Many local anesthetics promote reduction in sodium current during repetitive stimulation of excitable membranes. Use-, frequency-, and voltage-dependent responses describe patterns of peak INa when pulse width, pulse frequency, and pulse amplitude are varied. Such responses can be viewed as reflecting voltage-sensitive shifts in equilibrium between conducting, unblocked channels and nonconducting, blocked channels. The modulated-receptor hypothesis postulates shifts in equilibrium as the result of a variable-affinity receptor and modified inactivation gate kinetics in drug-complexed channels. An alternative view considers drug blocking in the absence of these two features. We propose that drug binds to a constant-affinity channel receptor where receptor access is regulated by the channel gates. Specifically, we view channel binding sites as guarded by the channel gate conformation, so that unlike receptors where ligands have continuous access, blocking agent access is variable during the course of an action potential. During the course of an action potential, the m and h gates change conformation in response to transmembrane potential. Conducting channels with both gates open leave the binding site unguarded and thus accessible to drug, whereas nonconducting channels, with gates in the closed conformation, act to restrict drug access to unbound receptors and possibly to trap drug in drug-complexed channels. We develop analytical expressions characterizing guarded receptors as "apparently" variable-affinity binding sites and predicting shifts in "apparent" channel inactivation in the hyperpolarizing direction. These results were confirmed with computer simulations. Furthermore, these results are in quantitative agreement with recent investigations of lidocaine binding in cardiac sodium channels.
This study provides evidence of bias in the open review of abstracts, favoring authors from the United States, English-speaking countries outside the United States, and prestigious academic institutions. Moreover, blinded review at least partially reduced reviewer bias.
Cholecystokinin (CCK) is produced by discrete endocrine cells in the proximal small intestine and is released following the ingestion of food. CCK is the primary hormone responsible for gallbladder contraction and has potent effects on pancreatic secretion, gastric emptying, and satiety. In addition to fats, digested proteins and aromatic amino acids are major stimulants of CCK release. However, the cellular mechanism by which amino acids affect CCK secretion is unknown. The Ca2+-sensing receptor (CaSR) that was originally identified on parathyroid cells is not only sensitive to extracellular Ca2+ but is activated by extracellular aromatic amino acids. It has been postulated that this receptor may be involved in gastrointestinal hormone secretion. Using transgenic mice expressing a CCK promoter driven/enhanced green fluorescent protein (GFP) transgene, we have been able to identify and purify viable intestinal CCK cells. Intestinal mucosal CCK cells were enriched >200-fold by fluorescence-activated cell sorting. These cells were then used for real-time PCR identification of CaSR. Immunohistochemical staining with an antibody specific for CaSR confirmed colocalization of CaSR to CCK cells. In isolated CCK cells loaded with a Ca2+-sensitive dye, the amino acids phenylalanine and tryptophan, but not nonaromatic amino acids, caused an increase in intracellular Ca2+ ([Ca2+]i). The increase in [Ca2+]i was blocked by the CaSR inhibitor Calhex 231. Phenylalanine and tryptophan stimulated CCK release from intestinal CCK cells, and this stimulation was also blocked by CaSR inhibition. Electrophysiological recordings from isolated CCK-GFP cells revealed these cells to possess a predominant outwardly rectifying potassium current. Administration of phenylalanine inhibited basal K+ channel activity and caused CCK cell depolarization, consistent with changes necessary for hormone secretion. These findings indicate that amino acids have a direct effect on CCK cells to stimulate CCK release by activating CaSR and suggest that CaSR is the physiological mechanism through which amino acids regulate CCK secretion.
SUMMARY Twelve patients with evidence of Mahaim fibers are reported, six with nodoventricular (NV) fibers and six with fasciculoventricular (FV) fibers. All patients with NV fibers had left bundle branch block morphology, and a sustained reentrant tachycardia with this morphology was proved in each case. In three of the six, ventriculoatrial dissociation occurred during tachycardia. We postulate that the mechanism of this tachycardia is a macroreentry circuit using the NV fiber for the antegrade limb and the His-Purkinje system with a portion of the atrioventricular node for the retrograde limb. ECGs of patients with FV fibers were varied, suggesting a functional relation to the right or left side of the septum. No direct relationship of FV fibers to observed arrhythmias could be found.THE ROLE of Mahaim fibers in the genesis of cardiac arrhythmias in man has been controversial since they were first described.' The initial report was limited to fibers connecting the His bundle to the septum, but this was soon broadened to include fibers connecting the atrioventricular (AV) Received March 25, 1980; revision accepted November 14, 1980. Circulation 64, No. 1, 1981. All patients were admitted to the hospital and placed on continuous telemetry; all cardioactive medications were discontinued. Before cardiac catheterization, all had history and physical examination, routine blood work, ECG, chest x-ray, and twodimensional echocardiography using a microcavitation technique. All patients gave informed consent before catheterization. Electrophysiologic StudyAll patients were studied in the postabsorptive, nonsedated state using techniques previously described.15' 60, 58, '9 Multiple electrode catheters were used to record and pace from the right atrium, the left atrium via the coronary sinus, and the right ventricle. Observations were made during overdrive pacing and refractory period determination from all three locations, during tachycardia and after deliberate induction of atrial fibrillation. TerminologyRecently, Anderson et al.'5 suggested that there are two main anatomic types of Mahaim fibers -nodoventricular (NV) fibers, which arise from the AV node, and fasciculoventricular (FV) fibers, which arise from the His bundle and bundle branches. Because the functional consequences are significant, we have found it useful to consider the two groups separately according to an anatomic and functional classification ( fig. 1). Anderson et al. proposed two varieties of NV fibers -those which arise from the transitional zone of the AV junction and those which arise from the deep, compact nodal portion of the AV junction. NV fibers, depending on level of takeoff relative to the area of physiologic delay, can be associated with either a short or normal PR interval. Ventricular activation in this case results from fusion of impulse propagation via the NV fiber and the normal conduction system, resulting in QRS complexes with varying degrees of anomalous conduction. The PR interval should be normal with isolated FV fibers...
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