Sympathoinhibitory and depressor responses to long-term infusion of nifedipine in spontaneously hypertensive rats on high-salt diet.

Short-term (by hour) intracerebroventricular (i.c.v.) or i.v. infusion of nifedipine at low rates evokes parallel decreases in renal sympathetic nerve activity (RSNA) and blood pressure (BP) in spontaneously hypertensive rats (SHR). In the present study, effects of long-term administration of nifedipine on BP and control of sympathetic tone were examined in SHR on a high-salt (8%) diet. From 6 to 8 weeks of age, for 2 weeks concomitant with taking a high-salt diet, rats were also treated with subcutaneous infusion of nifedipine at 10, 50, or 100 microg/kg/h or vehicle solvent as control using osmotic minipumps. At the end of the 2-week treatment period, mean arterial pressure (MAP), heart rate (HR), and RSNA at rest and in response to air-jet stress, i.c.v. injection of the alpha-adrenoceptor agonist guanabenz (25 microg), and i.v. injection of the ganglionic blocker hexamethonium were recorded in conscious rats. In rats on nifedipine 50 or 100 microg/kg/h, resting MAP was significantly lower (136+/-4 or 130+/-4 vs. 145+/-2 mm Hg in control rats, p < 0.05 for both), the sympathoinhibitory and depressor responses to i.c.v. guanabenz were significantly decreased, and the absolute decreases in MAP in response to i.v. injection of hexamethonium were significantly smaller. Sympathoexcitatory and pressor responses to air-jet stress, however, were not affected by nifedipine. Infusion of nifedipine at the three rates for 2 weeks caused concentrations of plasma nifedipine in a dose-related manner. Nifedipine was not detected in tissues of rats treated with 10 microg/kg/h nifedipine but was present in brain and other tissues of rats treated with nifedipine at the two higher rates. Thus in SHR on high-salt intake long-term treatment with nifedipine at 50 or 100 microg/kg/h decreased resting BP and the sympathetic component in BP control. In addition to possible peripheral effects, long-term administration of nifedipine may also act centrally to decrease sympathetic activity and BP, likely by increasing activity in central pathways involving sympathoinhibition, but not in pathways involving sympathoexcitation as evaluated by air-stress.

Sympathoinhibition by central and peripheral infusion of nifedipine in spontaneously hypertensive rats.

The present study assessed whether central mechanisms may contribute to the hypotensive effect of the calcium channel blocker nifedipine. In conscious, spontaneously hypertensive rats (SHR) on a high-salt diet, hemodynamic (mean arterial pressure [MAP] and heart rate) and sympathetic (renal sympathetic nerve activity) responses to low, central, intracerebroventricular infusion rates (25 microg. kg(-1). h(-1) for 2 hours) and peripheral intravenous rates (50 microg. kg(-1). h(-1) for 3 hours and then 100 microg. kg(-1). h(-1) for 2 hours) of nifedipine were evaluated. The distribution of nifedipine in the blood and tissues was assessed at the end of the infusions. Nifedipine significantly inhibited renal sympathetic nerve activity and lowered MAP in SHR beginning 30 minutes after the start of the intracerebroventricular infusion. The decrease of MAP by intravenous infusion began at 60 minutes and was more profound with 100 microg. kg(-1). h(-1). Inhibition of sympathetic activity preceded and then paralleled the decrease in blood pressure; it occurred earlier with central (15 to 30 minutes) than with peripheral (30 to 60 minutes) infusion. Intravenous infusion resulted in concentrations of nifedipine in brain structures (brain stem, midbrain, and cortex) that were 30% to 40% of those in the heart, kidneys, and liver. From the hemodynamic and sympathetic responses and the distribution of nifedipine into the central nervous system, we conclude that the peripheral infusion of nifedipine at relatively low rates may evoke a hypotensive response in SHR, not only via peripheral mechanisms, but also through central mechanisms, which will lead to an inhibition of sympathetic outflow and, therefore, a lowering of blood pressure.

[Neuroimmune relations in the rat thymus caused by recombinant interleukin-1beta administration]. / Izuchenie neroimmunnykh otnoshenii v timuse krys pri deistvii rekombinantnogo interleikina-1beta.

