IN VITRO DESENSITIZATION OF β-ADRENOCEPTORS IN GUINEA PIG TRACHEA: INTERACTIONS BETWEEN β-ADRENOCEPTOR AGONISTS AND INFLUENCE OF ADENOSINE AND OTHER DRUGS

The aim of this study was to investigate quantitatively the action of and the interaction between beta-adrenergic receptor agonists in desensitizing guinea pig isolated trachea. It was also to evaluate the influence of substances whose effects on desensitization are either disputed (theophylline, indomethacin, ketotifen, hydrocortisone) or unknown (nicardipine, Bay K 8644, fenspiride, adenosine). Tracheal strips were contracted with histamine (5 x 10(-5) M) or acetylcholine (5.10(-5) M) and concentration-response (C/R) curves for various beta-adrenoceptor agonists were determined before and after incubation (20 min to 4 h) with the same beta-adrenoceptor agonist (autodesensitization), with other beta-adrenoceptor agonists (cross-desensitization), or with a beta-adrenoceptor agonist and another substance. Our results show that the autodesensitization induced by isoprenaline is concentration dependent and that concentration dependence is more pronounced with salbutamol and fenoterol than with isoprenaline and adrenaline with respect to autodesensitization: shifts (log unit) of the C/R curves were 0.59 +/- 0.06 (N = 5) for salbutamol (10(-5) M), 0.78 +/- 0.09 (N = 5) for fenoterol (10(-6) M), 0.30 +/- 0.04 (N = 9) for isoprenaline (10(-5) M), and 0.33 +/- 0.05 (N = 5) for adrenaline (10(-5) M). Our studies of cross-desensitization (desensitization to isoprenaline, adrenaline, salbutamol, and fenoterol induced by incubation with isoprenaline 10(-5) M) showed a significantly greater shift in the C/R curves for fenoterol (0.56 +/- 0.08, N = 5) and salbutamol (0.62 +/- 0.05, N = 5) than for adrenaline (0.35 +/- 0.07, N = 5) and isoprenaline itself (0.30 +/- 0.05, N = 9). Of the substances we studied, none modified the desensitization induced by isoprenaline except hydrocortisone and adenosine. Hydrocortisone (10(-8) M) reduced it significantly, although to a negligible extent. Adenosine (3 x 10(-4) M) did not shift the C/R curve to isoprenaline by itself, but incubation of tracheal strips with adenosine and isoprenaline caused a significantly greater shift of C/R curves to isoprenaline (0.30 +/- 0.04) than incubation with isoprenaline alone (0.20 +/- 0.04) (P less than 0.05, N = 5). These experiments suggest that adenosine may have increased the uncoupling and/or down-regulation phenomena induced by isoprenaline, or modified adenylate cyclase-cAMP activity.     

INVESTIGATION OF THE EFFECTS OF β-2 STIMULATION ON FREE FATTY ACIDS IN MAN

In this study we present evidence that lipolysis in man is under beta-2 adrenergic control and that beta-2 stimulation produces a characteristic profile of individual free fatty acid (FFA) release. Twelve healthy volunteers received infusions of placebo (N Saline), terbutaline (a selective beta-2 agonist) and dilevalol (a new non-selective beta-blocker with beta-2 agonist activity). Plasma FFA concentrations during and after the infusions were measured using gas chromatography. A significant rise in total and individual FFAs was seen after 30 min of terbutaline infusion. This was most marked for oleic acid. Total and individual FFA concentrations also rose after 30 min of dilevalol infusion; this was only significant for oleic acid and was approximately 15% of the rise induced by terbutaline infusion. Placebo infusion did not cause any significant changes in FFA levels.     

ASSESSMENT OF β-1 SELECTIVITY OF BISOPROLOL AND ATENOLOL BY MEANS OF THEIR INFLUENCE ON THE LIPOLYTIC RESPONSE TO AN INFUSION OF TERBUTALINE

We have investigated the beta-1 selectivity of a new beta-blocker, Bisoprolol, by comparing its effect on lipolysis induced by intravenous terbutaline infusion with that of Atenolol. At a dose of 5 mg, Bisoprolol had virtually no beta-2 blocking activity as measured by free fatty acid (FFA) release during terbutaline infusion. At a dose of 10 mg, Bisoprolol had a small but statistically insignificant effect on FFA release similar to 50 mg Atenolol. At a dose of 20 mg, Bisoprolol had significant beta-2 blocking activity. At lower doses, therefore, Bisoprolol is a very selective beta-blocker.     

