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D G Lambert

Publications and source records attributed to D G Lambert.

At least 37 records · Page 2Linked to original sources
PubMed2001

Neuroprotective efficacy of AR-A008055, a clomethiazole analogue, in a global model of acute ischaemic stroke and its effect on ischaemia-induced glutamate and GABA efflux in vitro.

We have investigated the neuroprotective properties of AR-A008055 [(+/-)-1-(4-methyl-5-thiazolyl-1-phenyl-methylamine], a novel compound structurally related to clomethiazole. Administration (i.p.) of (+/-)-AR-A008055 60 min after 5 min of global cerebral ischaemia in gerbils produced a dose-dependent protection of the hippocampus from damage. Both enantiomers [(R)-(+)-AR-A008055 and (S)-(-)- AR-A008055] at 600 micromol/kg produced similar protection to that following clomethiazole (600& micromol/kg) and both produced similar and sustained neuroprotection, at 4, 7 and 21 days post-insult. When infused intravenously over a 2-h period, both enantiomers produced concentration-dependent neuroprotection, with the enantiomers providing similar protection at every plasma concentration (50-200 nmol/ml). The efficacy of (S)-(-)-AR-A008055 was similar to clomethiazole, but it was slightly less potent. Ischaemia-induced glutamate efflux from rat brain cortical prisms in vitro was inhibited by both isomers (100 microM). The inhibitory effect of (R)-(+)-AR-A008055 was blocked by bicuculline (10 microM) and picrotoxin (100 microM), while the effect of (S)-(-)-AR-A008055 was only antagonised by picrotoxin. This indicated that (S)-(-)-AR-A008055, like clomethiazole, is able to open the GABA(A)-chloride channel in the absence of endogenous GABA. (R)-(+)-AR-A008055 was more potent than (S)-(-)-AR-A008055 in enhancing the concentration of GABA in the medium following 30 min exposure of tissue to the ischaemic conditions, suggesting that it is an effective GABA uptake inhibitor. This action may explain both its effect on glutamate efflux in vitro and its neuroprotective effect in vivo.

Animals↗
PubMed2001

Orexin A and B evoke noradrenaline release from rat cerebrocortical slices.

1. Orexin A and B, recently identified in the rat hypothalamus are endogenous neuropeptide agonists for the G-protein coupled orexin-1 (OX1) and orexin-2 (OX2) receptors. 2. In the present study, we have examined the effects of orexin A, B and raised extracellular K(+) on noradrenaline release from the rat cerebrocortical slice. We have compared this with other sleep-wake-related (excitatory) neurotransmitters; dopamine, glutamate, serotonin and histamine. 3. Neurotransmitter release studies were performed in rat cerebrocortical slices incubated in modified Krebs buffer (with and without Ca(2+)+EGTA 1 mM) with various concentrations of orexin A, B and K(+) for various times. 4. Orexin A and B-evoked (10(-7) M) noradrenaline release was time-dependent reaching a maximum some 10 min after stimulation. K(+) (40 mM) evoked release was also time dependent but reached a maximum after 6 min. Orexin A, B and K(+) stimulation of release was concentration dependent with pEC(50) and E(max) (% of basal) values of 8.74+/-0.32 (1.8 nM) and 263+/-14% and 8.61+/-0.38 (2.4 nM) and 173+/-7% and 1.43+/-0.02 (37 mM) and 1430+/-70%, respectively. Orexin-evoked release was partially extracellular Ca(2+) dependent. 5. Of the other transmitters studied there was a weak orexin A and B stimulation of glutamate release. In contrast K(+) evoked dopamine, glutamate, histamine and serotonin release with pEC(50) and E(max) (% of basal) values of 1.47+/-0.05 (34 mM) and 3430+/-410%, 1.38+/-0.04 (42 mM) and 1240+/-50%, 1.47+/-0.02 (34 mM) and 480+/-10% and 1.40+/-0.05 (40 mM) and 560+/-60% respectively. 6. We conclude that the neuropeptides orexin A and B evoke noradrenaline release from rat cerebrocortical slices.

Animals↗
PubMed2001

Effects of nociceptin and endomorphin 1 on the electrically stimulated human vas deferens.