Interrelations among changes in 11-oxycorticosteroids (11-OSC) in blood plasma, catecholamines (CA), and acetylcholinesterase (AChE) activity in nerve fibres of the thymus, as well as qualitative content and proliferative capacity of thymic and blood cells under the effect of the rat recombinant interleukin-1 beta (IL-1beta) normally and under conditions of hypothalamic-pituitary-adrenocortical depression, were studied. The changes were the most obvious within 15 and 120 min following the IL-2 beta administration: elevation of the 11-OSC, increase in the CA content, and decrease in the AChE activity in thymic nerve fibres. Preliminary administration of dexamethasone prevented the effects.

Effects of interleukin-1beta on autonomic nervous activity and functional state of immunocompetent cells in the rat thymus.

The time course of IL-1beta effects on autonomic nervous activity and the functional state of lymphocytes in the rat thymus (15, 120 min and 24 hours) was studied. At 15 and 120 min after IL-1beta administration, an elevation of corticosterone (CS) in blood plasma, an increase in catecholamine (CA) content and a decrease in acetylcholinesterase (AChE) activity in thymic nerve fibers were observed as compared to intact and vehicle-treated animals. At 120 min, the percentage of T lymphocytes decreased in the thymus and increased nonsignificantly in the blood, as evaluated by flow cytometry. During this period, the proliferative response of thymocytes to mitogen was twice as high in animals treated with IL-1beta or vehicle as compared to intact rats, but did not differ 15 min and 24 hours later. Treatment with dexamethasone (DEX) prior to the administration of IL-1beta prevented the CS increase, diminished the CA increase and enhanced AChE activity in nerve fibers, and led to inhibition of the proliferative response of thymocytes to mitogen. Thus, IL-1beta induces substantial changes in the neuro-humoral supply of the rat thymus. The direction of the immune function changes depends on the balance between the CS content in blood, and CA and AChE activity in the nerve fibers of the rat thymus.

[Ultrastructural changes in the axons in the feline spleen under the influence of large doses of lipopolysaccharide]. / Izmenenie ul'trastruktury aksonov v selezenke koshki pod vliianiem bol'shikh doz lipopolisakharida.

The cytoarchitecture of the cat spleen early after two injections of large doses of S. typhi lipopolysaccharide was studied. Changes were found not only in axons containing granular vesicles but also in endotheliocytes and macrophages, nerve fibers with modified axons were located rather far from the splenic vessels. Vacuolization if endotheliocytes and macrophages in the cat spleen was observed. The coupling and interdependence of the changes is discussed.

[Effects of diazepam and piracetam on the rat behavior responses after combined exposure to the low doses of ionizing radiation and heat]. / Vliianie diazepama i piratsetama na povedencheskie reaktsii krys posle sochetannogo deistviia malykh doz radiatsii i tepla.

Effects of low doses of ionizing radiation and heat on behavioural responses of white rats and effects of diazepam and pyracetam long after separate and combined exposure to the two factors were studied. These changes were not present in a month after cessation of the exposure. Certain features of the modulating effect of pyracetam on behavioural responses, were revealed.

[Dynamics of the changes in various integral indices of the functional state of the body of white rats during the prolonged action of x-radiation and external heat]. / Dinamika izmenenii nekotorykh integral'nykh pokazatelei funktsional'nogo sostoianiia organizma belykh krys pri prolongirovannom deistvii rentgenovskogo oblucheniia i vneshnego tepla.

Effects of low doses of X-radiation (0.02 Gr. a session, for 25 days), external heat (daily 4-h exposure in a thermochamber at 37.0 degrees C) and combined (consecutive) action of these factors on mature Wistar male rats were studied. Experimental animals were somewhat behind in body mass increment during exposure to the physical factors as compared to control rats. Radiation promoted a rise in rectal temperature, external heating to its small decrease, while combined exposure to the factors levelled the effects. There were certain changes in the CNS, as indicated by a small increase in the summation-threshold index. The heart rate did not significantly change. The changes normalized within 1-5 weeks after cessation of the exposures.

Ultrastructure and functional state of rabbit lymphoid cells after repeated exposure to lipopolysaccharide and external heating.

