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Biomedical subjects

C Zhang

Publications and source records attributed to C Zhang.

At least 541 records · Page 30Linked to original sources
PubMed1996

Enhanced tumor suppressor gene therapy via replication-deficient adenovirus vectors expressing an N-terminal truncated retinoblastoma protein.

The preclinical studies presented here demonstrate that treatment of human non-small cell lung carcinoma and bladder carcinoma cells by a recombinant adenovirus vector, AdCMVpRB94, expressing the N-terminal truncated retinoblastoma (RB) protein (pRB94) completely suppressed the tumorigenicity of the treated tumor cells in nude mice. Furthermore, gene therapy of established human RB- and RB+ bladder xenograft cancers in nude mice by AdCMVpRB94 resulted in regression of the treated tumors. Of note, although both the full-length and the truncated forms of the RB protein, when overexpressed in tumor cells via replication-deficient adenovirus vectors, were capable of suppression of tumor growth, the pRB94 was evidently more potent than the full-length RB protein.

Adenoviruses, Human↗
PubMed1996

Long-term depression of a sympathetic ganglionic response to opioids by prolonged synaptic activity and by phorbol esters.

We studied the effect of the adenylate cyclase activator forskolin, of protein kinase C-activating phorbol esters and of prolonged preganglionic input activation on the inhibitory response of the perfused superior cervical ganglion of the cat to exogenous met-enkephalin (Met-ENK). Met-ENK inhibited, in a concentration-dependent manner, the postganglionic compound action potential evoked by cervical sympathetic trunk stimulation. The inhibition was reversible, was blocked by naloxone as well as by pertussis toxin and showed no homologous desensitization in the concentration range 0.01-10 microM. Pretreatment of the ganglion with 4 beta-phorbol 12,13-dibutyrate or 4 beta-phorbol 12,13-diacetate depressed the Met-ENK response for several hours, while pretreatment with forskolin had no effect. This action of phorbol esters was prevented by the protein kinase inhibitor H-7 but not by the calmodulin antagonist W-7 or the protein kinase A inhibitor HA 1004 and was calcium-dependent. Recovery of the response from the depression produced by phorbol esters was not affected by a protein synthesis inhibitor. A 40 Hz 20 min stimulus train to the cervical sympathetic trunk mimicked the effect of phorbol esters, depressing for several hours the inhibition produced by Met-ENK. Stimulus trains of duration shorter than 5 min or frequency lower than 5 Hz were ineffective. This effect of prolonged preganglionic stimulation occurred even when the stimulus train was delivered during complete block of nicotinic and muscarinic ganglionic transmission but was lost when the stimulus train was delivered during perfusion with calcium-free Krebs. The protein kinase inhibitor H-7 prevented the depression of the Met-ENK response by the train, while W-7 and HA 1004 had no effect. These findings suggest that, in the superior cervical ganglion of the cat, a kinase, activated by phorbol esters and inhibited by H-7, exerts a long-term control of the ganglion cell responsiveness to opiate receptor activation. A similar mechanism can be synaptically activated by a non-cholinergic transmitter, released by the preganglionic axons during prolonged, high frequency, activity.

Action Potentials↗
PubMed1996

Genetic alterations on chromosomes 3 and 9 of esophageal cancer tissues from China.