A STUDY OF THE RESISTANCE OF NORMAL HUMAN BEINGS TO RECENTLY ISOLATED STRAINS OF PATHOGENIC PNEUMOCOCCI

With a view to obtaining information as to the virulence of pneumococci for human beings a study was made of the pneumococcidal action of normal human serum-leucocyte mixtures for freshly isolated strains of pathogenic pneumococci. It was found that human beings as a group showed well marked pneumococcus destroying power in their blood for all types of organisms studied. Individuals, however, exhibited wide variations in their reactions against the different types. These ranged from marked killing effect for one type of pneumococcus to none or slight against another. While reactions against different strains within the type often varied considerably this difference was less, on the whole, than that between types. An interpretation of these findings in the light of previous animal experiments in which actual determination of resistance to pneumococcus infection was made leads to the inference that human beings in general possess a considerable degree of natural immunity to all types of pneumococci but that individuals may be relatively susceptible to one or more types and at the same time resistant to others; also that pathogenic strains of pneumococci vary much in their virulence for man.     

THE IMMUNE RESPONSE TO A HYBRID PROTEIN MOLECULE : SPECIFICITY OF SECONDARY STIMULATION AND OF TOLERANCE INDUCTION

Upon immunization with LDH-III (subunit composition AABB) rabbits produce anti-A and anti-B antibodies in comparable amounts. These antibodies fit equally well to the hybrid enzyme and to LDH-V (AAAA) or LDH-I (BBBB) respectively, as tested by passive hemagglutination inhibition. No antibodies reacting with both LDH-I and LDH-V were detected. A minority of hybrid-specific antibodies was, however, present in the sera. Animals primed with LDH-III respond regularly to a boosting injection of LDH-V with the production of large amounts of anti-A (but not anti-B) antibodies. A similar injection of LDH-I stimulates (if it has any effect at all) the production of anti-B antibodies only. Stimulation with one of the pure types does not impair a subsequent response to the other. The majority of the animals primed with LDH-III responded not at all or weakly to a boosting injection of LDH-I, though antibodies to LDH-I were present in the sera at the time of stimulation. This effect can hardly be explained on the basis of serological sepcificity. Hyporesponsiveness to LDH-III can be induced by injection of LDH-V into the newborn. Both anti-A and anti-B titers are equally depressed. Within the dose range tested, LDH-I does not exert any tolerogenic action with respect to LDH-III. The carrier property of subunit A is evident in the induction of both immunity and tolerance to LDH-III. The early phase of the immune response to the hybrid enzyme may be carrier-specific, and receptors for the haptenic subunit B may not exist at that stage.     

CELL POPULATIONS AND CELL PROLIFERATION IN THE IN VITRO RESPONSE OF NORMAL MOUSE SPLEEN TO HETEROLOGOUS ERYTHROCYTES : ANALYSIS BY THE HOT PULSE TECHNIQUE

The role of proliferation in the development of 19S antibody-forming cells in the primary response has been investigated in an in vitro system. Spleen cell suspensions from normal, unimmunized mice were cultured in vitro in the presence of mammalian erythrocytes and the number of 19S hemolytic plaque-forming cells that arose 4 days later was measured. The hot pulse technique for the selective irradiation of those cells which synthesize DNA during a defined period of time has been described. The effect of such hot pulses administered at various times after the addition of antigen on the subsequent appearance of antibody-forming cells was determined. The results established that: (a) the onset of DNA synthesis does not start for approximately 24–32 hr after the addition of antigen, (b) essentially all the antibody-forming cells arise by cell division, and (c) different cell populations are involved in the response to two non-cross-reacting antigens.     