The ultrastructure and proliferative activity of lymphoid tissue cells in rabbits after repeated exposures to lipopolysaccharide (LPS) or external heating were studied. It was shown that in conditions of the same increase in body temperature the production of IL-1-like activity by blood and splenic cells was inhibited to the same extent in both groups of animals. It was suggested that one of the causes of LPS-induced tolerance may be events provoked by temperature factor per se. There were similar changes in activity of epithelial cells in the thymus, reticular cells in the spleen, in activation of mast cells in these organs and in proliferative processes in the thymus after both exposures, however inhibition of proliferative activity of splenic and lymph node cells was observed only in LPS-treated animals.

[The local immunoneuroendocrine system of the pancreas and the development of type-1 diabetes mellitus. A hypothesis]. / Lokal'naia immunoneiroéndokrinnaia sistema podzheludochnoi zhelezy i razvitie sakharnogo diabeta I tipa. Gipoteza.

It is suggested that the development of insulin-dependent diabetes mellitus (IDDM) is due to insufficiency of local immunoneuroendocrine system (LINES), which prevents development of the pathological process in the insular tissue at the very early stages. The further disbalance between LINES and CNS and development of pathology occurs with a very active involvement of immunocompetent cells and their effector molecules (autoantibodies, cytokines). We believe that finding of mechanisms of cell interactions inside LINES (beta-cells, neurons, lymphocytes and macrophages) at the early stages will serve a basis for IDDM prevention.

[Acetylcholinesterase activity and catecholamine content in nerve fibers of the thymus gland and spleen in white rats at remote time after chronic exposure to physical factors and administration of interleukin-1 beta]. / Aktivnost' atsetilkholinéstgerazy i soderzhanie katekholaminov v nervnykh voloknakh timusa i selezenki belykh krys v otdalennye sroki posle khronicheskogo deistviia fizicheskikh faktorov i vvedeniia interleikina-1beta.

Acetylcholinesterase (AChE) activity and catecholamine (CA) content in nerve fibres of the thymus and spleen of white rats were studied 6 months after prolonged combined exposure to ionizing radiation and heat and after application of interleukin-1 beta (IL-1 beta). Combined action of the physical factors induced a certain decrease in AChE activity and increase in CA content in both organs. Application of the cytokine to animals exposed to radiation and heat elicited a more pronounced decrease in AChE in these lymphoid organs and increase, especially in the spleen, in CA. The results suggest about enhanced responsiveness of the autonomic nervous system to IL-1 beta animals which had been long before exposed to prolonged combined action of radiation and heat.

[The functional status of the immunocompetent cells in animals at different times after the chronic action of irradiation and heat]. / Funktsional'noe sostoianie immunokompetentnykh kletok u zhivotnykh v raznye sroki posle khronicheskogo deistviia oblucheniia i tepla.

The proliferative response of thymic and splenic cells and the production of interleukin-1 and interleukin-2 by splenocytes were studied a day, three and six months after 25-fold separate and combination radiation (total dose 0.5 Gy) and heat (37 degrees C, 4h). The proliferative activity of lymphocytes of both organs was found to enhance a day after heating. No changes were found three months later. The proliferative activity of thymocytes in rats exposed to radiation and combination of the two factors was inhibited after six months. The production of interleukin-1 was lowered after irradiation.

[The hormonal status and carbohydrate-energy metabolism of rats after the long-term action of low doses of ionizing radiation and heat]. / Gormonal'nyi status i uglevodno-énergeticheskii obmen u krys posle dlitel'nogo deistviia malykh doz ioniziruiushchego izlucheniia i tepla.

Hormonal status (blood content of triiodothyronine, thyroxin, insulin, 11-hydroxycorticosteroids), dehydration in the Krebs cycle, and activity of the first enzyme in the pentose-phosphate cycle, glucose-6-phosphate dehydrogenase, in the brain and myocardium of white rats were studied at different time periods after separate and combined prolonged exposure to radiation in relatively small doses and heat. It was found that combination of ionizing radiation and heat led to hypofunction of the endocrine glands and inhibition of dehydration processes in the Krebs Cycle.

[The effect of recombinant interleukin-1 beta on concanavalin A-induced lymphocyte reactions]. / Vliianie rekombinantnogo interleikina-1 beta na indutsirovannye konkanavalinom A reaktsii limfotsitov.