AIMS: To examine the effects of nociceptin (NC) and endomorphin 1 (EM1) on electrical field stimulation (EFS)-induced contractions of the human vas deferens (hVD). METHODS: Concentration-response curves to NC and EM1 were constructed in the absence and in presence of peptidase inhibitors (PI). In some experiments a NC receptor antagonist, [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 [F/G], 10 microM) or naloxone (1 microM) were included. RESULTS: All data are mean(95%CI). In the presence of PI, NC inhibited twitches (Emax = 67(44,90)%; pEC50 = 7.28(6.95,7.61)). NC inhibition was sensitive to [F/G]. EM1 also inhibited twitches both in the absence (Emax = 82(73,91)% pEC50 = 7.07(6.92,7.22)) and presence (Emax = 83(76,90)%; pEC50 = 7.00(6.91, 7.09)) of PI. EM1 inhibition was sensitive to naloxone. CONCLUSIONS: These data suggest that hVD express NC and opioid receptors that inhibit neurogenic contractions.

Analgesics, Opioid↗
PubMed2001

Bronchoconstrictive and relaxant effects of lidocaine on the airway in dogs.

OBJECTIVE: Intravenous lidocaine commonly is used to treat ventricular arrhythmias and to attenuate reflex airway constriction and intracranial pressure elevation during airway manipulation in intensive care units. There is much controversy as to the actions of lidocaine on the airway, so the aim of this study was to compare, in detail, the actions of lidocaine with those of bupivacaine and procaine on airway caliber and the associated changes in plasma catecholamine concentrations in the dog. DESIGN: Prospective, randomized, controlled experimental in vivo and in vitro study. SETTING: A university research laboratory. SUBJECTS: Mongrel dogs. INTERVENTIONS: In the first experiment, we evaluated the effects of intravenous local anesthetics--lidocaine 0-10 mg/kg (n = 7), bupivacaine 0-2.5 mg/kg (n = 7), or procaine 0-20 mg/kg (n = 7)--on basal airway tone. In second experiment, histamine (10 microg/kg + 500 microg x kg(-1) x hr(-1), n = 6), serotonin (10 microg/kg + 500 microg x kg(-1) x hr(-1), n = 7), and methacholine (0.5 microg/kg + 300 microg x kg(-1) x hr(-1), n = 7) were infused to determine the effects of lidocaine (0-10 mg/kg) on agonist-induced bronchoconstriction. In addition, the actions of lidocaine on vagal nerve stimulation were examined (n = 7). MEASUREMENTS AND MAIN RESULTS: Bronchial cross-sectional area at the third bronchial bifurcation of dogs was monitored continuously through a fiberoptic bronchoscope. In the first experiment, all local anesthetics produced a dose-dependent decrease in basal bronchial cross-sectional area. In the second experiment, lidocaine significantly potentiated histamine and serotonin-induced bronchoconstriction. In contrast, lidocaine antagonized methacholine- and vagal nerve stimulation-induced bronchoconstriction. CONCLUSION: We have clearly demonstrated that lidocaine may produce direct bronchoconstriction and worsen some agonist-induced bronchoconstriction, but it prevents reflex airway constriction. Therefore, we suggest that this agent be used with caution in asthmatics.

Anesthetics, Local↗
PubMed2000

Nociceptin/orphanin FQ inhibits ischaemia-induced glutamate efflux from rat cerebrocortical slices.

Nociceptin/orphanin FQ (NC), the endogenous ligand for the G-protein coupled nociceptin receptor (NCR), has a modulatory role in various physiological processes including neurotransmitter release. We have examined the effects of NC, the analogues NC(1-13)NH2 and [F/G]NC(1-13)NH2 and the competitive antagonist [Nphe1]NC(1-13)NH2 (Nphe1) on glutamate efflux during an acute simulated ischaemic challenge in rat cerebrocortical slices. The increase in glutamate efflux seen with ischaemia was inhibited by NC (EC50 250 nM). At micromolar concentrations, the analogues were found to have a similar effect on glutamate efflux compared to NC. In all cases, inhibition of glutamate efflux was abolished by Nphe1 (30 microM). These results suggest a neuroprotective action for NC.

