concentration-dependent manner, but such vasoconstrictions were smaller than those induced by phenylephrine and epinephrine. (+info)
Anesthetic profile of dexmedetomidine identified by stimulus-response and continuous measurements in rats.
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This study characterizes the anesthetic profile of dexmedetomidine on the basis of steady-state plasma concentrations using defined stimulus-response, ventilatory, and continuous electroencephalographic (EEG) and cardiovascular effect measures in rats. At constant plasma concentrations of dexmedetomidine (range, 0.5-19 ng/ml), targeted and maintained by target-controlled infusion, the whisker reflex, righting reflex, startle reflex (to noise), tail clamp response, hot water tail-flick latency, and attenuation of heart rate (HR) increase associated with tail-flick (sympathoadrenal block) and corneal reflex, were assessed in 22 rats. EEG (power in 0.5- to 3.5-Hz frequency band), mean arterial pressure, and HR were recorded continuously. Blood gas values and arterial drug concentrations were determined regularly. The following steady-state plasma EC(50) values of dexmedetomidine (mean +/- S.E. nanograms per milliliter) were estimated: HR decrease (0.51 +/- 0.04), EEG (1.02 +/- 0.08), whisker reflex (1.09 +/- 0.10), sympathoadrenal block (1.85 +/- 0.80), mean arterial blood pressure increase (1.99 +/- 0.44), righting reflex (2.13 +/- 0.15), tail-flick latency (3.65 +/- 0.87), startle reflex (3.75 +/- 0.64), tail clamp (5.49 +/- 1.34), and corneal reflex (24.5 +/- 12.3). At the EC(50) value of tail clamp, ventilatory depression was minor. In rats, dexmedetomidine creates bradycardia, sedation/hypnosis, sympathoadrenal blocking effects, and blood pressure-increasing effects at plasma concentrations below 2.5 ng/ml. Higher plasma concentrations are needed to loose the startle reflex, tail-flick, tail clamp, and corneal reflex responses. Ventilatory depressant effects are minor. The applied EEG measure seems to reflect sedation/hypnosis but seems to have limited value to predict the deeper levels of analgesia and anesthesia of dexmedetomidine. (+info)
Anesthesia of wood bison with medetomidine-zolazepam/tiletamine and xylazine-zolazepam/tiletamine combinations.
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This study was designed to evaluate 2 combinations for immobilization of bison. Seven wood bison received 1.5 mg/kg body weight (BW) of xylazine HCl + 1.5 mg/kg BW of zolazepam HCl and 1.5 mg/kg BW of tiletamine HCl on one occasion. The bison received 60 micrograms/kg BW of medetomidine HCl + 0.6 mg/kg BW of zolazepam HCl and 0.6 mg/kg BW of tiletamine HCL on another occasion. Xylazine was antagonized with 3 mg/kg BW of tolazoline HCl and medetomidine HCl was antagonized with 180 micrograms/kg (BW) of atipamezole HCl. Temporal characteristics of immobilization and physiological effects (acid-base status, thermoregulatory, cardiovascular, and respiratory effects) of the drug combinations were compared. Induction was significantly faster with xylazine HCl-zolazepam HCl/tiletamine HCl. Recovery following antagonist administration was significantly faster with medetomidine HCl-zolazepam HCl/tiletamine HCl. The average drug volumes required were 7.00 mL of xylazine HCl-zolazepam HCl/tiletamine HCL and 2.78 mL of medetomidine HCl-zolazepam HCl/tiletamine HCl. Hypoxemia, hypercarbia, and rumenal tympany were the major adverse effects with both drug combinations. (+info)
Comparative cardiopulmonary effects of carfentanil-xylazine and medetomidine-ketamine used for immobilization of mule deer and mule deer/white-tailed deer hybrids.
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Three mule deer and 4 mule deer/white-tailed deer hybrids were immobilized in a crossover study with carfentanil (10 microg/kg) + xylazine (0.3 mg/kg) (CX), and medetomidine (100 microg/kg) + ketamine (2.5 mg/kg) (MK). The deer were maintained in left lateral recumbency for 1 h with each combination. Deer were immobilized with MK in 230+/-68 s (mean +/- SD) and with CX in 282+/-83 seconds. Systolic, mean and diastolic arterial pressure were significantly higher with MK. Heart rate, PaO2, PaCO2, pH, and base excess were not significantly different between treatments. Base excess and pH increased significantly over time with both treatments. Both treatments produced hypoventilation (PaCO2 > 50 mm Hg) and hypoxemia (PaO2 < 60 mm Hg). PaO2 increased significantly over time with CX. Body temperature was significantly (P<0.05) higher with CX compared to MK. Ventricular premature contractions, atrial premature contractions, and a junctional escape rhythm were noted during CX immobilization. No arrhythmias were noted during MK immobilization. Quality of immobilization was superior with MK, with no observed movement present for the 60 min of immobilization. Movement of the head and limbs occurred in 4 animals immobilized with CX. The major complication observed with both of these treatments was hypoxemia, and supplemental inspired oxygen is recommended during immobilization. Hyperthermia can further complicate immobilization with CX, reinforcing the need for supplemental oxygen. (+info)
Combination of continuous intravenous infusion using a mixture of guaifenesin-ketamine-medetomidine and sevoflurane anesthesia in horses.