STUDIES ON IMMUNITY IN A TYPE OF HUMAN ALLERGY (HAY FEVER): SEROLOGIC RESPONSE OF NON-SENSITIVE INDIVIDUALS TO POLLEN INJECTIONS

Large injections of ragweed pollen extract into normal non-sensitive volunteers did not produce a sensitization to ragweed. Group 1 volunteers in whose skin many reactions were induced by injections of ragweed extract mixed with ragweed sensitive serum failed to show any serological changes. The theory that the immune substance found in the serum of treated ragweed sensitive cases was due to the reaction or to some substance created by it and not to the ragweed per se was not upheld. On the contrary in group 2, volunteers who received larger amounts of ragweed but no sensitive serum, serological changes were induced resembling those previously observed to occur in ragweed sensitive patients after treatment. They were demonstrable by an inhibition of the immediate reaction and by interference with the neutralization of sensitive serum by its antigen. These serological changes are therefore independent of the specific reaction characteristic of this type of allergy. The inhibiting factor was found to be related to the pseudoglobulin fraction of the serum and was shown to be specific.     

RELATION OF A β1-GLYCOPROTEIN OF HUMAN SERUM TO THE COMPLEMENT SYSTEM

The protein of human serum, tentatively designated β_1C-globulin, was shown to possess serological activity and to be related to the complement system. Another serum protein (β_1A-globulin) was identified as the inactivated form of β_1C-globulin. Incubation of fresh serum with various immune precipitates or with soluble γ-globulin aggregates at 37°C. resulted in the removal of β_1C-globulin. Treatment of fresh serum with zymosan at 17 and 37°C. had a similar effect. In both instances β_1C-globulin was removed from serum, apparently by conversion to β_1A-globulin. However, isolated β_1C-globulin did not react with immune precipitates or zymosan, nor did β_1C-globulin of serum previously heated at 56°C. Highly purified β_1C-globulin was tested for complement component activity by means of the usual reagents. All of the preparations examined were found to reconstitute the hemolytic activity of guinea pig R₃. However, they failed to reconstitute R₃ obtained from human serum. Isolated β_1A-globulin was found to be inactive in all systems. When isolated β_1C-globulin in either phosphate or in borate buffer was stored at 37°C., the activity detected by means of guinea pig R₃ declined within 6 days to 20 to 30 per cent of its original value. As the activity decreased, β_1C-globulin was gradually converted to β_1A-globulin. Addition of β_1C-globulin to a limited complement system (human C') caused an increase of both initial velocity and final degree of hemolysis. Although β_1C-globulin did not cause lysis of EAC'_{1, 4, 2}, it fully prevented the otherwise rapid decay of EAC'_{1, 4, 2} at 37°C., and so presumably interacted with this complex.     

小面积探头测量人体压痛阈影响因素及正常参考值调查

目的:分析0.1 cm2小面积探头用于压痛阈测量的影响因素,并计算其正常参考值。方法:以武汉某校男女各50名健康在校大学生为受试者,采用0.1 cm2探头的压力测痛仪,选定右侧前臂两个测痛点,测量两处皮脂厚度、压痛痛觉和耐痛阈值,然后分析影响压痛阈的因素并计算其正常参考值。结果:女性受试者两测痛点处压痛阈值比男性低(P<0.001);各测痛点压痛阈值与测痛点处皮脂厚度(P<0.05)呈正相关;纳入受试者测痛点1处压痛阈值低于测痛点2(P<0.001);通过计算得到不同性别受试者两测痛点处压痛阈值95%正常参考值。结论:0.1 cm2探头用于压痛阈测量受到性别、测痛点深部组织结构及皮脂厚度的影响;本研究所得的正常参考值可为今后0.1 cm2探头用于临床压痛测量提供一定参考。     

SHEEP RED CELL BINDING TO HUMAN LYMPHOCYTES TREATED WITH NEURAMINIDASE; ENHANCEMENT OF T CELL BINDING AND IDENTIFICATION OF A SUBPOPULATION OF B CELLS

Neuraminidase treatment of normal human lymphocytes enhances their capacity to form SRBC rosettes; more red cells are bound and the rosettes are more stable. Under these conditions approximately 90% of peripheral blood lymphocytes form rosettes. In addition to the effects on T cells, another population of lymphocytes which possess surface immunoglobulin and have the Fc receptor acquire the rosette-forming property after neuraminidase. This subpopulation of ‘B’ cells represents approximately half of the lymphocytes with surface immunoglobulin but is not found among the leukemic lymphocytes of patients with chronic lymphocytic leukemia. Electron microscope observations indicate close approximation and intimate association of the red cell and lymphocyte membranes after neuraminidase.