Chemistry, binding affinities, and behavioral properties of a new class of "antineophobic" mitochondrial DBI receptor complex (mDRC) ligands

The mitochondrial DBI receptor complex (mDRC; previously called the peripheral benzodiazepine receptors) is linked to the production of neurosteroids such as pregnenolone sulfate, dehydroepiandrosterone sulfate, and others. In order to gain further information as to the function of the mDRC in the brain, we have constructed and tested both in vitro and in vivo a novel series of ligands, 2-arylindole-3-acetamides. The SAR studies detailed herein delineate some of the structural features required for high affinity binding to the mDRCs. In most cases the new ligands were prepared by use of the Fischer indole synthesis. Variations in the length and number of the alkyl groups on the amide nitrogen were probed together with the effects of halogen substituents on one or both of the aryl rings. Some ligands were also synthesized for study which represent conformationally constrained versions of the parent structure. Broad screening studies revealed these indoleacetamides to be highly selective for the mDRC, since they failed to bind with any significant affinity to other receptor systems. Some of the ligands were found to exhibit Ki values in the low nanomolar range for the mDRC as measured by the displacement of [3H]4'-chlorodiazepam. A subset of these ligands was also shown to stimulate pregnenolone formation from the mitochondria of C6-2B glioma cells with an EC50 of about 3 nM. In animal experiments ligands selected for further study were found to exhibit antineophobic effects, in spite of the fact that they exhibit no direct action on GABAA receptors. Consequently, it is postulated that these ligands owe their action to an indirect modulation of GABAA receptor function, presumably by stimulation of neurosteroid production and release from glial cells, followed by neurosteroid modulation of GABA's action on the chloride ion channel conductance of GABAA receptors.     

Role of electric stimulation of the heart during selective contrast examination of the coronary arteries with the use of the data of continuous recording of the bundle of His potentials and arterial pressure

The frequency of disorders of the cardiac rhythm during injection of a contrast medium into the coronary vessel under different conditions was studied in 214 patients. Atropine premedication was applied as a preventive factor in 142 patients, atrial stimulation in 60, and both factors simultaneously in 12. In 10 patients a single injection of the contrast medium was performed without preventive measures. In 20 patients the changes were studied by recording the potentials of the bundle of His and the arterial pressure. On the basis of the bundle of His ECG data it is concluded that atropine and atrial stimulation produce an effect on individual links of the complex mechanism underlying the effect of the contrast medium on the cardiac conduction system.     

An endogenous calcium oscillator may control early embryonic division

Transient elevations in the concentration of free cytosolic calcium ion ([Ca2+]i) promote cell phase transitions in early embryonic division and persist even if these transitions are blocked. These observations suggest that a [Ca2+]i oscillator is an essential timing element of the early embryonic "master clock." We explore this possibility by coupling a [Ca2+]i oscillator model to an early embryonic cell cycle model based on the protein interactions that govern the activity of the M-phase-promoting factor (MPF). We hypothesize three dynamical states of the MPF system and choose parameter sets to represent each. We then investigate how [Ca2+]i dynamics may control early embryonic division in both sea urchin and Xenopus embryos. To investigate both systems, distinct [Ca2+]i profiles matching those observed in sea urchin embryos (in which [Ca2+]i exhibits sharp transients) and Xenopus embryos (in which [Ca2+]i is elevated and oscillates sinusoidally) are imposed on each of the hypothesized dynamical states of MPF. In the first hypothesis, [Ca2+]i oscillations entrain the autonomous MPF oscillator. In the second and third hypotheses, where the MPF system rests in excitatory and bistable states, respectively, [Ca2+]i oscillations drive MPF activation cycles. Simulation results show that hypotheses two and three, in which a [Ca2+]i oscillator is a fundamental timing element of the master clock, best account for key experimental observations and the questions that they raise. Finally, we propose experiments to elucidate further [Ca2+]i regulation and the fundamental components of the early embryonic master clock.