Biomedical subjects

M Maze

Publications and source records attributed to M Maze.

At least 73 records · Page 4Linked to original sources

PubMed1992

Dexmedetomidine synergism with midazolam in the elevated plus-maze test in rats.

The anxiolytic profile of dexmedetomidine, a novel, highly-selective alpha 2-adrenergic agonist, was examined in rats in the elevated plus-maze test when administered either alone or in combination with the benzodiazepine agonist midazolam. Dexmedetomidine, 0.1-10 micrograms/kg, was inactive in modifying the rats' behavioral response in this test. Midazolam, 0.1-10 mg/kg, dose-dependently produced an anxiolytic-like profile characterized by an increased time spent in the open arms of the elevated plus-maze. A combination of dexmedetomidine 0.5 micrograms/kg and midazolam 0.5 mg/kg produced a synergistic interaction. This heterergic interaction of dexmedetomidine on midazolam's anxiolytic-like profile was dose-dependently blocked by pretreatment with an alpha 2-adrenergic antagonist, atipamezole, 10-50 micrograms/kg, and a benzodiazepine antagonist flumazenil, 1.0 and 10 mg/kg, but not by the alpha 1-adrenergic antagonist, prazosin, 0.1-10 mg/kg. While the transmembrane signal transduction pathways for benzodiazepine- and alpha 2-agonist responses do not share any molecular component, there does appear to be "crosstalk" between these two systems. These may involve GABA or noradrenergic "downstream" effects of either dexmedetomidine or midazolam, respectively.

Adrenergic alpha-Antagonists↗

PubMed1992

Activation of alpha-1 adrenergic receptors modulates the control of left/right sidedness in rat embryos.

Presomite stage rat embryos were cultured for 45-49 hr with medium containing various adrenergic agonists and antagonists. L-Norepinephrine but not D-norepinephrine (several orders of magnitude less potent than the L-isomer at alpha-1 adrenergic receptors) resulted in a dose-dependent increase of situs inversus similar to that found for phenylephrine, an alpha-1 adrenergic agonist. Prazosin, an alpha-1 adrenergic antagonist, inhibited phenylephrine-induced situs inversus in a dose-dependent manner. Neither dexmedetomidine, an alpha-2 adrenergic agonist, nor isoproterenol, a beta adrenergic agonist, caused situs inversus. These results provide pharmacological evidence that stimulation of alpha-1 but not of alpha-2 and beta adrenergic receptors modulates the control of left/right sidedness in rat embryos.

Adrenergic alpha-Agonists↗

PubMed1992

Pertussis toxin-mediated ribosylation of G proteins blocks the hypnotic response to an alpha 2-agonist in the locus coeruleus of the rat.

Biologic responses mediated by adrenoceptors are transduced by a receptor-effector mechanism that involves a guanine nucleotide binding protein (G protein). Recently, we determined that the transduction mechanism for the hypnotic response to dexmedetomidine, a highly selective alpha 2-agonist, is located in the locus coeruleus (LC) of the rat. In this study, we examined the role of pertussis toxin-sensitive (PTX) G proteins in the LC for the hypnotic response to dexmedetomidine. The LC of rats were stereotactically cannulated and treated with PTX, 0.34 micrograms, or vehicle. Five days later, the hypnotic response to dexmedetomidine, 7 micrograms into the LC or 50 micrograms.kg-1 IP, was tested. On the following day, the LC was harvested and assayed to determine whether the G proteins had been ribosylated by pretreatment with PTX in vivo. Quantitative immunoblotting of G0 alpha, Gi alpha 1,2, and Gi alpha 3, the alpha-subunit of three PTX-sensitive proteins, was also performed. In vivo treatment with PTX into the LC blocked the hypnotic response to LC-administered dexmedetomidine and, to a lesser extent, IP-administered dexmedetomidine. The in vivo PTX treatment effectively ribosylated the G proteins. No alteration in the amount of the different species of PTX-sensitive alpha-subunit was produced by in vivo PTX treatment. These data suggest a pivotal role for PTX-sensitive G proteins in the LC in the hypnotic response to alpha 2-agonists in the rat.

Adenosine Diphosphate↗

PubMed1992

Ventilatory effects of clonidine alone and in the presence of alfentanil, in human volunteers.