Animals↗
PubMed2000

Barbiturates inhibit K(+)-evoked noradrenaline and dopamine release from rat striatal slices--involvement of voltage sensitive Ca(2+) channels.

The cellular target site(s) for anaesthetic action remain unclear. In rat striatal slices we have previously demonstrated that K(+)-evoked noradrenaline (NA) and dopamine (DA) release is mediated predominantly via P/Q-type voltage sensitive Ca(2+) channels (VSCC). Using this model of Ca(2+) dependent transmitter release we have evaluated the effects of anaesthetic and non-anaesthetic barbiturates. Rat brain striatal slices were incubated in the absence and presence of barbiturate for 10 min at 37 degrees C. The slices were then incubated for 6 min with 40 mM KCl. All anaesthetic barbiturates produced a concentration-dependent inhibition of K(+)-evoked NA and DA release. Non-anaesthetic barbiturate, barbituric acid was ineffective. The pIC(50) for NA and DA release (thiopental: 4.90+/-0.13 and 5.00+/-0.10, pentobarbital: 4.39+/-0.07 and 4.43+/-0.14, phenobarbital: 3.85+/-0.08 and 3.59+/-0.10, respectively) correlated with lipid solubility (NA: r(2)=0.999, DA: r(2)=0.987). We therefore suggest that barbiturates inhibit catecholamine release via an interaction with P/Q VSCC further implicating this channel in anaesthetic action.

Anesthetics↗
PubMed2000

Further studies on nociceptin-related peptides: discovery of a new chemical template with antagonist activity on the nociceptin receptor.

Three series of nociceptin (NC)-related peptides were synthesized and their abilities (i) to bind to the NC sites expressed in mouse forebrain membranes, (ii) to inhibit the electrically evoked contraction of the mouse vas deferens, and (iii) to inhibit forskolin-stimulated cAMP accumulation in Chinese hamster ovary cells expressing the human recombinant NC receptor (CHONCR) were investigated. The compounds of the first series (a series) have an ordinary Xaa1-Gly2 bond, those of the second series (b series) have a Xaa1psi(CH2-NH)Gly2 pseudopeptide bond, and those of the third series (c series) have a peptoid (Nxaa1-Gly2) structure. The affinity values measured in the binding assay and in the two functional assays with the compounds of the three series showed high levels of correlation. Thus, (I) the compounds of the a series in which Phe1 was substituted with Tyr, Cha, or Leu acted as potent NC receptor agonists; (II) the b series compounds behaved as NC receptor antagonists in the mouse vas deferens and as full agonists in CHO(NCR) cells with different potencies depending on the first amino acid residue, [Phe1psi(CH2-NH)Gly2]NC(1-17)NH2 and [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 being the most potent compounds; (III) the compounds of the third series were all inactive both as agonists and as antagonists with the exception of [Nphe1]NC(1-17)NH2 and [Nphe1]NC(1-13)NH2, which behaved as NC receptor antagonists both in the isolated tissue and in CHO(NCR) cells (pKB 6.1-6.4). In conclusion, this study demonstrates that chemical requirements for NC receptor agonists are different from those of antagonists. Moreover, modifications of the steric orientation of the aromatic residue Phe1 in the NC sequence as obtained with the pseudopeptide bond between Phe1 and Gly2 or with the displacement of the benzyl side chain by one atom, as in Nphe1, lead respectively to reduction or elimination of efficacy. Indeed, in contrast to [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2 which has been reported to exhibit agonist activity in several assays involving either central or recombinant NC receptors, [Nphe1]NC(1-13)NH2 antagonizes the effect of NC at human recombinant NC receptors and in the mouse tail withdrawal assay.

Animals↗
PubMed2000

Antagonistic effects of [Nphe1]nociceptin(1-13)NH2 on nociceptin receptor mediated inhibition of cAMP formation in Chinese hamster ovary cells stably expressing the recombinant human nociceptin receptor.

