Catheter-related bladder discomfort (CRBD) frequently occurs during recovery in patients who undergo intra-operative urinary catheterization. We conducted this study to compare the effect of intravenous lidocaine and dexmedetomidine infusion for preventing CRBD.

120 patients undergoing elective open abdominal hysterectomy or hysteromyomectomy requiring urinary bladder catheterization were randomly allocated into three groups of 40 each. Group L received a 2 mg/kg lidocaine bolus followed by infusion of 1.5 mg/kg/h; Group D received a 0.5 μg/kg dexmedetomidine bolus followed by infusion of 0.4 μg/kg/h; Group C received a bolus and infusion of normal saline of equivalent volume. The incidence and different severity (mild, moderate, and severe) of CRBD were assessed on arrival in the postanaesthesia care unit at 0, 1, 2, and 6 h postoperatively.

The incidence of CRBD was significantly lower in Group L and Group D compared with Group C at 0, 1, and 2 h. However, there was no significant difference among the three groups regarding the different severity of CRBD at all time points. The requirement of rescue tramadol for CRBD was lower in group L and group D than in group C. The incidence of sedation was significantly higher in Group D compared to Group L and Group C, though no difference in other adverse effects was observed.

Intravenous lidocaine and dexmedetomidine infusion reduced the incidence of CRBD as well as the additional tramadol requirement for CRBD, but had no effect on the different severity of CRBD.

ChiCTR-INR-16009162 . Registered on 5 September 2016.

Inflammation is clinically well known to decrease the efficiency of local anesthesia, an effect which has been explained mechanistically by tissue acidosis in the literature. However, recent studies offer no support to such a pharmacopathological background for anesthetic failure. Because inflammatory cells produce significant amounts of peroxynitrite, the peroxynitrite could interact with local anesthetics to decrease their effects. To examine this speculated interaction, we determined whether membrane fluidization, as one mode of local anesthetic action, was influenced by peroxynitrite. The membrane effects were analyzed by measuring the fluorescence polarization of liposomes prepared with 1, 2-dipalmitoylphosphatidylcholine. Although lidocaine, at a clinically relevant concentration, fluidized liposomal membranes, its fluidizing potency was reduced to 43.6 +/- 4.4% and 58.4 +/- 7.5% of that in membranes without peroxynitrite when membranes were pretreated with 50 and 250 microM peroxynitrite, respectively, for 15 min. A significant inhibition of membrane fluidization of 27.5 +/- 6.8%, was also observed after reaction for 5 min. Peroxynitrite released by inflammatory cells may affect local anesthesia through a possible interaction with lidocaine, inhibiting its membrane-fluidizing effect.

The analgesic interaction between cannabinoids and local anesthetics has not been investigated. We sought to determine the nature of the interaction between the intrathecal cannabinoid receptor agonist (WIN 55,212-2) and bupivacaine using the formalin test.

Lumbar intrathecal catheters were implanted in male Sprague-Dawley rats. After intrathecal administration of WIN 55,212-2, bupivacaine, or their combination, 50 microL of 5% formalin was injected subcutaneously into the hindpaw. Dose-response curves were established and the respective ED50 (50% effective dose) values were determined for each agent alone. Fixed-ratio combinations of WIN 55,212-2 and bupivacaine were tested for combined antinociceptive effects in the formalin test and an isobolographic analysis was performed to characterize the pharmacologic interaction of both drugs.

Intrathecally administered WIN 55,212-2, bupivacaine, or their combination produced a dose-dependent decrease in the number of flinches during Phase 1 and 2 of the formalin test. Isobolographic analysis revealed a synergistic interaction between intrathecal WIN 55,212-2 and bupivacaine in both phases of the formalin test. In combination, the ED50 value was significantly smaller than the theoretical additive value (P < 0.05).

These results demonstrate that intrathecally coadministered WIN 55,212-2 and bupivacaine provide synergistic antinociceptive interaction in both phases of the formalin test.