Clonidine, an alpha 2-adrenergic agonist, can potentiate opioid-induced analgesia. In a double-blind placebo-controlled study in human volunteers, we sought to determine whether clonidine also potentiates opioid-induced respiratory depression. Hypercapnic ventilatory responses (minute ventilation, mean inspiratory flow rate, and mouth occlusion pressure) were measured in five healthy male volunteers on two separate occasions (with or without clonidine, approximately 3.5 micrograms.kg-1 orally) under the following conditions: baseline, 2 h after clonidine/placebo (alfentanil concentration of 0), and during computer-controlled alfentanil infusions to approximate plasma concentrations of 5, 10, 20, 40, and 80 ng.ml-1. Plasma alfentanil concentrations were measured before and after each rebreathing test, and clonidine concentrations were measured after each rebreathing test. The end-tidal CO2 (PET(CO2)) was measured continuously. Data were analyzed by repeated-measures analysis of variance. The PET(CO2) and measured concentrations of alfentanil were included as covariates, and a compound symmetry error analysis was assumed. Statistical significance was achieved when P less than 0.05. For minute ventilation, mean inspiratory flow rate, and mouth occlusion pressure there was a statistically significant relationship to the covariates of PET(CO2) and plasma alfentanil concentration. Clonidine, when compared to placebo, caused a small but significant depression of mean inspiratory flow rate. There was similarly a small, but statistically insignificant, depression of minute ventilation by clonidine. The mouth occlusion pressure was not affected by clonidine treatment. Clonidine treatment did not potentiate alfentanil-induced respiratory depression. Although the combination of an opioid and an alpha 2-adrenergic agonist may act synergistically for the analgesic response, there is no synergistic effect by this drug combination on respiratory depression.

Adult↗

PubMed1992

A hypnotic response to dexmedetomidine, an alpha 2 agonist, is mediated in the locus coeruleus in rats.

Dexmedetomidine, the highly selective alpha 2-adrenergic agonist, produces a dose-dependent hypnotic response in rats through a central mechanism. Because the locus coeruleus (LC) contains pathways involved in the maintenance of vigilance and a high prevalence of alpha 2 adrenoceptors, we investigated the role of this brainstem nucleus in the hypnotic response to dexmedetomidine. The experimental model consisted of chronic, stereotactically cannulated rats (n = 157) in which the hypnotic response to dexmedetomidine was assessed by the duration of the loss of their righting reflex. Correct placement of the cannula was confirmed histologically at necropsy. The hypnotic response to dexmedetomidine 0.3-333.3 micrograms administered into the LC increased in a dose-dependent fashion. Dexmedetomidine 6.6 micrograms injected 2 mm lateral to the LC did not cause the animals to lose their righting response. Atipamezole 0.07 micrograms-12 micrograms, a selective alpha 2-adrenergic antagonist, blocked the hypnotic response to dexmedetomidine 6.6 micrograms when both were administered into the LC. Also, atipamezole 0.7-30 micrograms, administered into the LC, blocked in a dose-dependent manner the hypnotic response to intraperitoneal (ip) dexmedetomidine 50 micrograms.kg-1. Atipamezole injected into the LC did not block the hypnotic response to pentobarbital 40 mg.kg-1 ip. Prazosin, an alpha 1-adrenergic antagonist, 4.2 micrograms into the LC or 1.0 mg.kg-1 ip, did not alter the hypnotic response to dexmedetomidine 6.6 micrograms into the LC. The present data suggest that alpha 2-adrenergic receptors in the LC appear to be a major site for the hypnotic action of dexmedetomidine.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Synergistic interaction between alpha 2-adrenergic agonists and benzodiazepines in rats.

Both alpha 2-adrenergic agonists and benzodiazepines exert anxiolytic and sedative effects when administered as preoperative medications. Clinical effects achieved with a combination of drugs, representative of these classes of compounds, is greater than that which could be expected from a simple additive response. Therefore, we investigated the nature of the interaction between dexmedetomidine, the highly-selective alpha 2-adrenergic agonist, and midazolam in a series of in vivo and in vitro studies in rats. Rats were administered midazolam, dexmedetomidine, or a combination of midazolam and dexmedetomidine intravenously to derive three dose-response curves for loss of righting reflex (LRR). LRR was determined in rats in a rotating cage (4 rotations/min) by observing whether the rat failed to maintain its upright posture for greater than or equal to 15 s exactly 2.5 min after drug administration. The effect of either flumazenil (benzodiazepine receptor antagonist) or atipamezole (the alpha 2-adrenergic antagonist) on the LRR was also determined. A probit analysis was performed and an isobologram for the ED50 was derived to assess the nature of the interaction. Rat brain membranes were prepared for receptor binding assays using [3H]-flumazenil and [3H]-rauwolscine to characterize the benzodiazepine and alpha 2-adrenergic receptors, respectively. The ability of either midazolam or dexmedetomidine to displace the radiolabeled ligand from the alternative receptor was assessed. To detect a possible kinetic interaction between the two drugs, separate cohorts of rats were administered the two drugs individually or in combination at the combination ED50 doses.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenergic alpha-Agonists↗