Nociceptin/orphanin FQ (NC) is the endogenous ligand for the nociceptin receptor (NCR) which is negatively coupled to adenylyl cyclase to inhibit the formation of cAMP. In this study we describe the inhibitory action of the novel NC analogue, [Nphe1]nociceptin(1-13)NH2 on cAMP formation in Chinese hamster ovary cells expressing the human NCR. NC, NC(1-13)NH2, the pseudopeptides [Phe1psi(CH2-NH)Gly2]NC(1-17)NH2 and [Phe1psi(CH2-NH)Gly2]NC(1-13)NH2, the hexapeptide, acetyl-Arg-Tyr-Tyr-Arg-Trp-Lys-NH2 and buprenorphine all produced a concentration dependent inhibition of forskolin stimulated cAMP formation. This inhibition was competitively reversed by [Nphe1]NC(1-13)NH2 with essentially identical pA2 values (6.12-6.48). [Nphe1]NC(1-13)NH2 showed per se a negligible residual agonist activity (alpha < 0.15).

Animals↗
PubMed2000

Effects of intravenous and local anesthetic agents on omega-conotoxin MVII(A) binding to rat cerebrocortex.

PURPOSE: The cellular target site(s) for anesthetic action remain controversial. In this study we have examined any interaction of i.v. anesthetics (thiopental, pentobarbital, ketamine, etomidate, propofol, alphaxalone), local anesthetics (lidocaine, prilocaine, procaine and tetracaine), and the non anesthetic barbiturate, barbituric acid with the omega-conotoxin MVII(A) binding site on N-type voltage sensitive Ca2+ channels in rat cerebrocortical membranes. METHODS: [125I] omega-conotoxin MVII(A) binding assays were performed in 0.5 ml volumes of Tris.HCl buffer containing BSA 0.1% for 30 min at 20 degrees C using fresh cerebrocortical membranes (5 microg of protein). Non-specific binding was defined in the presence of excess (10(-8) M) omega-conotoxin MVII(A). The interaction of i.v. (alphaxolone, etomidate, propofol, pentobarbitone, ketamine and thiopentone), local (lidocaine, prilocaine, procaine and tetracaine) anesthetics and barbituric acid was determined by displacement of [125I] omega-conotoxin MVII(A) (approximately 1 pM). RESULTS: The binding of [125I] omega-conotoxin was concentration-dependent and saturable with Bmax and Kd of 223 +/- 15 fmol/mg protein and 2.13 +/- 0.14 pM, respectively. Unlabelled omega-conotoxin MVII(A) displaced [125I] omega-conotoxin MVII(A) yielding a pKd of 11.04 +/- 0.04 (9.2 pM). All i.v. and local anesthetics at clinically relevant concentrations did not show any interaction with the omega-conotoxin MVII(A) binding site. CONCLUSION: The present study suggests that omega-conotoxin MVII(A) binding site on N-type voltage sensitive Ca2+ channels may not be a target for i.v. and local anesthetic agents.

Anesthetics, Intravenous↗
PubMed2000

In vitro characterization of J-113397, a non-peptide nociceptin/orphanin FQ receptor antagonist.

The lack of availability of a selective, highly potent, competitive antagonist for the nociceptin receptor (OP4) devoid of residual agonistic activity has hampered studies in this area. We report here the in vitro pharmacological properties of the novel non-peptide OP4 antagonist, J-113397, which was recently discovered by Banyu Pharmaceutical investigators. The compound was synthesized as a racemic mixture in our laboratories. J-113397 was shown to antagonize (pA2 7.52) the nociceptin-induced inhibition of cAMP formation in cells expressing the recombinant human OP4 receptor (CHOhOP4) and to displace [125I]Tyr14nociceptin from CHOhOP4 membranes with a pKi of 8.56. It also competitively antagonized the contractile actions of nociceptin in the mouse colon (pA2 8.07) and the inhibitory effect of nociceptin in electrically stimulated preparations such as the mouse vas deferens (pA2 7.85), the guinea pig ileum (7.75), and the rat vas deferens (7.77). At high concentrations (10 microM), the compound was devoid of agonist activity in the mouse vas deferens and CHOhOP4, while it contracted the mouse colon and increased the twitch response of the rat vas deferens, and produced a naloxone-sensitive inhibition of the electrically evoked twitches in the guinea pig ileum. pA2 values for the new antagonist against deltorphin I in the mouse vas deferens (OP1 receptors), or against dermorphin in the guinea pig ileum (OP3 receptors), etorphine in the rat vas deferens (OP receptors), U69593 in the rabbit vas deferens (OP2 receptors) and endomorphin 1 in the mouse colon (OP3 receptors) were lower than 6. Taken together, these data indicate that J-113397 is a high-affinity, selective and competitive antagonist of the OP4 receptor; this novel pharmacological tool will be of great value in studies directed at evaluating the physiological roles of the nociceptin/OP4 system.