In previous studies, we had demonstrated that allelic losses in esophageal cancer (EC) tissues are frequently involved in chromosomes 3 and 9 and that EC patients and their blood relatives have low capacity to repair damaged DNA and showed genetic instability. To better define the deleted chromosomal loci and understand the genetic instability in EC tissues, we selected 12 microsatellite markers (D3S1232, D3S1238, D3S1289, D3S1480, D3S647, D3S966, D3S1317, D3S659, D9S156, D9S171, D9S176 and GSN) to examine 36 paired EC tissues for loss of heterozygosity (LOH) and microsatellite instability (MIN) on chromosomes 3 and 9. The frequent LOH was found at D9S156(9p21), D3S647(3p23) and D3S1480(3p14.2), implying the possible existence of tumor suppressor genes near the deleted loci. Higher LOH incidence at D9S156 (9/18) and D3S1480 (8/19) was observed in EC tissues from Beijing, a low EC area. More frequent LOH at D3S647 (6/14) was found in EC tissues from Yangquan, a high EC area. This geographic difference of LOH occurrence was indicative of genetic heterogeneity in the etiology of EC. 24 of 36 (66.7%) EC tissues showed MIN at one or more chromosomal loci. The putative EC suppressor genes on chromosomes 3 and 9 and the molecular basis of the genetic instability associated with EC remain to be elucidated.

Alleles↗
PubMed1996

Activation of a high affinity Gi protein-coupled plasma membrane receptor by sphingosine-1-phosphate.

Sphingosine-1-phosphate (SPP) has attracted much attention as a possible second messenger controlling cell proliferation and motility and as an intracellular Ca(2+)-releasing agent. Here, we present evidence that SPP activates a G protein-coupled receptor in the plasma membrane of various cells, leading to increase in cytoplasmic Ca2+ concentration ([Ca2+]i), inhibition of adenylyl cyclase, and opening of G protein-regulated potassium channels. In human enbryonic kidney (HEK) cells, SPP potently (EC50, 2 nM) and rapidly increased [Ca2+]i in a pertussis toxin-sensitive manner. Pertussis toxin-sensitive increase in [Ca2+]i was also observed with sphingosylphosphorylcholine (EC50, 460 nM), whereas other sphingolipids, including ceramide-1-phosphate, N-palmitoyl-sphingosine, psychosine, and D-erythro-sphingosine at micromolar concentrations did not or only marginally increased [Ca2+]i. Furthermore, SPP inhibited forskolin-stimulated cAMP accumulation in HEK cells and increased binding of guanosine 5'3-O-(thio) triphosphate to HEK cell membranes. Rapid [Ca2+]i responses were also observed in human transitional bladder carcinoma (J82) cells, monkey COS-1 cells, mouse NIH 3T3 cells, Chinese hamster ovary (CHO-K1) cells, and rat C6 glioma cells, whereas human HL-60 leukemia cells and human erythroleukemia cells failed to respond to SPP. In guinea pig atrial myocytes, SPP activated Gi protein-regulated inwardly rectifying potassium channels. Activation of these channels occurred strictly when SPP was applied at the extracellular face of atrial myocyte plasma membrane as measured in cell-attached and inside-out patch clamp current recordings. We conclude that SPP, in addition to its proposed direct action on intracellular Ca2+ stores, interacts with a high affinity Gi protein-coupled receptor in the plasma membrane of apparently many different cell types.

3T3 Cells↗
PubMed1996

BMP-like signals are required after the midblastula transition for blood cell development.

We have investigated the process by which the primitive erythroid cells develop during early vertebrate embryogenesis. Cultured Xenopus animal cap (AC) cells transiently activate the transcription of blood cell regulatory genes GATA-1 and GATA-2 but fail to commit stably to the blood lineage. By contrast, cells of the presumptive ventral marginal zone (VMZ), are committed by the midblastula transition (MBT) to express fully on erythroid program. Growth factor BMP-4, a member of the TGF-beta family of signaling molecules, has been implicated in the process of ventral mesoderm patterning. We show that expression of BMP-4 after MBT is sufficient to induce the blood program fully in AC cells. This includes high level expression of the blood markers SCL and globin, which are not activated in AC cells from uninjected embryos. Likewise, expression of a dominant negative receptor after MBT results in relatively normal embryos, which, however, completely lack differentiated blood cells. Our results are consistent with a role for BMP or BMP-like signaling during gastrulation in the differentiation of embryonic blood.

Animals↗
PubMed1996

A role for Rho in receptor- and G protein-stimulated phospholipase C. Reduction in phosphatidylinositol 4,5-bisphosphate by Clostridium difficile toxin B.

