Electrophysiologic effects of halothane and quinidine on canine Purkinje fibers: evidence for a synergistic interaction

The authors studied possible interactions between halothane and quinidine on the action potentials of canine Purkinje fibers superfused with Tyrode's solution. Using standard microelectrode techniques and a physiologic pacing rate (2 Hz), halothane in concentrations from 0.5% to 2% decreased the action potential duration to 50% repolarization (ADP50). Total ADP (APD100), in contrast, increased after 1% and 2% halothane. Resting membrane potential (RMP) and action potential amplitude (APamp) increased after 0.5% halothane, but returned to control with higher halothane levels. Conduction time (CT) increased at each halothane level. Pacing at faster (3 Hz) or slower (1 Hz) rates did not markedly alter the effects of halothane. Quinidine 1 X 10(-5)M decreased the phase O upstroke (Vmax) and prolonged APD100 and CT. When halothane was added, RMP and APamp decreased, Vmax decreased further, and APD100 and CT were markedly prolonged. This resulted in conduction block or inexcitability, especially at faster pacing rates (3 Hz). Synergistic interactions between halothane and quinidine were found on RMP, APamp, APD100, and CT. Effects on Vmax, APD50, and action potential duration to 90% repolarization (APD90) were additive. It is concluded that quinidine and halothane act synergistically to decrease action potential amplitude, lower RMP, and prolong conduction. Severe depression of conduction often progressed to conduction block or inexcitability when halothane, 2%, was administered during superfusion with therapeutic concentrations of quinidine.     

Behavioral state-specific changes in human hippocampal theta activity

Although there has been extensive examination of the behavioral and physiologic correlates of hippocampal theta activity in animals, the human literature consists of a single case study. We investigated the differential effects of four behavioral states on human hippocampal theta activity in 16 epilepsy surgery patients. Behavioral conditions included resting eyes closed (RC), resting eyes open (RO), eyes open with auditory word activation (AW), and eyes open with visuospatial activation (VS). Hippocampal theta activity decreased during both RO and VS compared to both RC and AW. There were reciprocal changes in delta activity. Comparisons of RO to VS and of RC to AW were nonsignificant. The results demonstrate state-specific changes in human hippocampal theta and are consistent with the animal literature that relates hippocampal theta to sensorimotor integration and forebrain volitional mechanisms.     

Conversion of Ouabain-Induced Ventricular Tachycardia in Dogs with Epicardial Lidocaine: Pharmacodynamics and Functional Effects

Epicardial antiarrhythmic drug administration was studied as a therapeutic approach for experimental ventricular tachycardia (VT) in an open-chest dog model. Lidocaine-polyurethane matrices (28%, w/w) were formulated as a model system. Matrices were placed on the left ventricular epicardium in each of 23 anesthetized open-chest dogs with ouabain-induced VT, to evaluate effectiveness in restoring sinus rhythm. Conversion occurred in all animals treated with matrices containing 300 mg or more of lidocaine after 1.5 to 7.0 min. The matrix lidocaine content correlated linearly with the time required for conversion to sinus rhythm (r = 0.75, P = 0.0002); irrespective of matrix size the myocardial/plasma lidocaine ratio was 20.1 ± 4.2 (mean ± SD) at the time of conversion. In a separate series of five dogs without ventricular tachycardia, systolic wall thickening measured with sonomicrometers after 5 min of controlled-release lidocaine administration (500- to 1000-mg matrix lidocaine content, 7.48 ± 3.49-mg/kg dose) was only minimally diminished (–14.1%) and this effect was observed only at the site of matrix placement on the anterior-apical epicardium. In contrast, intracoronary injection of 0.3 or 1.0 mg/kg of lidocaine-HCl resulted in complete elimination of wall thickening or replacement by systolic thinning. Thus epicardial administration of lidocaine from polyurethane matrices was an effective means of treating ouabain-induced ventricular tachycardia. Regional myocardial function in the vicinity of the matrices was modified to a very limited degree, supporting the view that the matrices can be used safely, without serious risk to ventricular contractile performance.     

