The alpha and gamma subunit-dependent effects of local anesthetics on recombinant GABA(A) receptors.

Although convulsions due to local anesthetic systemic toxicity are thought to be due to inhibition of GABA(A) receptor-linked currents in the central nervous system, the mechanism of action remains unclear. We therefore examined the effects of local anesthetics on gamma-aminobutyric acid (GABA)-induced currents using recombinant GABA(A) receptors with specific combinations of subunits. Murine GABA(A) receptors were expressed by injection of cRNAs encoding each subunit into Xenopus oocytes. The effects of local anesthetics (lidocaine, bupivacaine, procaine and tetracaine) on GABA-induced currents of receptors expressing different subunit combinations (alpha1beta2, alpha1beta2gamma2s, alpha4beta2gamma2s and beta2) were examined via the two electrode voltage clamp method. At alpha1beta2, alpha1beta2gamma2s and alpha4beta2gamma2s GABA(A) receptors, all local anesthetics inhibited GABA-induced currents in a dose-dependent manner. The presence of the gamma2s subunit resulted in a greater inhibition by all local anesthetics, but the presence of the alpha4 subunit resulted in less inhibition. At beta2 homomeric receptors, local anesthetics directly induced an outward current similar to that of picrotoxin. These data indicated that (1) the alpha and gamma subunits of GABA(A) receptors modulated the inhibitory effects of local anesthetics on GABA(A) function, and (2) local anesthetics can activate the beta2 subunit and may block the GABA(A) receptor channel pore.

Optimal level of pressure support ventilation for recovery from diaphragmatic fatigue in rabbits.

OBJECTIVE: To determine whether there is an optimal level of pressure support ventilation (PSV) for recovery from acute diaphragmatic fatigue. DESIGN: Prospective laboratory trial. SETTING: Experimental laboratory. SUBJECTS: Twenty healthy adult New Zealand White rabbits. INTERVENTIONS: Diaphragmatic fatigue was induced with 50 Hz of phrenic nerve stimulation for 30 mins. Recovery was compared between inspiratory load + PSV of 0 cm H2O (L0), inspiratory load + PSV of 60 cm H2O (L60), inspiratory load + PSV of 80 cm H2O (L80), and PSV of 0 cm H2O without inspiratory load (SB) for 90 mins immediately after the end of the fatigue-inducing procedure. To add inspiratory load during the recovery phase, three pressure threshold valves, each having an opening pressure of -20 cm H2O, were used. MEASUREMENTS AND MAIN RESULTS: After the fatigue-inducing procedure, diaphragmatic electromyogram and transdiaphragmatic pressure remained at baseline in both SB and L60, decreased in L80, and increased in L0. Recovery was assessed by abdominal cavity pressure (Pabd) generated by high-frequency (100 Hz) and low-frequency (20 Hz) stimulation. Pabd at 100 Hz recovered to baseline in L60 and SB but not in L0 and L80 (69.1%, 81.3%, 100.3%, and 100.7% of the baseline at 90 mins for L0, L80, L60, and SB, respectively). Pabd at 20 Hz did not differ among ventilatory settings. CONCLUSION: There is an optimal range of PSV assist level to improve recovery from diaphragmatic fatigue. Recovery was hampered not only by inadequate PSV but also by excessive PSV.

Treatment of acute right coronary artery occlusion during anesthesia.

PURPOSE: Perioperative coronary artery occlusion is a potentially dangerous complication causing myocardial infarction and circulatory collapse. We report a case showing severe ST segment depression in leads II and V5 during anesthesia. Diltiazem and nifedipine, but not nitroglycerine, partially improved the ST changes which were normalized by a percutaneous cardiopulmonary system (PCPS). CLINICAL FEATURES: A 71-yr-old man with cerebrovascular disease was scheduled for coronary artery bypass grafting (CABG). Past medical history included myocardial infarction due to right coronary artery (RCA) occlusion. Both the femoral artery and vein were cannulated percutaneously before operation and the PCPS was prepared as a back-up system. Depression of the ST segments in leads V5 and II was observed following heparinization. Although hemodynamic stability was maintained with continuous infusion of catecholamines, the ST changes were not improved by intravenous nitroglycerine. Intravenous diltiazem followed by nasal nifedipine partially improved the ST changes. The changes were normalized after induction of PCPS. No neurological complications were observed. The postoperative coronary angiography confirmed the total occlusion of RCA. CONCLUSION: Calcium channel blockers were more effective than nitroglycerine in treating perioperative ST depression. However, none of them produced complete reversal of the ischemic changes which were normalized with PCPS.

The effect of electroconvulsive treatment on thermal hyperalgesia and mechanical allodynia in a rat model of peripheral neuropathy.

UNLABELLED: We tested the ability of electroconvulsive treatment (ECT) to block thermal hyperalgesia and mechanical allodynia in rats with peripheral neuropathy. Repeated ECT (six times daily) significantly reduced thermal hyperalgesia 48 h after the end of the final treatment but had no significant effects on mechanical allodynia. Single ECT had no significant effect on thermal hyperalgesia or mechanical allodynia. Neither single nor repeated ECT had any significant effect on the withdrawal response of sham-operated paws and untreated rats to thermal and mechanical stimuli. The anti-thermal hyperalgesic effect of repeated ECT was reversed by the previous administration of nifedipine (L-type Ca2+ channel blocker). We conclude that, due to effects on the voltage dependent calcium channel, ECT modified one of the pain behaviors induced by nerve injury. ECT may be of use in the treatment of human neuropathic pain. IMPLICATIONS: We showed that repeated electroconvulsive treatment reduced pain responses to heat stimulation after sciatic nerve injury in rats. This study implies a possible therapeutic effect of electroconvulsive treatment on neuropathic pain.

Dual effect of local anesthetics on the function of excitable rod outer segment disk membrane.

The effects of local anesthetics and a divalent cation, Ca2+, on the function of rhodopsin were estimated from the measurements of light-induced proton uptake. The light-induced proton uptake by rhodopsin in the rod outer segment disk membrane was enhanced at lower pH (4) but depressed at higher pHs (6 to 8) by the tertiary amine local anesthetics lidocaine, bupivacaine, tetracaine, and dibucaine. The order of local anesthetic-induced depression of the proton uptake followed that of their clinical anesthetic potencies. The depression of the proton uptake versus the concentration of the uncharged form of local anesthetic nearly describes the same curve for small and large dose of added anesthetic. Furthermore, a neutral local anesthetic, benzocaine, depressed the proton uptake at all pHs between 4 and 7. These results indicate that the depression of the proton uptake is due to the effect of only the uncharged form. It is hypothesized that the uncharged form of local anesthetics interacts hydrophobically with the rhodopsin in the disk membrane. The dual effect of local anesthetics on the proton uptake, on the other hand, suggests that the activation of the function of rhodopsin may be caused by the charged form. There was no significant change in the light-induced proton uptake by rhodopsin when 1 mM of Ca2+ was introduced into the disk membrane at varying pHs in the absence or presence of local anesthetics. This fact indicates that Ca2+ ion does not influence the diprotonating process of metarhodopsin; neither does it interfere with the local anesthetic-induced changes in the rhodopsin molecule.