Receptors coupled to heterotrimeric guanine nucleotide-binding proteins (G proteins) activate phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2)-hydrolyzing phospholipase C (PLC) enzymes by activated alpha of free beta gamma subunits of the relevant G proteins. To study whether low molecular weight G proteins of the Rho family are involved in receptor signaling to PLC, we examined the effect of Clostridium difficile toxin B, which glucosylates and thereby inactivates Rho proteins, on the regulation of PLC activity in human embryonic kidney (HEK) cells stably expressing the m3 muscarinic acetylcholine receptor (mAChR) subtype. Toxin B treatment of HEK cells did not affect basal PLC activity, but potently and efficiently inhibited mAChR-stimulated inositol phosphate formation. PLC activation by the endogenously expressed thrombin receptor and by the direct G protein activators, A1F-4 and guanosine 5'-[gamma-thio]triphosphate (GTP gamma S), studied in intact and permeabilized cells, respectively, were also inhibited by toxin B treatment. C3 exoenzyme, which ADP-ribosylates Rho proteins, mimicked the inhibitory effect of toxin B on GTP gamma S-stimulated PLC activity. Finally both toxin B and C3 exoenzyme significantly reduced, by 40 to 50%, the total level of PtdIns(4,5)P2 in HEK cells, without affecting the levels of phosphatidylinositol and phosphatidylinositol 4-phosphate. Accordingly, When PLC activity was measured with exogenous PtdIns(4,5)P2 as enzyme substrate, Ca(2+)- as well as GTP gamma S- or A1F-4-stimulated PLC activities were not altered by prior toxin B treatment. In conclusion, evidence is provided that toxin B and C3 exoenzyme, apparently by inactivating Rho proteins, inhibit G protein-coupled receptor signalling to PLC, most likely by reducing the cellular substrate supply.

ADP Ribose Transferases↗
PubMed1996

Muscarinic acetylcholine receptor trafficking in streptolysin O-permeabilized MDCK cells.

We investigated the validity of streptolysin O (SLO)-permeabilized Madin-Darbin canine kidney (MDCK) cells which express muscarinic acetylcholine receptors (mAChRs) coupled to pertussis toxin-sensitive guanine nucleotide-binding proteins (G proteins) for the study of the molecular machinery that regulated mAChR internalization and recycling. Exposure of SLO-permeabilized cells to carbachol-reduced cell surface receptor number by up to 40% without changing total receptor number. The kinetics and maximal extent of receptor internalization as well as the potency of carbachol to induce receptor internalization were almost identical in SLO-permeabilized and non-permeabilized cells. Using this semi-intact cell system, we studied the effect of various agents affecting components potentially involved in receptor trafficking. Internalization was prevented by treatment of the SLO-permeabilized MDCK cells with (i) the stable ATP analogues, adenosine 5'-O-(3-thiotriphosphate) and adenylylimidodiphosphate, to block ATP-dependent processes, and (ii) heparin to block G protein-coupled receptor kinases. Inclusion of the stable GTP analogue, guanosine 5'-O-(3-thiotriphosphate), increased the rate but not the extent of receptor internalization. None of the membrane-impermeant agents affected receptor internalization in intact MDCK cells. This model system also allowed recycling of internalized receptors back to the plasma membrane. After removal of the agonist, cell surface receptor number in SLO-permeabilized cells returned to control values within 90 min with the same kinetics as seen in intact cells. Inclusion of guanosine 5'O-(3-thiotriphosphate) shortened the recovery time. These data suggest that both ATP-dependent kinases including G protein-coupled receptor kinases and G proteins participate in receptor internalization and recycling. In summary, the SLO-permeabilized MDCK cell is a feasible model system for the study of mAChR internalization and recycling and allows manipulation of the intracellular milieu with membrane-impermeable macromolecules.

