Dose-response effects of spinal neostigmine added to bupivacaine spinal anesthesia in volunteers. (1/445)

BACKGROUND: Intrathecal adjuncts often are used to enhance small-dose spinal bupivacaine for ambulatory anesthesia. Neostigmine is a novel spinal analgesic that could be a useful adjunct, but no data exist to assess the effects of neostigmine on small-dose bupivacaine spinal anesthesia. METHODS: Eighteen volunteers received two bupivacaine spinal anesthetics (7.5 mg) in a randomized, double-blinded, crossover design. Dextrose, 5% (1 ml), was added to one spinal infusion and 6.25, 12.5, or 50 microg neostigmine in dextrose, 5%, was added to the other spinal. Sensory block was assessed with pinprick; by the duration of tolerance to electric stimulation equivalent to surgical incision at the pubis, knee, and ankle; and by the duration of tolerance to thigh tourniquet. Motor block at the quadriceps was assessed with surface electromyography. Side effects (nausea, vomiting, pruritus, and sedation) were noted. Hemodynamic and respiratory parameters were recorded every 5 min. Dose-response relations were assessed with analysis of variance, paired t tests, or Spearman rank correlation. RESULTS: The addition of 50 microg neostigmine significantly increased the duration of sensory and motor block and the time until discharge criteria were achieved. The addition of neostigmine produced dose-dependent nausea (33-67%) and vomiting (17-50%). Neostigmine at these doses had no effect on hemodynamic or respiratory parameters. CONCLUSIONS: The addition of 50 microg neostigmine prolonged the duration of sensory and motor block. However, high incidences of side effects and delayed recovery from anesthesia with the addition of 6.25 to 50 microg neostigmine may limit the clinical use of these doses for outpatient spinal anesthesia.  (+info)

Molecular probes for muscarinic receptors: functionalized congeners of selective muscarinic antagonists. (2/445)

The muscarinic agonist oxotremorine and the tricyclic muscarinic antagonists pirenzepine and telenzepine have been derivatized using a functionalized congener approach for the purpose of synthesizing high affinity ligand probes that are suitable for conjugation with prosthetic groups, for receptor cross-linking, fluorescent and radioactive detection, etc. A novel fluorescent conjugate of TAC (telenzepine amine congener), an n-decylamino derivative of the m1-selective antagonist, with the fluorescent trisulfonated pyrene dye Cascade Blue may be useful for assaying the receptor as an alternative to radiotracers. In a rat m3 receptor mutant containing a single amino acid substitution in the sixth transmembrane domain (Asn507 to Ala) the parent telenzepine lost 636-fold in affinity, while TAC lost only 27-fold. Thus, the decylamino group of TAC stabilizes the bound state and thus enhances potency by acting as a distal anchor in the receptor binding site. We have built a computer-assisted molecular model of the transmembrane regions of muscarinic receptors based on homology with the G-protein coupled receptor rhodopsin, for which a low resolution structure is known. We have coordinated the antagonist pharmacophore (tricyclic and piperazine moieties) with residues of the third and seventh helices of the rat m3 receptor. Although the decylamino chain of TAC is likely to be highly flexible and may adopt many conformations, we located one possible site for a salt bridge formation with the positively charged -NH3+ group, i.e. Asp113 in helix II.  (+info)

Pituitary-adrenal cortical responses to low-dose physostigmine and arginine vasopressin administration in normal women and men. (3/445)

Animal studies indicate that central cholinergic neurotransmission stimulates CRH secretion, but several human studies suggest that the hypothalamo-pituitary-adrenal cortical (HPA) axis may be activated only by doses of cholinergic agonists that produce noxious side effects and, by inference, a nonspecific stress response. Physostigmine (PHYSO), a reversible cholinesterase inhibitor, was administered to normal women and men at a dose that elevated plasma ACTH1-39, cortisol, and arginine vasopressin (AVP) concentrations but produced few or no side effects. Exogenous AVP also was administered alone and following PHYSO, to determine if it would augment the effect of PHYSO on the HPA axis. Fourteen normal women and 14 normal men matched to the women on age and race underwent four test sessions 5 to 7 days apart: PHYSO (8 micrograms/kg i.v.), AVP (0.08 U/kg i.m.), PHYSO plus AVP, and saline control. Serial blood samples taken before and after pharmacologic challenge were analyzed for ACTH1-39, cortisol, and AVP. PHYSO and AVP administration produced no side effects in about half the subjects and mild side effects in the other half, with no significant female-male differences overall. There also were no significant female-male differences in ACTH1-39 or cortisol responses to AVP. In contrast, the men had significantly greater ACTH1-39 responses to PHYSO administration than did the women. The endogenous AVP response to PHYSO also was significantly greater in the men than in the women, and the ACTH1-39 and AVP responses to PHYSO were significantly correlated in the men (both = +0.70) but not in the women. None of the hormone responses was significantly correlated with the presence or absence of side effects in either group of subjects. These results indicate a greater sensitivity of the HPA axis to low-dose PHYSO in normal men than in normal women, which likely is mediated by increased secretion of AVP. The lack of difference in side effects between the two groups of subjects and the lack of significant correlations between presence or absence of side effects and hormone responses in either group suggest that the increased hormone responses in the men were due to increased responsivity of central cholinergic systems and not to a nonspecific stress response.  (+info)

