Dexmedetomidine, a selective alpha 2-agonist, does not potentiate the cardiorespiratory depression of alfentanil in the rat.
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The authors examined the cardiovascular and respiratory effects of the highly selective alpha 2-adrenergic agonist dexmedetomidine, both alone and in combination with the synthetic opiate alfentanil. Spontaneously ventilating rats (n = 28) were pretreated with dexmedetomidine, 10 or 30 micrograms/kg; dexmedetomidine, 30 micrograms/kg in combination with the central-acting alpha 2-antagonist idazoxan, 10 mg/kg; or vehicle. Fifteen minutes later all rats received alfentanil, 500 micrograms/kg. Pretreatment with dexmedetomidine reduced heart rate in a dose-related fashion. Administration of alfentanil also caused a significant reduction in heart rate. However, following alfentanil, the dexmedetomidine-treated animals did not have significantly greater bradycardia than control animals. An increase in blood pressure was observed in those animals receiving the larger dose of dexmedetomidine, but this difference disappeared following injection of alfentanil. The addition of idazoxan to the pretreatment regimen prevented the changes seen with dexmedetomidine. Pretreatment with dexmedetomidine produced no significant changes in arterial pH or PCO2. In all groups, administration of alfentanil resulted in a decrease in arterial pH that ultimately became a mixed respiratory and metabolic acidosis. The acidosis promptly resolved following injection of naloxone (1 mg/kg). It appears that dexmedetomidine, at the doses given, has little or no effect on respiration. Dexmedetomidine decreases heart rate but does not add to bradycardia following alfentanil. There is a hypertensive effect seen at the higher dose of dexmedetomidine, but this effect disappears when the drug is given in conjunction with alfentanil. These data show that addition of the alpha 2-agonist dexmedetomidine will not worsen the cardiovascular and respiratory depression associated with high-dose opiates in the spontaneously ventilating rat. (+info)
Dexmedetomidine, an alpha 2-adrenoceptor agonist, reduces anesthetic requirements for patients undergoing minor gynecologic surgery.
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The effects of dexmedetomidine, an alpha 2-adrenoceptor agonist, on vigilance, thiopental anesthetic requirements, and the hemodynamic, catecholamine, and hormonal responses to surgery were investigated in healthy (ASA physical status 1) women scheduled for dilatation and curettage (D & C) of the uterus. Fifteen minutes before induction they received single iv doses of either dexmedetomidine (0.5 micrograms/kg; n = 19) or saline (n = 20) in a double-blind fashion. Anesthesia was induced with thiopental and maintained with N2O/O2 (70/30%) and thiopental. Dexmedetomidine was well tolerated and no serious drug-related subjective side-effects or adverse events were observed. The most prominent subjective effects were fatigue and decreased salivation. The total amount of thiopental needed to perform D & C of the uterus was reduced approximately 30% (from 456 +/- 141 mg [mean +/- SD] after saline to 316 +/- 79 mg after dexmedetomidine). This was mostly due to a smaller induction dose in the group receiving dexmedetomidine. Dexmedetomidine appeared to improve the recovery from anesthesia as measured by visual analogue scales (VAS) on fatigue and nausea. The plasma concentration of norepinephrine was decreased by 56% after dexmedetomidine implying decreased sympathetic nervous activity. Systolic and diastolic blood pressure were moderately reduced after dexmedetomidine administration. The authors conclude that dexmedetomidine preanesthetic medication decreases thiopental anesthetic requirements and improves the recuperation from anesthesia with no serious hemodynamic or other adverse effects. Further studies in patients undergoing more stressful surgery are indicated. (+info)
Pertussis toxin and 4-aminopyridine differentially affect the hypnotic-anesthetic action of dexmedetomidine and pentobarbital.