PubMed1992

Effects of intravenous dexmedetomidine in humans. I. Sedation, ventilation, and metabolic rate.

Dexmedetomidine (DMED) is a highly selective centrally acting alpha 2-adrenergic agonist thought to provide significant sedation without appreciable ventilatory effects. This double-blind, placebo-controlled experiment evaluated four dose levels of DMED (0.25, 0.5, 1.0, and 2.0 micrograms/kg intravenously over 2 min) in 37 healthy male volunteers. Measurements of sedation, arterial blood gases, resting ventilation, hypercapnic ventilatory response (HVR), and metabolic rate (O2 consumption and CO2 production) were performed at baseline, 10 min after DMED infusion, and thereafter at the end of each subsequent 45-min period. DMED caused sedation resulting in loss of responsiveness in most of the subjects administered 1.0 and 2.0 micrograms/kg; sedation was evident for 195 min following 2.0 micrograms/kg (P < .05). Ten minutes following infusion of 1.0 and 2.0 micrograms/kg, PaCO2 had increased by 5.0 and 4.2 mmHg, respectively (P < .05), and 60 min following 2.0 micrograms/kg, VE had decreased by 28% (P < .05). The placebo group showed a progressive increase in the HVR slope (50% increase by 330 min following the infusion; P < .05). Overall, across all the DMED doses, the slope was decreased (P < .05) at all times after DMED. The calculated ventilation at a PaCO2 of 55 mmHg was decreased (39%; P < .05) 10 min following 1.0 and 2.0 micrograms/kg, returning to control values by 285 min following 2.0 micrograms/kg. O2 consumption increased 16% (P < .05) at 10 min following 2.0 micrograms/kg; CO2 production decreased (22% at 60 min). By 5 h postinfusion, both had returned to normal.(ABSTRACT TRUNCATED AT 250 WORDS)

Adolescent↗

PubMed1992

Effects of intravenous dexmedetomidine in humans. II. Hemodynamic changes.

Dexmedetomidine (DMED) is a novel clonidine-like compound known to have sedative, analgesic, and cardiovascular stabilizing qualities. DMED is a more highly selective alpha 2-adrenergic agonist than clonidine. This investigation examined the hemodynamic effects of four selected iv doses in consenting healthy male volunteers. In a randomized, double-blind, placebo-controlled trial subjects received 0 (n = 9), 0.25 (n = 6) 0.5 (n = 6), 1.0 (n = 6), or 2.0 (n = 10) micrograms/kg of DMED by infusion (2 min). ECG, heart rate (HR), arterial blood pressure (MABP), bioimpedance cardiac output (CO), and plasma catecholamines concentrations (CA) were monitored from 90 min before to 360 min after infusion. Plasma DMED concentrations were measured. DMED produced a maximum decrease in MABP at 60 min of 14%, 16%, 23%, and 27% for the 0.25, 0.5, 1.0, and 2.0 micrograms/kg groups, respectively (P < .05). At 330 min MABP remained below baseline by 8% and 17% at the two largest doses (P < .05). Both HR and CO decreased maximally by both 17% at 105 min. The two largest doses produced a transient (peak at 3 min lasting < 11 min) increased in MABP (16 +/- 2.5 and 24 +/- 10 mmHg, respectively; P < .05) with a concomitantly reduced CO (41%, 2 micrograms/kg; P < .05) and HR (22%, 2 micrograms/kg; P < .05), whereas systemic vascular resistance doubled. Even the lowest dose decreased CA immediately to values close to 20 pg/ml for 5 h. A 2-min iv infusion of DMED produced a transient increase in MABP and a longer lasting decrease in MABP and CA. These DMED doses were well tolerated in the healthy volunteers.