Adenosine Triphosphate↗
PubMed1996

AG2034: a novel inhibitor of glycinamide ribonucleotide formyltransferase.

The glycinamide ribonucleotide formyltransferase (GARFT) inhibitor, 4-[2-(2-amino-4-oxo-4,6,7,8-tetrahydro-3H-pyrimidino[5,4-6] [1,4]thiazin-6-yl)-(S)-ethyl]-2,5-thienoyl-L-glutamic acid (AG2034), was designed from the X-ray structure of the GARFT domain of the human tri functional enzyme. AG2034 inhibits human GARFT (Ki = 28 nM), has a high affinity for the folate receptor (Kd = 0.0042 nM), and is a substrate for rat liver folylpolyglutamate synthetase (K(m) = 6.4 microM, Vmax = 0.48 nmole/hr/mg). The IC50 for growth inhibition was 4 nM against L1210 cells and 2.9 nM for CCRF-CEM cells in culture. In vitro growth inhibition can be reversed by addition of either hypoxanthine or AICA (5-aminoimidazole-4-carboxamide) to the culture medium. A cell line with impaired transport of reduced folates, L1210/C1920, was resistant to AG2034 indicating that this compound can enter cells by utilizing the reduced folate carrier. AG2034 showed in vivo antitumor activity against the 6C3HED, C3HBA, and B-16 murine tumors and in the HxGC3, KM20L2, LX-1, and H460 human xenograft models, and has been selected for preclinical development towards clinical trials.

Acyltransferases↗
PubMed1996

Effect of temperature and yeast extract on microbial respiration of sediments from a shallow coastal subsurface and vadose zone.

As a part of our study on microbial heterogeneity in subsurface environments, we have examined the microbial respiration of sediment samples obtained from a coastal site near Oyster, VA. The sediments at the site are unconsolidated, fine to coarse beach sand and gravel. A Columbus Instruments Micro-Oxymax Respirometer was used to measure the rate of carbon dioxide (CO2) production during the respiration of the sediment samples. The rate of respiration of the sediment samples ranged from 0.035-0.6 microL CO2/h/g of the sediment. The sediment samples showing maximum (0.6 microL CO2/h/g) and minimum (0.035 microL CO2/h/g) production of CO2 were selected to study the effect of micronutrient-yeast extract (0.5 and 1.0 micrograms/g of the sediment) and water (0.5 and 1.0 mL) on the rate of CO2 production. The rate of CO2 production increased with the addition of water, but increased approx 2 orders of magnitude (from 0.26 to an average of 23.5 microL CO2/h/g) when 1.0 g/g yeast extract was added to the sediment samples. In these coastal sediments, temperature, depth, and addition of water influenced microbial activity, but the addition of 1.0 microgram/g yeast extract as a micronutrient rapidly increased the rate of CO2 production 2 orders of magnitude.

Biotechnology↗
PubMed1996

Spatial projections to the olfactory bulb of functionally distinct and randomly distributed primary neurons in salmonid fishes.

In fish, olfactory sensory neurons expressing specific odorant receptors are randomly distributed throughout the olfactory epithelium, and, yet, these subsets of olfactory neurons segregate as they enter the olfactory bulb and project to restricted regions. We investigated the functional significance of this projection pattern by recording electroencephalographic responses (EEGs) from the olfactory bulb, while simultaneously monitoring electro-olfactograms (EOGs) in response to two distinct odorant groups, amino acids (AA) and a bile acid, taurocholic acid (TCA), in Atlantic salmon (Salmo salar) and rainbow trout (Oncorhynchus mykiss). EEGs to AA and TCA distributed in two segregated regions, lateroposterior and mid olfactory bulb. When olfactory rosettes were subjected to partial lamellectomy (removal of the anterior, posterior, medial, or lateral half), both EOGs and EEGs to these odorants were uniformly reduced, and the degree of reduction was not dependent on the rosette region removed. These results indicate that the entire rosette contributes to the generation of EOGs, leading to transmission to the bulb. We conclude that in salmonid fishes olfactory neurons responsive to AA and TCA are randomly distributed throughout the olfactory epithelium, and yet project to spatially segregated regions and thereby generated signals are encoded independently in the bulb.