Animals↗
PubMed2000

Cellular actions of nociceptin: transduction mechanisms.

The recent identification of the nociceptin receptor-nociceptin system and the description of its role in nociceptive processing has produced numerous investigative studies. A fundamental part of this research is to understand the cellular signaling events (i.e. the building blocks) upon which the pharmacology of this intriguing system is based. As anticipated, nociceptin receptor activation inhibits the formation of cAMP formation via a pertussis toxin-sensitive G-protein. This indicates that nociceptin receptor couples to the G(i)/G(o) class of G-protein(s). However, there is now growing evidence for nociceptin activation of additional signaling pathways, including MAP kinase and phospholipase C/[Ca(2+)](i). These signaling events are discussed in this review.

Adenylyl Cyclases↗
PubMed2000

Characterization of [Nphe(1)]nociceptin(1-13)NH(2), a new selective nociceptin receptor antagonist.

1.. Nociceptin (orphanin FQ) is a novel neuropeptide capable of inducing a variety of biological actions via activation of a specific G-protein coupled receptor. However, the lack of a selective nociceptin receptor antagonist has hampered our understanding of nociceptin actions and the role of this peptide in pathophysiological states. As part of a broader programme of research, geared to the identification and characterization of nociceptin receptor ligands, we report that the novel peptide [Nphe(1)]nociceptin(1-13)NH(2) acts as the first truly selective and competitive nociceptin receptor antagonist and is devoid of any residual agonist activity. 2. [Nphe(1)]nociceptin(1-13)NH(2) binds selectively to recombinant nociceptin receptors expressed in Chinese hamster ovary (CHO) cells (pK(i) 8.4) and competitively antagonizes the inhibitory effects of nociceptin (i) on cyclic AMP accumulation in CHO cells (pA(2) 6.0) and (ii) on electrically evoked contractions in isolated tissues of the mouse, rat and guinea-pig with pA(2) values ranging from 6.0 to 6.4. 3. [Nphe(1)]nociceptin(1-13)NH(2) is also active in vivo, where it prevents the pronociceptive and antimorphine actions of intracerebroventricularly applied nociceptin, measured in the mouse tail withdrawal assay. Moreover, [Nphe(1)]nociceptin(1-13)NH(2) produces per se a dose dependent, naloxone resistant antinociceptive action and, at relatively low doses, potentiates morphine-induced analgesia. 4. Collectively our data indicate that [Nphe(1)]nociceptin(1-13)NH(2), acting as a nociceptin receptor antagonist, may be the prototype of a new class of analgesics.

Analgesics, Opioid↗
PubMed2000

On the regulation of ischaemia-induced glutamate efflux from rat cortex by GABA; in vitro studies with GABA, clomethiazole and pentobarbitone.

Prisms of adult rat cortex were maintained in vitro in either aerobic conditions (control) or conditions simulating an acute ischaemic challenge (hypoxia with no added glucose). Endogenous glutamate efflux increased with time in ischaemic conditions, being 2.7 fold higher than control efflux at 45 min. Returning prisms to control solution after 20 min of simulated ischaemia resulted in glutamate efflux returning to near-control values. Endogenous GABA efflux in ischaemic conditions also increased, being 4.5 fold higher than control efflux at 45 min. Ischaemia-induced glutamate efflux was not accompanied by increased lactate dehydrogenase efflux and was unaltered by omitting calcium from the extra-cellular solution and adding EGTA (0.1 mM). Both GABA and the GABA-mimetic clomethiazole inhibited ischaemia-induced glutamate efflux, with IC(50) values of 26 and 24 microM respectively. The maximum inhibition by either drug was 60 - 70%. Bicuculline (10 microM) abolished the inhibitory effect of GABA (100 microM) but not clomethiazole (100 microM). Picrotoxin (100 microM) abolished the action of both GABA and clomethiazole. Pentobarbitone inhibited glutamate efflux at 100 - 300 microM (maximal inhibition: 39%). Bicuculline (10 microM) abolished this effect. These data suggest that ischaemia-induced glutamate efflux from rat cerebral cortex is calcium-independent and not due to cell damage up to 45 min. The inhibitory effect of GABA, clomethiazole and pentobarbitone on ischaemia-induced glutamate efflux appears to be mediated by GABA(A) receptors. The results suggest that clomethiazole, unlike pentobarbitone, is able to activate the GABAA receptor-linked chloride channel directly and not merely potentiate the effect of endogenous GABA.