Genotype at a major locus with large effects on apolipoprotein B levels predicts familial combined hyperlipidemia

A sample enriched for familial combined hyperlipidemia (FCHL) was examined for evidence of an association between genotype at an apolipoprotein B (apoB) elevating locus defined by complex segregation analysis and FCHL. Complex segregation analysis detected a locus with a large effect on plasma apoB levels and was used to compute the most probable genotype of family members. None of the 35 normolipidemic adults carried a copy of the allele associated with elevated apoB levels, yet 58% of the 109 adults with FCHL carried 1 (29%) or 2 (28%) copies. Two of 28 (7%) normal children had 1 copy of this allele and none had 2 copies, while 88 of 182 (48%) children with FCHL had 1 (26%) or 2 (22%) copies. Further, 4l of 48 (85%) individuals classified as having hyperapobetalipoproteinemia did not carry a copy of this “elevated apoB” allele. Therefore, the presence of the allele associated with elevation of apoB level is highly predictive of FCHL and this association cannot be explained solely by the presence of elevated apoB levels in FCHL, suggesting that the locus controlling apoB levels may play an etiologic role in FCHL. © 1993 Wiley-Liss, Inc.     

Are common mutations of cystathionine β-synthase involved in the aetiology of neural tube defects?

Mildly elevated maternal plasma homocysteine (Hcy) levels (hyperhomocysteinemia) have recently been observed in some neural tube defect (NTD) pregnancies. Plasma levels of Hcy are governed by both genetic and nutritional factors and the aetiology of NTDs is also known to have both genetic and nutritional components. We therefore examined the frequency of relatively common mutations in the enzyme cystathionine β-synthase (CBS), which is one of the main enzymes that controls Hcy levels, in the NTD population. Neither the severely dysfunctional G307S CBS allele nor the recently reported 68 bp insertion/I278T CBS allele was observed at increased frequency in the cases relative to controls. We therefore conclude that loss of function CBS alleles do not account for a significant proportion of NTDs in Ireland.     

Pathologic laughter and crying in ALS: a search for their origin

Spells of laughter and crying are well known in patients with amyotrophic lateral sclerosis (ALS). Since ALS occurs mostly in older age groups, this brings up the possibility that aging changes in the brain could play a causative role in the origin of such spells. To rule out or at least reduce the complicating factor of aging, a study was made of the incidence of pathologic laughter and crying in patients whose motor neuron disease had started before the age of 45 years. The data were collected from 73 such individuals, all with confirmed ALS. All told, 36 had experienced episodes of pathologic laughter and/or crying. Of these, 20 had bouts of both laughter and crying. 9 bouts of crying alone and 7 spells of laughter alone. Nearly all with such emotional spells had developed bulbar involvement with the illness. The youngest patient with spells was 31 when his illness began and 35 when he started to have bouts of crying.     

Nonheme iron in sickle erythrocyte membranes: association with phospholipids and potential role in lipid peroxidation

Previous studies documented the abnormal association of heme and heme proteins with the sickle RBC membrane. We have now examined RBC ghosts and inside-out membranes (IOM) for the presence of nonheme iron as detected by its formation of a colored complex with ferrozine. Sickle ghosts have 33.8 +/- 18.2 nmol nonheme iron/mg membrane protein, and sickle IOM have 4.3 +/- 3.0 nmol/mg. In contrast, normal RBC ghosts and IOM have no detectable nonheme iron. The combination of heme and nonheme iron in sickle IOM averages nine times the amount of membrane- associated iron in normal IOM. Kinetics of the ferrozine reaction show that some of this nonheme iron on IOM reacts slowly and is probably in the form of ferritin, but most (72% +/- 18%) reacts rapidly and is in the form of some other biologic chelate. The latter iron compartment is removed by deferoxamine and by treatment of IOM with phospholipase D, which suggests that it represents an abnormal association of iron with polar head groups of aminophospholipids. The biologic feasibility of such a chelate was demonstrated by using an admixture of iron with model liposomes. Even in the presence of tenfold excess adenosine diphosphate, iron partitions readily into phosphatidylserine liposomes; there is no detectable association with phosphatidylcholine liposomes. To examine the bioavailability of membrane iron, we admixed membranes and t-butylhydroperoxide and found that sickle membranes show a tenfold greater peroxidation response than do normal membranes. This is not due simply to a deficiency of vitamin E, and this is profoundly inhibited by deferoxamine. Thus, while thiol oxidation in sickle membranes previously was shown to correlate with heme iron, the present data suggest that lipid peroxidation is related to nonheme iron. In control studies, we did not find this pathologic association of nonferritin, nonheme iron with IOM prepared from sickle trait, high-reticulocyte, postsplenectomy, or iron-overloaded individuals. These data provide additional support for the concept that iron decompartmentalization is a characteristic of sickle RBCs.