Amino Acids↗
PubMed1996

Anesthesia during hormone administration abolishes the estrogen induction of preproenkephalin mRNA in ventromedial hypothalamus of female rats.

Estrogen treatment increases preproenkephalin (PPE) mRNA levels in the ventromedial nucleus of the hypothalamus (VMH). Roy et al. (Brain Res., 337 (1985) 163-166) discovered that anesthesia during estrogen priming could reduce female rat sexual receptivity. In the present study we tested whether the action of estrogen to induce PPE gene expression in the VMH could be similarly affected by anesthesia. By quantitative in situ hybridization and slot-blot analysis techniques we found a 1.8-fold increase in PPE mRNA levels in the VMH after 1 hour of estrogen treatment in ovariectomized (OVX) Sprague-Dawley female rats. Anesthetizing the rats with pentobarbital for 1 h during the exposure to estrogen blocked the estrogen induction of PPE mRNA in the VMH. By way of contrast no changes in the PPE mRNA levels were observed in the caudate putamen. A similar trend was seen using chloral hydrate. It appears that neuronal activity is required for the early phase of estrogen induction of PPE mRNA levels in the VMH. This in turn could be correlated with changes in female sociosexual behaviors.

Anesthesia, General↗
PubMed1996

Sequential mediation of norepinephrine-and dopamine-induced antinociception at the spinal level: involvement of different local neuroactive substances.

The effects of intrathecally (i.t.) administered opioid antagonist naloxone (Nal), adenosine antagonist aminophylline (Aph), and gamma-aminobutyric acid (GABAA)-receptor antagonist picrotoxin (PTX) or Bicuculline (BIC) on the antinociception produced by i.t. norepinephrine (NE), dopamine (DA), morphine (Mor), 5'-N-ethylcarboxamidoadenosine (NECA, an adenosine agonist) or muscimol (MUS, a selective GABAA-receptor agonist) were studied and compared using the tail-flick test in rats. The results showed that: (1) both i.t. NE (0.3, 0.5 and 1.0 nmol) and DA (5.5, 8.3 and 16.5 nmol) produced significant and dose-dependent increases in tail-flick latencies (antinociception); (2) both Nal (240 nmol) and Aph (120 nmol) blocked the antinociception produced by NE (1.0 nmol); (3) both Nal (240 nmol) and Aph (120 nmol) blocked the antinociception produced by Mor (0.5 nmol), but only Aph (120 nmol) blocked the antinociception produced by NECA (0.5 nmol), while Nal (240 nmol) did not; (4) neither Nal (240 nmol) nor Aph (120 nmol) altered the antinociception produced by DA (16.5 nmol); (5) both i.t. PTX (1.5 nmol) and BIC (0.5 nmol) completely blocked the antinociception produced by DA (16.5 nmol), but showed no effects on that produced by NE (1.0 nmol); and (6) both PTX and BIC blocked the antinociception produced by MUS (1.0 nmol). These results suggest that: (a) endogenous opiate and adenosine may be involved in the mediation of NE-induced, but not DA-induced, antinociception; (b) NE, opioid and adenosine may act in a sequential order in NE-induced antinociception at the spinal level; (c) endogenous GABA may be involved in the mediation of DA-induced antinociception through the GABAA-receptors, but is not involved in NE-induced antinociception at the spinal level.

Animals↗
PubMed1996

Computational determination of side chain specificity for pockets in class I MHC molecules.