Recurrent mossy fiber pathway in rat dentate gyrus: synaptic currents evoked in presence and absence of seizure-induced growth. (4/445)

A common feature of temporal lobe epilepsy and of animal models of epilepsy is the growth of hippocampal mossy fibers into the dentate molecular layer, where at least some of them innervate granule cells. Because the mossy fibers are axons of granule cells, the recurrent mossy fiber pathway provides monosynaptic excitatory feedback to these neurons that could facilitate seizure discharge. We used the pilocarpine model of temporal lobe epilepsy to study the synaptic responses evoked by activating this pathway. Whole cell patch-clamp recording demonstrated that antidromic stimulation of the mossy fibers evoked an excitatory postsynaptic current (EPSC) in approximately 74% of granule cells from rats that had survived >10 wk after pilocarpine-induced status epilepticus. Recurrent mossy fiber growth was demonstrated with the Timm stain in all instances. In contrast, antidromic stimulation of the mossy fibers evoked an EPSC in only 5% of granule cells studied 4-6 days after status epilepticus, before recurrent mossy fiber growth became detectable. Notably, antidromic mossy fiber stimulation also evoked an EPSC in many granule cells from control rats. Clusters of mossy fiber-like Timm staining normally were present in the inner third of the dentate molecular layer at the level of the hippocampal formation from which slices were prepared, and several considerations suggested that the recorded EPSCs depended mainly on activation of recurrent mossy fibers rather than associational fibers. In both status epilepticus and control groups, the antidromically evoked EPSC was glutamatergic and involved the activation of both AMPA/kainate and N-methyl-D-aspartate (NMDA) receptors. EPSCs recorded in granule cells from rats with recurrent mossy fiber growth differed in three respects from those recorded in control granule cells: they were much more frequently evoked, a number of them were unusually large, and the NMDA component of the response was generally much more prominent. In contrast to the antidromically evoked EPSC, the EPSC evoked by stimulation of the perforant path appeared to be unaffected by a prior episode of status epilepticus. These results support the hypothesis that recurrent mossy fiber growth and synapse formation increases the excitatory drive to dentate granule cells and thus facilitates repetitive synchronous discharge. Activation of NMDA receptors in the recurrent pathway may contribute to seizure propagation under depolarizing conditions. Mossy fiber-granule cell synapses also are present in normal rats, where they may contribute to repetitive granule cell discharge in regions of the dentate gyrus where their numbers are significant.  (+info)

Ionic mechanism of isoflurane's actions on thalamocortical neurons. (5/445)

We studied the actions of isoflurane (IFL) applied in aqueous solutions on ventrobasal neurons from thalamic brain slices of juvenile rats. By using the whole cell, patch-clamp method with current- and voltage-clamp recording techniques, we found that IFL increased a noninactivating membrane conductance in a concentration-dependent reversible manner. In an eightfold concentration range that extended into equivalent in vivo lethal concentrations, IFL did not produce a maximal effect on the conductance; this is consistent with a nonreceptor-mediated mechanism of action. TTX eliminated action potential activity but did not alter IFL effects. The effects on the membrane potential and current induced by IFL were voltage independent but depended on the external [K+], reversing near the equilibrium potential for K+. External Ba2+ or internal Cs+ applications, which block K+ channels, suppressed the conductance increase caused by IFL. External applications of the Ca2+ channel blockers Co2+ or Cd2+ or internal application of the Ca2+ chelator 1,2-bis-(2-aminophenoxy)-ethane-N,N, N',N'-tetraacetic acid did not prevent the effects of IFL, implying little involvement of Ca2+-dependent K+ currents. A contribution of inwardly rectifying K+ channels to the increased steady-state conductance seemed unlikely because IFL decreased inward rectification. An involvement of ATP-mediated K+ channels also was unlikely because application of the ATP-mediated K+ channel blocker glibenclamide (1-80 microM) did not prevent IFL's actions. In contrast to spiking cells, IFL depolarized presumed glial cells, consistent with an efflux of K+ from thalamocortical neurons. The results imply that a leak K+ channel mediated the IFL-induced increase in postsynaptic membrane conductance in thalamic relay neurons. Thus a single nonreceptor-mediated mechanism of IFL action was responsible for the hyperpolarization and conductance shunt of voltage-dependent Na+ and Ca2+ spikes, as reported in the preceding paper. Although anesthetics influence various neurological systems, an enhanced K+ leak generalized in thalamocortical neurons alone could account for anesthesia in vivo.  (+info)