We investigated the interaction between spinally administered bupivacaine and clonidine using an animal model of acute and inflammatory pain. Rats implanted with lumbar intrathecal catheters were injected intrathecally with saline (control), bupivacaine (1 to 100 microg), or clonidine (0.1 to 3 microg) and tested for their responses to thermal stimulation to the tail (tail flick test) and subcutaneous formalin injection into the hindpaw (formalin test). The effects of the combination of bupivacaine and clonidine on both stimuli were tested by isobolographic analysis. General behavior and motor function were examined as side effects. The 50% effective doses of bupivacaine and clonidine were significantly smaller when combined compared with each single drug in both the tail flick test (2.82 and 0.11 microg versus 7.1 and 0.29 microg, respectively) and phase 1 (0.24 and 0.009 microg versus 5.7 and 0.15 microg) and phase 2 (0.31 and 0.012 microg versus 3.2 and 0.16 microg) of the formalin test. Side effects were decreased by the combination. These results suggest a favorable combination of intrathecal bupivacaine and clonidine in the management of acute and inflammatory pain.

The analgesic interaction between intrathecally administered bupivacaine and clonidine was examined during acute thermal and inflammatory-induced pain in rats. The analgesia produced by the combination of these two drugs was synergistic in both acute thermal and inflammatory induced pain, with a decrease in behavioral side effects.

The interaction of amine local anaesthetics and related compounds with histamine H1 receptors was investigated in guinea-pig ileal longitudinal muscle. Quinacrine, chloroquine, tetracaine and procaine inhibited [3H]mepyramine binding to solubilized membrane from ileal muscle with pKi values of 5.27 +/- 0.11, 5.66 +/- 0.01, 4.28 +/- 0.08 and 3.97 +/- 0.11, respectively. The pKB values obtained from the initial parallel shift of the dose-response curves for histamine in the presence of these drugs were 5.49 +/- 0.11, 6.14 +/- 0.09, 4.86 +/- 0.06 and 4.58 +/- 0.06, respectively, in reasonable agreement with the pKi values. The combined dose-ratio test with both local anaesthetics and antagonist (mepyramine) present showed that tetracaine and procaine were competitive and chloroquine was partially competitive, but that quinacrine was not competitive at histamine H1 receptors. These local anaesthetics inhibited histamine-induced desensitization in guinea-pig ileum. Receptor occupancy (%) by agonist decreased from 95.2 (without inhibitor) to 73.9, 42.8, 35.9 and 33.9 in the presence of quinacrine, chloroquine, tetracaine or procaine, respectively, under the conditions where each inhibitor drug induced half maximum inhibition of desensitization. The results suggested that most of these local anaesthetics interacted competitively at histamine H1 receptors and inhibited desensitization through their antagonizing actions, whereas quinacrine interacted allosterically and inhibited desensitization through a separate action.

1. Desensitization of contractile responses dependent on release of intracellularly stored Ca elicited by carbachol, histamine or caffeine was measured after desensitizing treatment with carbachol or histamine in the presence or absence of local anaesthetics in Ca-free solution containing 2 mM EGTA in the smooth muscle of guinea-pig taenia caecum. 2. Histamine-induced homologous desensitization was inhibited by tetracaine and procainamide. Dibucaine did not exert an inhibitory effect on the desensitization. This is consistent with our previous findings concerning the effects of local anaesthetics on the desensitization of histamine H1-receptors measured under normal physiological conditions. 3. Carbachol induced a functional change of intracellular Ca stores which resulted in heterologous desensitization. Tetracaine completely blocked carbachol-induced desensitization of the caffeine-elicited contraction, but in the case of carbachol-induced desensitization of carbachol- and histamine-elicited contractions, this blocking effect of tetracaine was very weak and absent, respectively. The other local anaesthetics used did not affect the desensitization. These results suggest that the Ca-induced and inositol trisphosphate-induced Ca release mechanisms were both desensitized by carbachol and that the desensitization of the Ca-induced Ca release mechanism was selectively blocked by tetracaine.

