Antidepressive properties of propranolol

Department of Pharmacology, Stavropol' Medical Institute. (Presented by Academician of the Russian Academy of Medical Sciences D. A. Kharkevich.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 114, No. 10, pp. 372–374, October, 1992.     

Human T-lymphocyte subset production of immune (γ) interferon

Human T, T, and T lymphocyte subpopulations have the capacity to respond to phytohemagglutinin (PHA)in vitro with proliferation and the production of a pH 2 and heat-labile interferon. This occurs both when the subsets are isolated by direct rosetting techniques or by negative selection. Macrophages enhance the production of the interferon by each lymphocyte subset and do not themselves produce interferon in response to products of PHA-activated lymphocyte subsets. Thus our studies indicate that subpopulations of T lymphocytes known to differ with regard to morphology, surface receptors, RNA content, response to corticosteroids and X-irradiation, and other functional capabilities do not differ with regard to their capacity to produce interferon.     

Glucocorticoids modulate TGF-beta production

TGF- is thought to play a central role in pulmonary fibrosis inducing fibroblast differentiation and extracellular matrix synthesis. In human lung fibroblasts, it is still unclear how various TGB- isoforms affect TGF- production and whether glucocorticoids, commonly used agents to treat fibrotic lung disease, modulate these processes. To this end, human fetal lung fibroblasts (HFL-1) were cultured with various concentrations of glucocorticoids (budesonide, dexamethasone or hydrocortisone) with and without TFG-1, -2, and -3. TGF- mRNA was assessed by real time RT-PCR. Smad 2, 3, and 4 and AP-1 complex (c-fos and c-Jun) cellular localization were evaluated by immunostaining. TGF-2 and -3 stimulated TGF-1 production significantly (p < 0.01 relative to control). TGF-1 stimulated TGF-2 production (p < 0.01 relative to control). TGF-3 was undetectable. Glucocorticoids significantly inhibited TGF-1 and -2 production and reduced expression of the upregulated TGF-1 and -2 mRNA induced by exogenous TGF-1, -2 or -3 (p < 0.01 for each) but had no effect on Smads. Although c-jun-related nuclear staining was not intensified in TGF--stimulated cells, it was reduced by glucocorticoids. Thus, TGF- isoforms may stimulate production of various TGF- isoforms in the lung. Glucocorticoids then may block TGF- production by modulating mRNA levels and c-Jun.     

“Exercise pyrogens”

Blood plasma taken from subjects either at rest or during muscular exercise was injected intravenously into rabbits. The rectal temperature of the animals changed differently: After injection of exercise plasma the temperature was at a higher level. This effect can be explained by the presence of exercise pyrogens in the plasma.Department of Physiology, Moscow Regional Institute of Physical Culture, Malakhova, Moscow Province. (Presented by Academician of the Academy of Medical Sciences of the USSR V. A. Negovskii.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 88, No. 8, pp. 144–145, August, 1979.     

Cow milk angiogenin induces cytokine production in human blood leukocytes

Angiogenin isolated from cow milk induces the production of cytokines IL-1, IL-6, and TNF- in human leukocytes; the level of production of each cytokine depends on the concentration of the preparation, and the dynamics of production depends on the time from the beginning of induction. Simultaneous treatment with angiogenin and phytohemagglutinin had an additive effect on the production of cytokines, the time of this effect manifestation being individual for each cytokine.     

Effect of chronic β-adrenergic blockade on exercise-induced leukocytosis

Summary Chronic -receptor blockade on exercise-induced leukocytosis was studied in 11 hypertensive males. Blood samples for determinating leukocytes were taken before and during the 6th min and the 30th min of submaximal exercise, at maximal exercise, and 5 and 15 min after work. Lymphocytosis and granulocytosis were found to be dependent on the intensity and duration of the exercise. Leukocytosis during short-term and long-term exercise was due to both a lymphocytosis and graulocytosis. Under resting conditions, the chronic -receptor blockade caused a significant decrease of neutrophil granulocytes. Both the patients and the controls showed the same percent increase in leukocytes compared with the untreated control study. This suggests that the adrenergic system does not play the primary role in exercise-induced leukocytosis.Abbreviations Ps systolic blood pressure - P25 25th percentile point - P75 75th percentile point - W Watt Supported by Bundesinstitut für Sportwissenschaft, Köln     