The effect of miotics on the intraocular pressure of conscious owl monkeys. (6/445)

The intraocular pressure of conscious, unsedated owl monkeys (Aotus trivirgatus) was measured with an applanation tonometer. Untreated eyes of the conscious animals were found to have higher values than those reported for owl monkeys anesthetized with pentobarbitone. Locally applied pilocarpine, carbachol, and oxotremorine gave concentration-related reduction in pressure, oxotremorine being the most potent and having longer duration of effect than the other compounds. Slight reductions were also observed with aceclidine and R. S. 86. These results are discussed in relation to the effects of miotics in man.  (+info)

Agonist-dependent phosphorylation of the inositol 1,4,5-trisphosphate receptor: A possible mechanism for agonist-specific calcium oscillations in pancreatic acinar cells. (7/445)

The properties of inositol 1,4,5-trisphosphate (IP3)-dependent intracellular calcium oscillations in pancreatic acinar cells depend crucially on the agonist used to stimulate them. Acetylcholine or carbachol (CCh) cause high-frequency (10-12-s period) calcium oscillations that are superimposed on a raised baseline, while cholecystokinin (CCK) causes long-period (>100-s period) baseline spiking. We show that physiological concentrations of CCK induce rapid phosphorylation of the IP3 receptor, which is not true of physiological concentrations of CCh. Based on this and other experimental data, we construct a mathematical model of agonist-specific intracellular calcium oscillations in pancreatic acinar cells. Model simulations agree with previous experimental work on the rates of activation and inactivation of the IP3 receptor by calcium (DuFour, J.-F., I.M. Arias, and T.J. Turner. 1997. J. Biol. Chem. 272:2675-2681), and reproduce both short-period, raised baseline oscillations, and long-period baseline spiking. The steady state open probability curve of the model IP3 receptor is an increasing function of calcium concentration, as found for type-III IP3 receptors by Hagar et al. (Hagar, R.E., A.D. Burgstahler, M.H. Nathanson, and B.E. Ehrlich. 1998. Nature. 396:81-84). We use the model to predict the effect of the removal of external calcium, and this prediction is confirmed experimentally. We also predict that, for type-III IP3 receptors, the steady state open probability curve will shift to lower calcium concentrations as the background IP3 concentration increases. We conclude that the differences between CCh- and CCK-induced calcium oscillations in pancreatic acinar cells can be explained by two principal mechanisms: (a) CCK causes more phosphorylation of the IP3 receptor than does CCh, and the phosphorylated receptor cannot pass calcium current; and (b) the rate of calcium ATPase pumping and the rate of calcium influx from the outside the cell are greater in the presence of CCh than in the presence of CCK.  (+info)

Rapid report: postsynaptic bursting is essential for 'Hebbian' induction of associative long-term potentiation at excitatory synapses in rat hippocampus. (8/445)

1. The biologically relevant rules of synaptic potentiation were investigated in hippocampal slices from adult rat by mimicking neuronal activity seen during learning behaviours. Synaptic efficacy was monitored in two separate afferent pathways among the Schaffer collaterals during intracellular recording of CA1 pyramidal neurones. The effects of pairing presynaptic single spikes or bursts with postsynaptic single spikes or bursts, repeated at 5 Hz ('theta' frequency), were compared. 2. The pairing of ten single evoked excitatory synaptic events with ten postsynaptic single action potentials at 5 Hz, repeated twelve times, failed to induce synaptic enhancement (EPSP amplitude 95% of baseline amplitude 20 min after pairing; n = 5). In contrast, pairing the same number of action potentials, but clustered in bursts, induced robust synaptic potentiation (EPSP amplitude 163%; P < 0.01, Student's t test; n = 5). This potentiation was input specific, long lasting ( > 1 h; n = 3) and its induction was blocked by an antagonist at NMDA receptors (20-50 microM D(-)-2-amino-5-phosphonopentanoic acid; EPSP amplitude 109%; n = 6). 3. Presynaptic bursting paired with postsynaptic single action potentials did not induce input specific synaptic change (113 % in the test input vs. 111 % in the control; n = 8). In contrast, postsynaptic bursting when paired with presynaptic single action potentials was sufficient to induce synaptic potentiation when the presynaptic activity preceded the postsynaptic activity by 10 ms (150 vs. 84 % in the control input; P < 0.01; n = 10). 4. These results indicate that, under our conditions, postsynaptic bursting activity is necessary for associative synaptic potentiation at CA1 excitatory synapses in adult hippocampus. The existence of a distinct postsynaptic signal for induction of synaptic change calls for refinement of the common interpretation of Hebb's rule, and is likely to have important implications for our understanding of cortical network operation.  (+info)

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