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The anesthetic and cardiovascular effects of a combination of continuous intravenous infusion using a mixture of 100 g/L guaifenesin-4 g/L ketamine-5 mg/L medetomidine (0.25 ml/kg/hr) and oxygen-sevoflurane (OS) anesthesia (GKM-OS anesthesia) in horses were evaluated. The right carotid artery of each of 12 horses was raised surgically into a subcutaneous position under GKM-OS anesthesia (n=6) or OS anesthesia (n=6). The end-tidal concentration of sevoflurane (EtSEV) required to maintain surgical anesthesia was around 1.5% in GKM-OS and 3.0% in OS anesthesia. Mean arterial blood pressure (MABP) was maintained at around 80 mmHg under GKM-OS anesthesia, while infusion of dobutamine (0.39+/-0.10 microg/kg/min) was necessary to maintain MABP at 60 mmHg under OS anesthesia. The horses were able to stand at 36+/-26 min after cessation of GKM-OS anesthesia and at 48+/-19 minutes after OS anesthesia. The cardiovascular effects were evaluated in 12 horses anesthetized with GKM-OS anesthesia using 1.5% of EtSEV (n=6) or OS anesthesia using 3.0% of EtSEV (n=6). During GKM-OS anesthesia, cardiac output and peripheral vascular resistance was maintained at about 70% of the baseline value before anesthesia, and MABP was maintained over 70 mmHg. During OS anesthesia, infusion of dobutamine (0.59+/-0.24 microg/kg/min) was necessary to maintain MABP at 70 mmHg. Infusion of dobutamine enabled to maintaine cardiac output at about 80% of the baseline value; however, it induced the development of severe tachycardia in a horse anesthetized with sevoflurane. GKM-OS anesthesia may be useful for prolonged equine surgery because of its minimal cardiovascular effect and good recovery. (+info)
Cardiovascular effects of medetomidine, detomidine and xylazine in horses.
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The cardiovascular effects of medetomidine, detomidine, and xylazine in horses were studied. Fifteen horses, whose right carotid arteries had previously been surgically raised to a subcutaneous position during general anesthesia were used. Five horses each were given the following 8 treatments: an intravenous injection of 4 doses of medetomidine (3, 5, 7.5, and 10 microg/kg), 3 doses of detomidine (10, 20, and 40 microg/kg), and one dose of xylazine (1 mg/kg). Heart rate decreased, but not statistically significant. Atrio-ventricular block was observed following all treatments and prolonged with detomidine. Cardiac index (CI) and stroke volume (SV) were decreased with all treatments. The CI decreased to about 50% of baseline values for 5 min after 7.5 and 10 microg/kg medetomidine and 1 mg/kg xylazine, for 20 min after 20 microg/kg detomidine, and for 50 min after 40 microg/kg detomidine. All treatments produced an initial hypertension within 2 min of drug administration followed by a significant decrease in arterial blood pressure (ABP) in horses administered 3 to 7.5 microg/kg medetomidine and 1 mg/kg xylazine. Hypertension was significantly prolonged in 20 and 40 microg/kg detomidine. The hypotensive phase was not observed in 10 microg/kg medetomidine or detomidine. The changes in ABP were associated with an increase in peripheral vascular resistance. Respiratory rate was decreased for 40 to 120 min in 5, 7.5, and 10 microg/kg medetomidine and detomidine. The partial pressure of arterial oxygen decreased significantly in 10 microg/kg medetomidine and detomidine, while the partial pressure of arterial carbon dioxide did not change significantly. Medetomidine induced dose-dependent cardiovascular depression similar to detomidine. The cardiovascular effects of medetomidine and xylazine were not as prolonged as that of detomidine. (+info)
Partial to complete antagonism by putative antagonists at the wild-type alpha(2C)-adrenoceptor based on kinetic analyses of agonist:antagonist interactions.
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1. Activation of the recombinant human alpha(2C)-adrenoceptor (alpha(2C) AR) by (-)-adrenaline in CHO-K1 cells transiently co-expressing a chimeric G(alpha q/i1) protein induced a rapid, transient Ca(2+) response with a high-magnitude followed by a low-magnitude phase which continued throughout the recorded time period (15 min). 2. Activation of the alpha(2C) AR by various alpha(2) AR agonists revealed the following rank order of high-magnitude Ca(2+) response [E(max) (%) versus 10 microM (-)-adrenaline]: UK 14304 (102+/-4)=talipexole (101+/-3)=(-)-adrenaline (100)=d-medetomidine (98+/-1)>oxymetazoline (81+/-4) reverse similarclonidine (75+/-5). 3. The methoxy- (RX 821002) and ethoxy-derivatives (RX 811059) of idazoxan and the dexefaroxan analogue atipamezole were fully effective as antagonists of both the high- and the low-magnitude Ca(2+) response. However, though acting as full antagonists of the high-magnitude response, the further putative alpha(2) AR antagonists idazoxan (27%), SKF 86466 (29%) and dexefaroxan (59%) reversed the low-magnitude response only partially. 4. In conclusion, kinetic analyses of agonist : antagonist interactions at the alpha(2C) AR demonstrate a wide spectrum of partial to complete antagonism of the low-magnitude Ca(2+) response for structurally related alpha(2) AR ligands. (+info)