Adolescent↗

PubMed1992

Inhibition of adenylate cyclase in the locus coeruleus mediates the hypnotic response to an alpha 2 agonist in the rat.

Recently, we determined that the transduction mechanism for the hypnotic response to dexmedetomidine, a highly selective alpha 2 agonist, resides in the locus coeruleus (LC) of the rat. Candidates for the effector mechanism of this alpha 2 adrenoceptor-mediated hypnotic response include inhibition of adenylate cyclase, which has been shown to be pivotal to the cellular response of alpha 2 agonists in some, but not in all, cases. The LC of rats were stereotaxically cannulated with an indwelling catheter, and after the 2nd day, the hypnotic response to 7 micrograms of dexmedetomidine into the LC (an effective hypnotic dose for 95% of animals) was tested. Other groups of rats were pretreated with the permeable nonhydrolyzable cyclic AMP (cAMP) analog, dibutyryl cAMP (dB cAMP), at a dose of 0.2 to 1.2 ng into the LC, or 2.75 to 275 micrograms.kg-1 i.p. rolipram, a cAMP-specific phosphodiesterase inhibitor, and the hypnotic response to 7 micrograms of dexmedetomidine into the LC was tested. Both dB cAMP and rolipram reversed the hypnotic response to dexmedetomidine. To test for the specificity of these hypnotic-reversing perturbations, rats were pretreated with Rp-adenosine-3',5'-cyclic phosphorothioate, a cAMP-dependent protein kinase inhibitor, and the experiments were repeated. The hypnotic-reversing property of either dB cAMP or rolipram could be prevented by blocking cAMP-dependent protein kinase ("A" kinase) activity with Rp-adenosine-3',5'-cyclic phosphorothioate.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenylyl Cyclase Inhibitors↗

PubMed1991

The alpha 2-adrenoceptor agonist dexmedetomidine increases the apparent potency of the volatile anesthetic isoflurane in rats in vivo and in hippocampal slice in vitro.

Alpha 2-adrenoceptor agonists such as clonidine are sedatives and enhance the effectiveness of several different kinds of anesthetics. This study was performed to quantitate the effect of dexmedetomidine, a novel alpha 2-adrenoceptor agonist, on the action of the volatile anesthetic agent isoflurane in rats in vivo. A separate set of experiments in rat hippocampal slices was designed to determine whether isoflurane and dexmedetomidine exerted similar effects on synaptic transmission in vitro and to examine the interaction between the two agents. In vivo, dexmedetomidine (100 micrograms/kg i.p.) reduced isoflurane minimum alveolar anesthetic requirement (MAC), determined by loss of response to tail pinch, by approximately 90%. In hippocampal CA1 neurons, on the other hand, there was a relatively small potentiation of the effects of isoflurane at the maximally effective dexmedetomidine concentration (1 nM). The hippocampal CA1 area, at least in the slice preparation, may thus not be representative of the CNS site(s) at which alpha 2 adrenoceptor agonists lessen anesthetic requirement in vivo.

Adrenergic alpha-Agonists↗

PubMed1991

Alpha 2-adrenoceptors inhibit a nociceptive response in neonatal rat spinal cord.

Alpha 2-Adrenoceptors mediate analgesia in vivo. The present study explored the actions of the alpha 2-adrenoceptor agonists dexmedetomidine and clonidine on a nociceptive response in isolated neonatal rat spinal cord. Stimulation of a dorsal root generates a slow ventral root potential (slow VRP) at the corresponding ipsilateral ventral root. The slow VRP meets several criteria for a nociceptive response. Dexmedetomidine (10 nM) and clonidine (200 nM) depressed the slow VRP by approximately 80%. Dexmedetomidine's action was approximately linear over the concentration range 0.5-500 nM, whereas clonidine (20 nM-5 microM) exerted biphasic effects. The profile of agonist and antagonist effectiveness characterized the receptor(s) as alpha 2-adrenoceptors; the subtype could not be identified as either alpha 2A or alpha 2B. Naloxone pretreatment partially blocked dexmedetomidine's effect, suggesting a possible endogenous opiate involvement. Dexmedetomidine (0.5-2.0 nM) also depressed the VRP evoked by application of substance P to the cord, implicating postsynaptic as well as possible presynaptic actions. At high concentrations, dexmedetomidine (50-500 nM) depressed the monosynaptic reflex, probably through non-alpha 2-receptor(s). Results from the neonatal spinal cord correlate well with those from in vivo analgesia studies. They suggest an important direct spinal contribution to alpha 2-adrenoceptor-mediated analgesia.