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Dexmedetomidine, a highly selective and potent agonist at alpha-2 adrenoceptors, produces a hypnotic-anesthetic action in rats. The mechanism for this response may involve an inhibitory G-protein and increased conductance through a potassium channel. To investigate this, the effects of pertussis toxin, a specific inactivator of inhibitory G-proteins, and 4-aminopyridine, a blocker of potassium channels, on the hypnotic-anesthetic response to dexmedetomidine were studied in rats. Pertussis toxin and 4-aminopyridine both decreased the hypnotic-anesthetic action of dexmedetomidine in a dose-dependent fashion. To preclude the possibility that pertussis toxin and 4-aminopyridine attenuated the hypnotic-anesthetic action of dexmedetomidine via indirect central nervous system excitation, the effects of pertussis toxin and 4-aminopyridine on the hypnotic-anesthetic action of pentobarbital also were assessed. Pentobarbital-induced hypnosis was not attenuated by either treatment. These results suggest that the receptor-effector mechanism for the hypnotic-anesthetic action of dexmedetomidine involves an inhibitory G-protein and increased conductance through a potassium channel. (+info)
Effects of dexmedetomidine on contractility, relaxation, and intracellular calcium transients of isolated ventricular myocardium.
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The effects of the highly selective alpha 2-adrenoceptor agonist dexmedetomidine on contractility, relaxation, and the intracellular Ca2+ transients of isolated ventricular myocardium were studied in isolated right ventricular papillary muscles obtained from reserpinized ferrets. Dexmedetomidine (10(-10)-10(-5) M) did not alter amplitude and time variables of isometric, isotonic and zero-load-clamped twitches, except for a slight increase in maximal isotonic relaxation rate at 10(-5) M. Dexmedetomidine (10(-8)-10(-5) M) caused no changes in the intracellular Ca2+ transient detected with aequorin. These results suggest that dexmedetomidine has no intrinsic myocardial contractile effects. (+info)
Pharmacology of intrathecal adrenergic agonists: cardiovascular and nociceptive reflexes in halothane-anesthetized rats.
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The effects of intrathecally administered adrenergic agonists (alpha-1-methoxamine, alpha-2-dexmedetomidine, clonidine, and ST-91, beta-isoproterenol) on nociceptive (tail-flick reflex) and cardiovascular changes (blood pressure and heart rate) evoked by immersing the tail in 53 degrees C water were examined in rats anesthetized with halothane (0.75%) and in which intrathecal catheters had been chronically implanted. Administration of intrathecal alpha-2, but not alpha-1 or beta agonists, produced a dose-dependent block of the tail-flick and evoked cardiovascular responses with the order of activity being as follows: dexmedetomidine greater than clonidine greater than ST-91 much greater than methoxamine greater than or equal to isoproterenol. These effects were readily reversed by the alpha-2 antagonist idazoxan. Intravenously administered dexmedetomidine at a dose that is active when given intrathecally (0.33 micrograms) was without effect on either the tail-flick or the evoked cardiovascular responses. Without drugs, the halothane MAC was 1.23 +/- 0.07%. In the presence of intrathecally administered dexmedetomidine (0.33 micrograms), the MAC was significantly reduced to 0.9 +/- 0.09%. The intrathecal administration of alpha-2 agonists resulted in a rapid decrease in resting blood pressure and heart rate with the magnitude of hypotension being as follows: dexmedetomidine greater than clonidine greater than ST-91. These data suggest a potent spinal alpha-2-receptor-mediated modulation of somatomotor and autonomic responses to pain. (+info)
Antinociceptive interaction between opioids and medetomidine: systemic additivity and spinal synergy.