As revealed by investigations made by the use of the method of luminol-dependent chemiluminescence and light dispersion, the addition of concanavalin A (ConA) to the suspension of human peripheral blood lymphocytes and subsequent incubation with recombinant interleukin-1 beta leads to a sharp increase in the yield of chemiluminescence and the rate of cell aggregation in comparison with similar parameters obtained for cells, not treated with interleukin-1 beta. The study revealed the potentiating action of recombinant interleukin-1 beta on ConA-induced proliferative response of thymocytes in the culture. The mechanisms of the priming action of recombinant interleukin-1 beta on ConA-induced reaction of lymphocytes are discussed.

Changes in the ultrastructure and functions of immunocompetent cells under the influence of external heating, interleukin 1 beta and leukocytic pyrogen.

The structural and functional organization of the rabbit immunocompetent cells after injection of human recombinant interleukin 1 beta (IL-1 beta), partially purified leukocytic pyrogen (LP), or after external heating (36 degrees C, 1.5 h) was compared. A rectal temperature increase being the same, there were similar and transient changes in epithelial and endothelial cells and macrophages, a rise in the proliferative activity of thymocytes and synthesis of IL-1-like activity, and a decrease in the interleukin 2 (IL-2) production by cultured splenic cells.

[Effects of pulmonary surfactant on the activity of interleukin-1 secreted by macrophages in normal state and in pulmonary fibrosis]. / Vliianie surfaktanta legkikh na aktivnost' interleikina-1, sekretiruemogo makrofagami v norme i pri pnevmofibrose.

The article deals with the study of the influence produced by pulmonary surfactant on the activity of interleukin-1 secreted by macrophages which were isolated from the lungs of Wistar male rats 3 weeks after they were given a one-time administration of bleomycin or sodium chloride isotonic solution. Under conditions of prostaglandin synthesis stimulated by lipopolysaccharides and simultaneously inhibited by indomethacin macrophages of the lungs with forming fibrosis secrete an increased amount of interleukin-1. Cultivation of macrophages isolated from fibrosis-affected lungs with surfactant was also accompanied by enhanced activity of this monokine. Interleukin-1 secretion by macrophages of animals with fibrosis was drastically increased in the presence of polymyxin B. Under the same conditions pulmonary surfactant significantly stimulated the activity of monokine which was secreted both by cells of the normal animals and by those obtained from the lungs with fibrosis. Consideration is given to the importance of this phenomenon for the pathogenesis of pulmonary fibrosis.

[Functional state of immunocompetent cells in rabbits partially tolerant to lipopolysaccharide]. / Funktsional'noe sostoianie immunokompetentnykh kletok u chastichno tolerantnykh k lipopolisakharidu krolikov.

The author studied the regular features of interleukin-1 (IL-1) formation and proliferative activity of cells of the lymphoid organs in rabbits tolerant to lipopolysaccharide (LPS). A weak temperature response of LPS tolerant rabbits to LPS administration was linked with decrease of IL-1 secretion by blood and splenic cells and the formation in the spleen of a cell population which had a suppressive effect on IL-1 production. In administration of large LPS doses, the changes of the processes of IL-1 proliferation and production in the various lymphoid organs of the rabbits differed. The proliferative response of the splenic cells to T- and B-cell mitogens reduced, a tendency to intensification of the proliferative processes was noted in the thymus. The secretion and accumulation of IL-1 by blood and splenic cells was reduced, the secretion and intracellular content of this mediator in the thymus and lymph nodes was increased.

[Interleukin-1 formation during inhibition of proteolytic enzyme activity]. / Obrazovanie interleikina-1 v usloviiakh ugneteniia aktivnosti proteoliticheskikh fermentov.

Contrycal and phosphomethylsulfonyl fluoride prevented a decrease in activity of interleukin-1 (IL) in 3-days-old culture of mononuclear cells from human peripheral blood stimulated with lipopolysaccharide. These protease inhibitors did not affect per se the IL formation as distinct from soy bean trypsin inhibitor which developed immunostimulating and pyrogenic activities of IL in the cell culture. Use of contrycal enabled to increase content of IL in human and rabbit whole blood culture stimulated by lipopolysaccharide as well as to reinforce the rate of rabbit fever caused by exogenous pyrogen.