Adrenergic alpha-Agonists↗

PubMed1991

Attenuation of central alpha 2 adrenergic action in diabetic rats.

Molecular components in transmembrane signaling may be dysfunctional in insulin-deficient states. To investigate whether the alpha 2 adrenergic receptor-effector mechanism is functionally altered by insulin deficiency, we determined the hypnotic response to dexmedetomidine [(+)4-[1-(2,3-dimethylphenyl)ethyl]-1H-imidazole, a highly-selective alpha 2 agonist, in streptozotocin-induced diabetic rats. The duration of the loss of righting reflex (sleep time) in response to dexmedetomidine, 0.25 mg.kg-1 IP, was measured in rats pretreated with streptozotocin, 50 mg.kg-1 IP. Dexmedetomidine sleep time was significantly shortened when tested 10 days (-25%), 3 (-29%), 6 (-35%) and 8 (-47%) weeks into the diabetic state. Supplementation of the diabetic rats with insulin normalized alpha 2 responsiveness. Acute hyperglycemia did not reduce dexmedetomidine-induced sleep time. Sleep time was also reduced when dexmedetomidine was administered via the intracerebroventricular (ICV) route at 4 (-21%) and 8 (-29%) weeks after streptozotocin. Thus the central nervous system response to the alpha 2 adrenergic agonist has become attenuated. The mechanism may involve a perturbation of an insulin-sensitive molecular component of the signal transduction pathway responsible for alpha 2 adrenoceptor-mediated anesthetic action.

Adrenergic alpha-Agonists↗

PubMed1991

A comparison of etomidate and thiopental anesthesia for cardioversion.

Sixteen ASA class II or III male patients (aged, 52 to 66 years) undergoing elective cardioversion were randomly assigned to receive either thiopental or etomidate according to an observer-blinded, parallel study design. The appropriate drug was administered in 2-mL aliquots every 15 seconds until the patient no longer responded to verbal commands, at which time cardioversion was attempted. The total dose for induction was 0.22 +/- 0.2 mg/kg and 3.2 +/- 0.4 mg/kg for etomidate and thiopental, respectively. The cardiorespiratory data after induction were evaluated for maximal percent change from baseline. The baseline heart rate was 106 +/- 6 beats/min and 98 +/- 8 beats/min for the etomidate and thiopental groups, respectively (mean +/- SEM). The heart rate decreased 5% after induction with etomidate and increased 7% with thiopental (P less than 0.05). The baseline mean arterial pressure (MAP) was 96 +/- 3 mm Hg and 105 +/- 11 mm Hg for the etomidate and thiopental groups, respectively (mean +/- SEM). The MAP decreased 4% with etomidate and 3% with thiopental. Respiratory rate was significantly increased by 22% after etomidate compared with a 22% decrease in respiratory rate with thiopental (P less than 0.05). Seven of eight patients in the thiopental group required only one countershock, whereas four of eight patients in the etomidate group required only one shock. One patient in each group could not be successfully cardioverted. Recovery time and clinical side effects were similar between groups except for mild myoclonus in the etomidate group. Titration to effect of either etomidate or thiopental provided satisfactory anesthesia for elective cardioversion in hemodynamically stable patients.(ABSTRACT TRUNCATED AT 250 WORDS)

Aged↗

PubMed1991

Clinical efficacy of oral-transdermal clonidine combinations during the perioperative period.