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The antinociceptive interaction on the tail flick (TF) and hot plate (HP) tests between opioid analgesics and medetomidine after intravenous (iv) or intrathecal administration were examined by isobolographic analysis. Male Sprague-Dawley rats received fixed ratios of medetomidine to morphine, fentanyl, and meperidine of 1:10 and 1:30, 10:1, and 1:3, respectively, by iv administration or 10:1, 3:1 and 10:1, and 1:3 by intrathecal administration, respectively. Data were expressed as the percentage maximal possible effect (%MPE). The A50 (dose producing 50% MPE) for each drug or drug combination was determined from the dose-response curve. Isobolographic analysis revealed that the effect of medetomidine combined with fentanyl, morphine, or meperidine was additive after iv administration. The intrathecal administration of combinations of medetomidine with the opioids produced a synergistic antinociceptive effect in the TF but not HP test. These data confirmed that the interaction between medetomidine and opioids in producing antinociception may be additive or synergistic, depending on the route of administration, drug ratio administered, and level of processing of the nociceptive input (i.e., spinal vs. supraspinal). Moreover, these results were consistent with a spinal role for alpha-2 adrenoceptors in mediating antinociception. The authors suggest that the interaction between the opioid and alpha-2 adrenergic receptors occurs within the spinal cord. (+info)
Diuretic effects of medetomidine compared with xylazine in healthy dogs.
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This study aimed to investigate and compare the effects of medetomidine and xylazine on diuretic and hormonal variables in healthy dogs. Five dogs, used in each of 11 groups, were injected intramuscularly with physiological saline solution (control), 5, 10, 20, 40, and 80 microg/kg of medetomidine, and 0.25, 0.5, 1, 2, and 4 mg/kg of xylazine. Urine and blood samples were taken 11 times over 24 h. Both medetomidine and xylazine increased urine production in a dose-dependent manner up to 4 h after injection, but the increase was much less with medetomidine than with xylazine at the tested doses. Urine specific gravity, pH, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and arginine vasopressin (AVP) were decreased in a dose-dependent manner with both medetomidine and xylazine. Plasma osmolality and concentrations of sodium, potassium, and chloride were increased significantly with both drugs. Total amounts of urine AVP excreted and plasma AVP concentrations were significantly decreased by higher doses of medetomidine but were not significantly decreased by xylazine. Higher doses of both drugs significantly increased the plasma concentration of atrial natriuretic peptide (ANP), but the effect was greater with medetomidine than with xylazine. The results revealed that both drugs induce a profound diuresis, but medetomidine's effect is less dose-dependent than xylazine's effect. Although changes in plasma concentrations of AVP and ANP may partially influence the diuresis induced by medetomidine, other factors may be involved in the mechanism of the diuretic response to both drugs. Thus, both agents can be used clinically for transient but effective diuresis accompanied by sedation. (+info)
Antagonistic effects of atipamezole and yohimbine on medetomidine-induced diuresis in healthy dogs.
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This study aimed to investigate and compare the antagonistic effects of atipamezole and yohimbine on medetomidine-induced diuresis in healthy dogs. Five dogs were used repeatedly in each of 8 groups. One group was not medicated. Dogs in the other groups received 20 microg/kg of medetomidine intramuscularly and, 0.5 h later, saline (as the control injection), 50, 100, or 300 microg/kg of atipamezole, or 50, 100, or 300 microg/kg of yohimbine intramuscularly. Urine and blood samples were taken 11 times over 24 h for measurement of the following: urine volume, specific gravity, and creatinine concentration; urine and plasma osmolality; urine and plasma concentrations of electrolytes and arginine vasopressin (AVP); and the plasma concentration of atrial natriuretic peptide (ANP). Both atipamezole and yohimbine antagonized the diuretic effect of medetomidine, inhibiting medetomidine-induced decreases in urine specific gravity, osmolality, and concentrations of creatinine, sodium, potassium, chloride, and AVP and reversing both the medetomidine-induced increase in plasma concentrations of sodium, potassium, and chloride and the medetomidine-induced decrease in the plasma AVP concentration. Atipamezole significantly stimulated ANP release. The antidiuretic action of yohimbine was more potent than that of atipamezole but was not dose-dependent, in contrast to the action of atipamezole. The effects of these drugs may not be due only to actions mediated by alpha(2)-adrenoceptors. (+info)