Animals↗
PubMed2000

Endomorphin-1 induced desensitization and down-regulation of the recombinant mu-opioid receptor.

1. Endomorphin-1 (E1) is a peptide with high affinity and selectivity for the mu-opioid receptor. The aim of this study was to determine if endomorphin-1 caused desensitization and down-regulation of the mu-opioid receptor expressed in Chinese hamster ovary cells. 2. Following 10 microM E1 pre-treatment, desensitization was assessed by measuring cyclic AMP inhibition, down-regulation was assessed by [(3)H]-diprenorphine ([(3)H]-DPN) binding and immuno-blotting. 3. Pre-treatment of CHO mu cells with 10 microM E1 for 11 and 18 h caused significant reduction in cyclic AMP inhibition. (11 h=39.0+/-16.7%, 18 h 47.0+/-11.1% reduction). 4. At 18 h E1 pre-treatment there was an enhancement (4.5 fold) of cyclic AMP production under forskolin stimulated conditions accompanied by a small rightward shift in the concentration-response curve (pEC(50) control=7.8+/-0.3, pEC(50) E1=7.3+/-0.2) when cells were re-challenged with E1. 5. In membranes prepared from untreated and 0.5 h E1 pre-treated cells, addition of GTP gamma S produced a significant rightward shift in the concentration response curves for E1 displacement of [(3)H]-DPN (0 h K(i) control=7.86+/-0.11, GTP gamma S=7.37+/-0.15; 0.5 h K(i) control=7.92+/-0.12, GTP gamma S=7.36+/-0.08) This was not observed in membranes prepared from cells that had been treated with E1 for 18 h (18 h K(i) control=7.69+/-0. 11, GTP gamma S=7.75+/-0.08). 6. In whole cells E1 treatment caused a rapid loss of cell surface receptors such that at 0.5 h there was a 30.5+/-1.5 reduction (this was unchanged for 18 h). In crude membranes a loss of receptors was also observed using radioligand binding or immuno-blotting protocols. 7. These data show that E1 causes desensitization and down-regulation of the rat mu-opioid receptor expressed in CHO cells. However, these two responses appear temporally distinct.

Animals↗
PubMed2000

Interaction of local anaesthetics with recombinant mu, kappa, and delta-opioid receptors expressed in Chinese hamster ovary cells.

Local anaesthetics potentiate epidural or intrathecal opioid analgesia via a poorly defined mechanism. In this study, we have examined the interaction of local anaesthetics (lidocaine, bupivacaine and its optical isomers, tetracaine, procaine and prilocaine) with recombinant mu-, kappa-, and delta-opioid receptors expressed in Chinese hamster ovary cells (CHO-mu, kappa, and delta, respectively). Lidocaine produced a concentration-dependent displacement of radiolabelled opioid antagonist [3H]diprenorphine ([3H]DPN) binding with the following rank order of inhibitor constant (Ki): kappa (210 microM) > mu (552 microM) > delta (1810 microM). Procaine, prilocaine, tetracaine and bupivacaine also displaced [3H]DPN binding in CHO-mu with Ki values of 244, 204, 43 and 161 microM respectively. Lidocaine produced a concentration-dependent and naloxone-insensitive inhibition of cAMP formation in all cell lines including untransfected cells. Concentration producing 50% inhibition of maximum was mu, 1.32 mM; kappa, 2.41 mM; delta, 1.27 mM; untransfected, 2.78 mM. When lidocaine (300 microM) was co-incubated with spiradoline (kappa-selective) and [D-Ala2, MePhe4, Gly(ol)5] enkephalin (DAMGO mu-selective) in CHO-kappa and mu cells we did not observe an additive interaction for cAMP formation. In contrast, there was an apparent inhibitory action of the combination at the kappa receptor. This study suggests that clinical concentrations of local anaesthetics interact with mu and kappa but not delta opioid receptors. As there was no synergism between local anaesthetics and opioids we suggest that the interaction of these agents in the clinical setting does not occur at the cellular level.