In an attempt to maintain stable levels of an alpha 2-adrenergic agonist throughout the perioperative period, two different oral-transdermal clonidine dosage regimens were administered according to a randomized, double-blind, placebo-controlled study in patients undergoing abdominal surgery. We determined the clinical efficacy of a high- and a low-dose clonidine regimen on sedation, hemodynamic parameters, anesthesia, and analgesia. The low-dose clonidine group of patients (n = 14) received a 7-cm2 clonidine transdermal patch (Catapres-TTS #2), which was supplemented with oral doses of clonidine approximately 3 micrograms.kg-1 on the evening prior to surgery and on the morning of surgery. The high-dose clonidine group (n = 14) received a 10.5-cm2 clonidine transdermal patch (Catapres-TTS #3) with oral clonidine approximately 4.5 micrograms.kg-1 at bedtime and 6.0 micrograms.kg-1 on the morning of surgery. Placebo-treated (control) patients received the same occlusive patch without active ingredient and oral placebo tablets at bedtime and on the morning of surgery. Preanesthetic medication included midazolam 50 micrograms.kg-1 intramuscularly (im). Anesthesia was induced with alfentanil 30 micrograms.kg-1 intravenously (iv), thiopental 3 mg.kg-1 iv, and vecuronium 0.1 mg.kg-1 iv, and was maintained with 70% nitrous oxide in oxygen and a continuous infusion of alfentanil 0.5 microgram.kg-1.min-1. Isoflurane was added when the blood pressure exceeded 110% of the patient's prestudy value. For pain relief postoperatively, the patients received morphine, 1-2-mg iv boluses, via a patient-controlled analgesia pump. The low-dose clonidine patient group had mean plasma clonidine concentrations that varied from 1.47 ng.ml-1 (preoperative) to 1.32 ng.ml-1 (postoperative day 2).(ABSTRACT TRUNCATED AT 250 WORDS)

Adjuvants, Anesthesia↗

PubMed1991

Dexmedetomidine prevents epinephrine-induced arrhythmias through stimulation of central alpha 2 adrenoceptors in halothane-anesthetized dogs.

Since alpha 2-adrenergic agonists have important effects on the adrenergic system that have recently been applied to the anesthetic setting, we investigated the effect of stimulation of alpha 2 adrenoceptors on epinephrine-induced arrhythmias in halothane-anesthetized dogs. The arrhythmogenic threshold for epinephrine was determined during halothane anesthesia in the presence of dexmedetomidine, a selective alpha 2 agonist, and L-medetomidine, a stereoisomer of medetomidine that lacks alpha 2-agonist activity. Dexmedetomidine increased the arrhythmogenic threshold for epinephrine in a dose-dependent manner during halothane anesthesia. At the highest dose of dexmedetomidine, 0.5 microgram.kg-1.min-1, there was a three-fold increase in both the arrhythmogenic dose of epinephrine and the plasma epinephrine concentration that was reached at this dose. On the other hand, L-medetomidine over the same dose range did not effect the arrhythmogenic dose of epinephrine. Atipamezole, a central alpha 2 antagonist that crossed the blood-brain barrier, blocked the antiarrhythmic action of dexmedetomidine. L-659,066 a peripheral alpha 2 antagonist that does not penetrate the blood-brain barrier, did not affect the antiarrhythmic action of dexmedetomidine. Thus, dexmedetomidine's antiarrhythmic effect on epinephrine-induced arrhythmias during halothane anesthesia appears to be mediated at least in part by stimulation of central alpha 2 adrenoceptors.

Adrenergic alpha-Agonists↗

PubMed1991

Central alpha 1-adrenoceptor stimulation functionally antagonizes the hypnotic response to dexmedetomidine, an alpha 2-adrenoceptor agonist.

Previously, we demonstrated that dexmedetomidine, an alpha 2 agonist, produces a hypnotic-anesthetic response in rats via activation of central alpha 2 adrenoceptors and that this response could be enhanced by the alpha 1 antagonist prazosin. In the current experiment we investigated whether central alpha 1 adrenoceptor stimulation antagonizes the alpha 2 adrenoceptor-mediated hypnotic response. Cirazoline, an alpha 1 adrenoceptor agonist that partitions into the central nervous system, attenuated dexmedetomidine's hypnotic response whether administered systemically (0.3-1 mg.kg-1 intraperitoneally [ip]) or centrally (0.1 mg.kg-1 intracerebroventricularly). Prazosin, an alpha 1 adrenoceptor antagonist that effectively crosses the blood-brain barrier, fully blocked cirazoline's attenuating effect on dexmedetomidine-induced hypnosis, whereas doxazosin, which partitions poorly into the brain, did not block cirazoline's effect. Administration of phenylephrine, 0.3-3 mg.kg-1 ip, an alpha 1 adrenoceptor agonist that does not penetrate into the brain, did not attenuate dexmedetomidine's hypnotic effect. These results indicate that central alpha 1-adrenoceptor stimulation functionally antagonizes the hypnotic response to an alpha 2-adrenoceptor agonist. These data underscore the important requirement for alpha 2 adrenoceptor selectivity if these agonists are to be useful in the anesthetic setting.

