Single channel sodium current in rat cardiomyocytes: use-dependent block by ethacizin

Ethacizin is a phenothiazine derivative antiarrhythmic agent that blocks sodium current. The cell-attached patch clamp of single adult rat ventricular cells was used to investigate mechanisms of use-dependent block of sodium current. Under control conditions peak open probability, first latency, fraction of null sweeps, mean open time and single channel current amplitude were not different at both 1 and 4 Hz. Ethacizin (5 microM) caused a significant decrease in the peak open probability, a significant increase in the first latency and an increase in the fraction of null sweeps at 4 Hz compared with 1 Hz; mean open time and single channel current amplitude were unchanged. These observations support a model of antiarrhythmic action which proposes complete block of single channel conductance resulting from drug binding. A "runs analysis" revealed nonrandom clustering of null traces in the presence of ethacizin and no clustering in control patches. Increasing stimulation frequency makes this nonrandom behavior more apparent. We conclude that the relatively slow cycling of a few channels between blocked and unblocked states induces null sweeps clustering. The implications of these findings for mechanisms of drug block of the Na channel are discussed.     

The role of the type-III secretion system of Gram-negative bacteria in the regulation of chronic infections

This review article focuses on the discussion about the role of the type III secretion system (T3SS), which was found in several Gram-negative bacteria, in the development of chronic infectious processes. The latest investigations on this issue have revealed that most severe chronic somatic diseases derive from prolonged chronic inflammation induced by various infectious agents. The T3SS may play a crucial role in the transition of an infection from an acute form to persistent one. Numerous clinical and bacteriological studies have shown that pathogenic microorganisms are persistent in a form resistant to various antibiotics. Therefore, one of the most promising goals for the development of novel antibiotics is the T3SS, which transports bacterial pathogenic factors directly into the eukaryotic cell. The functioning of the T3SS is essential for occurrence and development of both acute and chronic infectious processes.     

Proarrhythmic response to sodium channel blockade. Theoretical model and numerical experiments.

BACKGROUND. The use of flecainide and encainide was terminated in the Cardiac Arrhythmia Suppression Trial because of an excess of sudden cardiac deaths in the active treatment group. Such events might arise from reentrant rhythms initiated by premature stimulation in the presence of anisotropic sodium channel availability. Drugs that bind to sodium channels increase the functional dispersion of refractoriness by slowing (a result of the drug-unbinding process) the transition from an inexcitable state to an excitable state. It is interesting that encainide and flecainide unbind slowly (15-20 seconds), whereas lidocaine and moricizine unbind rapidly (0.2-1.3 seconds). METHODS AND RESULTS. With a computer representation of a cable with Beeler-Reuter membrane properties, we found a small (6 msec) vulnerable window that occurred 338 msec after the last drive stimulus. Premature stimuli falling within the vulnerable window resulted in unidirectional block and reentrant activation. In the presence of a slowly unbinding drug, the window was delayed an additional 341 msec, and its duration was extended to 38 msec. The delay (antiarrhythmic effect) before the onset of the vulnerable window and its duration (proarrhythmic effect) were both dependent on the sodium channel availability and the recovery process. Both effects were also prolonged when sodium channel availability was reduced by membrane depolarization. Defining the proarrhythmic potential as the duration of the vulnerable window, we found that hypothetical use-dependent class I drugs have a greater proarrhythmic potential than non-use-dependent drugs. CONCLUSIONS. The antiarrhythmic and proarrhythmic properties of pure sodium channel antagonists are both dependent on sodium channel availability. Consequently, the price for increased antiarrhythmic efficacy (suppressed premature ventricular contractions) is an increased proarrhythmic vulnerability to unsuppressed premature ventricular contractions.     

Insulin-glucose parameters in healthy women and patients with arterial hypertension and ischemic heart disease in dependence on age and follicle-stimulating hormone levels

Insulin-glucose parameters in healthy women do not significantly change with changes of functional state of ovaries. Women with hypertension and normal levels of glycemia have significantly higher values of basal insulinemia and HOMA-R index reflecting presence of moderate insulin resistance degree of which is more pronounced in middle aged patients. In women with documented ischemic heart disease values of basal insulinemia, HOMA-R index, and glycemia are comparable with those in patients with hypertension and follicle-stimulating hormone level above 30 IE/l and significantly differ from corresponding parameters in healthy women in peri- and postmenopause.     

Preparation and characterization of monoclonal antibodies to group-specific antigenic determinant of group a streptococcus polysaccharide

Group A streptococcus polysaccharide contains at least two different group-specific determinants including N-acetyl-β-D-glucosamine (more important) and rhamnose. Monoclonal antibodies to group-specific determinants of group A streptococcus polysaccharide do not react with tissue antigens. Cross reactions with tissues were detected in tests with monoclonal antibodies to rhamnose-enriched epitopes of group A streptococcus polysaccharide. Translated fromByulleten' Eksperimental'noi Biologii i Meditsiny, Vol. 128, No. 10, pp. 433–436, October, 1999