Anesthetics, Local↗
PubMed2000

Inhibitory effects of intravenous anaesthetic agents on K+-evoked norepinephrine and dopamine release from rat striatal slices: possible involvement of P/Q-type voltage-sensitive Ca2+ channels.

The role of the voltage-sensitive Ca2+ channel (VSCC) as a target for anaesthetic action remains controversial. In this study we characterized the VSCC subtypes involved in K+-evoked norepinephrine and dopamine release from rat striatal slices and used this model system to examine the effects of a range of i.v. anaesthetics on release. Nifedipine (L-channel-selective), omega-conotoxin GVI(A) (N-channel-selective), omega-agatoxin IV(A) (P-channel-selective), omega-conotoxin MVIIc (P/Q-channel-selective) and Cd2+ (non-selective), along with alphaxalone, propofol and ketamine, were used in various combinations. Omega-Agatoxin IV(A), omega-conotoxin MVIIc and Cd2+ fully (100%) inhibited norepinephrine and dopamine release. Clinically achievable concentrations of alphaxalone inhibited norepinephrine and dopamine release, with concentrations producing 25 and 50% inhibition (IC25 and IC50) of the maximum of 2.1 and 7.8 microM respectively for norepinephrine and 2.9 and 7.2 microM for dopamine. The effects of propofol were observed at the top of the clinical range and those of ketamine exceeded this range. In addition, IC50 values for alphaxalone in the presence and absence of nifedipine and omega-conotoxin GVI(A) did not differ from the control. Our data suggest that clinically achievable concentrations of alphaxalone and propofol inhibit norepinephrine and dopamine release, which is mediated predominantly through P/Q-type VSCCs, suggesting a role for these channels in anaesthetic action.

Anesthetics, Intravenous↗
PubMed2000

Nimodipine premedication and induction dose of propofol.

UNLABELLED: Antagonists at the L-type voltage sensitive calcium channel (L-VSCC) potentiate anesthetic potency in experimental models, suggesting that it may be a target site for IV anesthetics. Nimodipine is a 1, 4-dihydro- pyridine antagonist of L-VSCC which crosses the blood-brain barrier. We tested the hypothesis that premedication with oral nimodipine in healthy patients would reduce the induction dose of propofol, independently of its effects on the cerebral circulation. Sixty ASA physical status I or II patients (18-60 yr), undergoing knee arthroscopy or minor urological surgery, were randomized to receive either nimodipine 60 mg or placebo, orally 1-2 h before induction. Noninvasive mean blood pressure, heart rate, and time-averaged mean velocity in the middle cerebral artery by using transcranial Doppler ultrasonography were obtained before and 5 min after the induction of anesthesia. Propofol 1% was administered by an infusion pump at a rate of 10 mL/min. Both groups of patients had a reduction in mean blood pressure after the induction (P < 0.01), but there were no significant differences between the groups. The induction dose of propofol was 2.19 mg/kg (95% confidence interval [CI]: 1.97-2.42) in the nimodipine group, compared with 2.16 mg/kg (95% CI 1.98-2.34) in the control group, P = 0.8. Time-averaged mean velocity remained unchanged after the induction of anesthesia in both patients receiving nimodipine premedication (51% CI 43-59 cm/s to 52% CI 46-58 cm/s, P = 0.6) and those receiving placebo (50% CI 43-58 cm/s to 53% CI 45-59 cm/s, P = 0.3). Premedication with oral nimodipine 60 mg does not reduce the induction dose of propofol compared with placebo, casting doubt on the hypothesis that propofol has an anesthetic action at L-VSCC. IMPLICATIONS: Premedication with oral nimodipine 60 mg does not reduce the induction dose of propofol compared with placebo, casting doubt on the hypothesis that propofol has an anesthetic action at L-type voltage sensitive calcium channels.

Adolescent↗