We show that a rapidly executable computational procedure provides the basis for a predictive understanding of antigenic peptide side chain specificity, for binding to class I major histocompatibility complex (MHC) molecules. The procedure consists of a combined search to identify the joint conformations of peptide side chains and side chains comprising the MHC pocket, followed by conformational selection, using a target function, based on solvation energies and modified electrostatic energies. The method was applied to the B pocket region of five MHC molecules, which were chosen to encompass the full range of specificities displayed by anchors at peptide position 2. These were a medium hydrophobic residue (Leu or Met) for HLA-A*0201, a basic residue (Arg or Lys) for HLA-B*2705; a small hydrophobic residue (Val) for HLA-A*6801, an acidic residue (Glu) for HLA-B*4001 and a bulky residue (Tyr) for H-2K(d). The observed anchors are correctly predicted in each case. The agreement for HLA-B40 and H-2K(d) is especially promising, since their structures have not yet been determined experimentally. Because the experimental determination of motifs by elution is difficult and these calculations take only hours on a high speed workstation, the results open the possibility of routine determination of motifs computationally.

Amino Acid Sequence↗
PubMed1996

The distribution and origin of keratin 20-containing taste buds in rat and human.

Sections of tissues containing lingual and extra-lingual taste buds were evaluated with monoclonal antibodies against cytokeratins. In the caudal third of the rat's tongue, keratin 20 immunoreactivity was restricted to taste buds, whereas keratins 7, 8, 18, and 19 were expressed in vallate and foliate taste buds and in cells of salivary ducts that merge with these taste epithelia. Hence, antibodies against keratin 20 most clearly distinguished differentiated taste cells from all other cells. In rat epiglottis, taste buds and isolated bipolar cells were keratin-20-positive. In rat nasopalatine papilla and palate, antibodies against keratin 20 identified Merkel cells, none of which was near to the keratin-20-negative taste buds. Nor were Merkel cells present at epiglottal taste buds or the keratin-20-negative fungiform taste buds or elsewhere in rat tongue. Hence, Merkel cells make no contribution to rat fungiform, epiglottal, nasopalatine, or palatal taste buds. Human and rat keratin-20-positive tissues are reported to be endodermal derivatives with the exception of Merkel cells and luminal urothelial cells. In rats the distribution of keratin-20-positive taste buds was in full agreement with the classical view that the posterior third of the tongue is derived from endoderm (keratin-20-positive taste buds), whereas the anterior two-thirds of the tongue is derived from stomadeal ectoderm (keratin-20-negative taste buds). The equally intense keratin 20 immunoreactivity of human fungiform and vallate taste buds violates this traditional rostro-caudal segregation and suggests that endodermally derived tissues may be present in the tip of the human tongue.

Adult↗
PubMed1996

The effects of pulsed Nd:YAG laser irradiation with fluoride on root surface.

This study evaluated the effects of pulsed Nd:YAG laser treatment on root surface in vitro with or without fluoride. Fifty specimens of human teeth were randomly assigned to five different treatment groups: (1) untreated group; (2) laser-treated only; (3) laser-treated after applying black ink; (4) laser-treated after applying 38% Ag(NH3)2F for 1 min; (5) laser-treated followed by applying 2% NaF for 4 min. Following their respective treatments, all specimens were prepared for evaluation by light microscopy, scanning electron microscopy, and EDX (Energy dispersive x-ray spectroscopy). Specimens from group 2 to 4 exhibited gross alterations of root surface not observed in controls such as pitting, crater formation, cracking, and porous globules. The specimens of group 5 had rough surfaces with some particles of approximately 1-micron diameter on the root surface. The fluoride uptake into the root measured by EDX was higher in groups 4 and 5. The depth of penetration of fluoride and silver was approximately 20 microns. Under light microscopy, the specimens of group 2, 3, 4, and 5 revealed some melted cementum, with no changes of underlying dentin. The results of this in vitro study suggested that the laser irradiation with or without fluoride, altered the morphology of the root surface and improved the fluoride uptake into the root surface. Whether the laser-induced surface changes with or without fluoride are beneficial to prevention of root surface caries needs to be studied further.