We have compared the effect of ethanol, a membrane perturbant, on the muscarinic binding sites in neural membranes from a vertebrate (rat) and an insect (locust). The binding of the muscarinic antagonist [3H]quinuclidinyl benzilate ([3H]QNB) to both rat and locust neural membranes was inhibited by ethanol at 10-500 mM concentrations; but this inhibition was greater in the locust. Ethanol (500 mM) increased the apparent dissociation constant (KD') of [3H]QNB binding to rat membranes from 0.13 +/- 0.01 nM in control to 0.20 +/- 0.02 nM; there was also an small but significant reduction in the number of binding sites Bmax. In locust, 500 mM ethanol reduced the Bmax of [3H]QNB binding from 590 +/- 30 in control to 320 +/- 40 pmol/g protein; no significant alteration in the KD was detected. The dissociation rate constant (koff) of [3H]QNB increased from 0.020 +/- 0.003 in controls to 0.031 +/- 0.004 (min-1) in the presence of 500 mM ethanol, the association rate constant (Kon) did not change significantly. In locust, 500 mM ethanol did not affect either Kon or Koff. Competition experiments revealed that the binding affinities of both the agonist carbamylcholine and the antagonist atropine to the rat membranes were reduced in the presence of ethanol. In contrast, ethanol caused no alteration in the binding affinities of these ligands to the locust membranes. This differential effect of ethanol on rat and locust muscarinic binding suggests a difference in the hydrophobic domains and/or the membrane interactions of the muscarinic receptors in the two species.

Membranes isolated from bovine atria were labeled with [3H]quinuclidinyl benzylate (3H-QNB), in control conditions and after 0.02% Triton X-100. This treatment inactivated about 20% of muscarinic receptor sites without loss of protein. The remaining 80% sites showed no changes in affinity, as determined by equilibrium or kinetic binding. Competition experiments with carbachol showed no differences in IC50 and Hill number between the control and detergent-membranes, suggesting that the different populations of agonist binding sites are inactivated in equal proportions by the detergent. In binding experiments, done in the presence of carbachol and guanine nucleotides, the detergent treated membranes were slightly more sensitive to the enhancing action of the nucleotide. The inhibition caused by ammonium ions was also more marked in the Triton X-100 treated membranes. The decay of binding with thermal inactivation was faster in the detergent treated membranes and this effect was enhanced in the presence of ammonium ions. These results may be interpreted as an indication that the receptors, remaining after the mild Triton X-100 treatment, are equally sensitive to the inactivation. We suggest that, while maintaining the heterogeneity of sites, the detergent produces a perturbation that could affect the molecular interactions between the receptor and other components of the membrane.

The muscarinic cholinergic antagonist 3H-quinuclidinyl benzilate was used to study muscarinic cholinergic receptors in the brain and the heart from triiodothyronine, thyroxine and 6-propyl-2-thiouracil treated rats. Scatchard analysis of the saturation binding studies revealed for each rat in both brain and heart tissue a single group of muscarinic cholinergic receptor binding sites of high affinity. The density and the affinity of muscarinic cholinergic receptors in brain and heart homogenates from treated rats were not different from values obtained in control rats with the exception of triiodothyronine treated rats which showed a slightly but significantly increased equilibrium dissociation constant in the brain homogenates. Furthermore, we observed that the density of the muscarinic cholinergic receptors in the brain was significantly lower in the month of August as compared to March-April, which suggests a seasonal variation. No similar change was observed in heart homogenates. Our results suggest that cardiovascular and central nervous symptoms in patients with thyroid diseases cannot be ascribed to changes in muscarinic cholinergic receptors.

Muscarinic cholinergic receptors (mAChR) are degraded on the addition of agonists through energy- and temperature-dependent processes, probably with clustering and endocytosis. Pretreatment of guinea-pig vas deferens with 0.5 mM quinacrine or 5 mM tetracaine, phospholipase A2 (PLase A2) inhibitors, inhibited the ACh-induced degradation of mAChR in the smooth muscle and kept mAChR on the surface membrane, while cocaine and procaine were not effective. On pretreatment with quinacrine or tetracaine the PLase A2 activity in the smooth muscle decreased continuously during culture without change in the contractile response of the tissue. Pretreatment with cocaine and procaine which had no significant effect on the down regulation of mAChR did not inhibit PLase A2 activity. However, activation of PLase A2 by long-term culture of the muscle with ACh and formation of endogenous inhibitor of PLase A2 were not observed under our experimental conditions. The participation of PLase A2 in the agonist-induced degradation of mAChR is discussed in the light of these findings.