Adrenergic alpha-Agonists↗

PubMed1991

Isoflurane and an alpha 2-adrenoceptor agonist suppress nociceptive neurotransmission in neonatal rat spinal cord.

Analgesia is an important component of general anesthesia. alpha 2-adrenoceptor agonists such as clonidine and dexmedetomidine are effective analgesics at the spinal level, and furthermore, they reduce the volatile anesthetic requirement. In order to probe a possible spinal-level contribution to general anesthetic-induced analgesia, the effects of dexmedetomidine were tested in an isolated spinal cord preparation. The effects of dexmedetomidine were compared with those of isoflurane, and dexmedetomidine-isoflurane interactions were explored. The test response was a nociceptive-related slow ventral root potential (slow VRP) recorded from the isolated neonatal rat spinal cord in response to electrical stimulation of a dorsal root. At 0.2-1.28 vol%, isoflurane reversibly depressed the slow VRP. At a lower concentration (0.14 vol%), isoflurane increased the slow VRP in three of five preparations. At 1.0-1.28 vol%, isoflurane also depressed the monosynaptic reflex. Recovery on washout usually was to a level greater than control. The N-methyl-D-aspartate (NMDA) receptor antagonist (DL)-2-amino 5-phosphonovalerate (10 microM) prevented the rebound to levels above control on isoflurane washout. The earlier components of the slow VRP were more sensitive to isoflurane than were the later. Dexmedetomidine (0.5-10 nM) depressed the slow VRP and had no effect on the monosynaptic reflex. The slow VRP depends on both substance P and glutamate NMDA-receptor-mediated neurotransmission; isoflurance and dexmedetomidine depressed responses to both substance P and NMDA. Although the two agents depress responses to the same neurotransmitters, there is no evidence that they act at the same cellular site(s). There was no significant interaction between dexmedetomidine and isoflurane. The results suggest that isoflurane exerts marked inhibitory effects on spinal neurotransmission, depressing both substance P and glutamate-mediated pathways. There is a possible biphasic effect on the NMDA receptor. To the extent that nociception depends on these neurotransmitters, isoflurane may be expected to exert profound analgesic effects at the spinal level. By blocking responses to strongly arousing stimuli, these effects may contribute to general anesthesia. Suppression of nociceptive neurotransmission at the spinal level may contribute to dexmedetomidine's anesthetic-sparing properties as well as to analgesia by this agent.

Adrenergic alpha-Agonists↗

PubMed1991

Role of signal transduction in anesthetic action. Alpha 2 adrenergic agonists.

The molecular mechanism for general anesthetic action is not known. The alpha 2 adrenergic agonists represent a novel class of "anesthetic-like" agent because of their selectivity for receptor binding sites and because the transmembrane signaling systems mediating their biologic responses in non-CNS systems are known. We have begun to characterize the signal transduction pathway involved in the anesthetic-like action of the alpha 2 adrenergic agonists. The alpha 2 adrenergic agonists potently decrease both central noradrenergic neurotransmission and halothane anesthetic requirements (MAC). Since MAC is only reduced by 30-40% when noradrenergic neurotransmission is totally abolished and since the reduction in MAC with the highly selective alpha 2 adrenergic agonists exceeds 90%, factors in addition to noradrenergic neurotransmission must be contributing to the anesthetic action of the alpha 2 agonists. Studies with the superselective alpha 2 agonist dexmedetomidine confirmed this, as the alpha 2 agonist could still reduce the MAC for halothane in rats depleted of their central norepinephrine stores. The profound reduction in anesthetic requirements with dexmedetomidine raised the possibility that alpha 2 adrenergic agonists may be considered an anesthetic hypnotic agent by itself. This sole anesthetic hypnotic response was established together with the confirmation that a central alpha 2 adrenoceptor mediated this action. Subsequently, data using molecular biologic techniques suggested that the alpha 2 C4 isoreceptor was the probable receptor that mediated the anesthetic response. We further explored the postreceptor effector mechanism for the signal transduction pathway for alpha 2 anesthetic action and identified the participation of two other molecular components, namely, a pertussis-toxin-sensitive G protein and a 4-aminopyridine-sensitive ion channel. Whether the signal transduction pathway for alpha 2 anesthetic action mediates the further response to other non-alpha 2 anesthetic agents needs to be defined.

Adrenergic alpha-Agonists↗