Cariostatic Agents↗
PubMed1996

Propofol induces dilation and inhibits constriction in guinea pig basilar arteries.

The present study investigated the direct action of propofol on guinea pig basilar arterial rings and the possible underlying mechanisms. Arterial rings, with and without endothelium, were mounted in an organ bath and connected to an isometric tension recording system. The effects of propofol (0.63-20 micrograms/mL) were compared with those of Intralipid (n = 13) after equilibration and precontraction by 5-hydroxytryptamine (5-HT). In another group (n = 8), after pretreatment with either propofol (5 micrograms/mL) or Intralipid, a contraction by 35 mM KCl was obtained and compared. Another group (n = 12) were incubated in Ca(2+)-free Krebs buffer and after depolarization by 45 mM KCl, a dose-response curve to CaCl2 was obtained to compare the effect of propofol (5 micrograms/mL) and Intralipid on the influx of Ca2+. Finally, in Ca(2+)-free Krebs buffer, the effect of Intralipid or propofol on 5-HT-evoked contractions (n = 6) were assessed. Propofol caused significant dilation with or without endothelium present, inhibited KCl-induced contraction, and significantly lowered the dose-response curve for CaCl2. In Ca(2+)-free Krebs buffer, propofol significantly inhibited 5-HT-evoked contraction, which is dependent on intracellular Ca(2+)-release. In conclusion, propofol inhibited vaso-constriction and induced vasodilation by mechanisms consistent with reduced extracellular calcium influx and suppressed intracellular calcium release.

Anesthetics↗
PubMed1996

Sympatholytic and minimum anesthetic concentration-sparing responses are preserved in rats rendered tolerant to the hypnotic and analgesic action of dexmedetomidine, a selective alpha(2)-adrenergic agonist.

BACKGROUND: The development of tolerance to the sympatholytic and anesthetic-reducing effects of alpha(2) agonists after prolonged administration of dexmedetomidine and how the number of available alpha(2) adrenoceptors affects these dexmedetomidine-induced responses was studied. METHODS: The sympatholytic action of acute and chronic (3 and 10 micrograms.kg-1.h-1 for 7 days) dexmedetomidine, was assessed by the decrease in norepinephrine turnover in the locus coeruleus and hippocampus. The anesthetic-reducing effect of chronic (7 days) dexmedetomidine (5 and 10 micrograms.kg-1.h-1) was studied by determining the minimum alveolar concentration (MAC) for halothane that prevented rats from responding to a supramaximal noxious stimulus of dexmedetomidine (10 or 30 micrograms.kg-1), doses in the steep part of the dose-response curve. The receptor reserve for the norepinephrine turnover and anesthetic-sparing responses to dexmedetomidine was delineated with 0.3-1.0 mg.kg-1 N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline, an irreversible alkylating agent. RESULTS: After chronic administration of dexmedetomidine at both doses, acute dexmedetomidine significantly decreased norepinephrine turnover in the hippocampus and locus coeruleus. The baseline minimum anesthetic concentration (MAC) and the MAC-sparing effect to acutely administered dexmedetomidine were preserved after chronic dexmedetomidine treatment. In the N-ethoxycarbonyl-2-ethoxy-1,2-dihydroquinoline experiments, the dexmedetomidine-induced norepinephrine turnover effect required less than 20% and greater than 4% alpha(2) adrenoceptor availability in the locus coeruleus and the dexmedetomidine induced MAC-sparing effect required less than 40% and greater than 20% alpha(2) adrenoceptor availability in the locus coeruleus. CONCLUSION: Tolerance does not develop for either the sympatholytic or MAC-sparing actions of dexmedetomidine, although it is present for the hypnotic response. The durable quality of the sympatholytic and MAC-sparing responses to dexmedetomidine after chronic treatment is explained by a comparatively larger receptor reserve than is needed for the hypnotic and analgesic responses, which are blunted by the same drug treatment regimen.

Adrenergic alpha-2 Receptor Agonists↗