The effect of beta-adrenergic blockade on leg blood flow with repeated maximal contractions of the triceps surae muscle group in man

Summary The effect of -adrenergic blockade on torque output and leg blood flow was examined in seven healthy young men during repeated maximal isometric voluntary contractions of the triceps surae muscle group. Exercise was performed in either a bent- or straight-leg position during each of four drug treatments: placebo, propranolol, metoprolol, oxprenolol. Contractions were sustained for 5 s with 5 s relaxation for a total of 10 min followed by a 10-min recovery. Leg blood flow was measured during the 5 s relaxation separating contractions using strain gauge plethysmography. Torque output decreased during the 10-min contractions with no differences between the four drug treatments. Leg blood flow was lower with -blockade during the initial stages of exercise and recovery in the bent-leg position but no differences were observed after 3 min exercise or recovery. Leg blood flow in the straight-leg position was not different between any of the four drug treatments, but it was significantly less than in bent-leg exercise. The lower blood flows during the initial stages of exercise in the -blocked conditions probably reflect a slowing of the central cardiovascular response because of ₁-receptor blockade of the heart rather than on the ₂-receptors effects on peripheral vacular resistance. It is concluded that local vasodilator substances released from the working muscle may play a more important role than ₂-receptor stimulation of smooth muscle in skeletal muscle resistance vessels in regulating local muscle blood flow during maximal exercise of the triceps surae muscle group.     

Free radical lipid peroxidation inhibits enzymatic conversion of beta-carotene into vitamin A

Free radical oxidation of arachidonic acid with soybean lipoxygenase was accompanied by inhibition of retinal synthesis from -carotene catalyzed by enzyme preparation from rabbit intestinal mucosa. Lipoxygenase inhibitor salicylhydroxamic acid and antioxidants suppressing free radical reactions (ethyl gallate, -tocopherol, astaxanthine, and quercetin) promoted conversion of -carotene into retinal catalyzed by -carotene-15,15'-dioxygenase. These results indicate that lipoperoxides and/or products of their homolysis attenuate enzymatic conversion of -carotene and confirm the important role of natural antioxidants in the maintenance of stable vitamin A content in mammals.     

Myocardial β-adrenergic receptor signaling in vivo: insights from transgenic mice

Heart failure is a problem of increasing importance in cardiovascular medicine. An important characteristic of heart failure is reduced agonist-stimulated adenylyl cyclase activity (receptor desensitization) due to both diminished receptor number (receptor downregulation) and impaired receptor function (receptor uncoupling). These changes in the §-adrenergic receptor (§ AR) system may in part account for some of the abnormalities of contractile function in this disease. Myocardial contraction is closely regulated by G protein coupled -adrenergic receptors through the action of the second messenger cAMP. The -adrenergic receptors themselves are regulated by a set of specific kinases, termed the G protein-coupled receptor kinases. The study of this complex system in vivo has recently been advanced by the development of transgenic and gene targeted (knock out) mouse models. Combining transgenic technology with sophisticated physiological measurements of cardiac hemodynamics is an extremely powerful strategy to study the regulation of myocardial contractility in the normal and failing heart.Abbreviations -AR -Adrenergic receptor - GRK G protein coupled receptor kinase - LV Left ventricular     

Synoviocytes in chronic synovitis in situ and cytokine stimulated synovial cells in vitro neo-express α1, α3 and α5 chains of β1 integrins

The expression of the 1 integrins was examined immunohistochemically in synoviocytes from normal synovial membrane and from chronic synovitis of different aetiology and intensity. Normal synoviocytes were 61-positive but lacked 1 through 5. In mild inflammation type A synoviocytes neo-expressed 1, 3, and 5 chains. In severe inflammation both type A and B synoviocytes expressed 3, 4, 5, and 6 chains. The effects of inflammatory cytokines, as single agents or in combination, on the 1 integrin expression in cultured normal synoviocytes was determined by immunocytochemistry and flow cytometry. The 1 chain, while absent in unstimulated synoviocytes, was induced by interleukin-1 (IL-1), tumour necrosis factor- (TNF-), and interferon- (INF-). This effect was enhanced by combining IL-1 and TNF-. Expression of the 3 chain was up-regulated by IL-1 and, more intensely, by IFN-. Transforming growth factor (TGF-) inhibited the up-regulating effect of IL-1 and antagonized the effect of IFN- on 3 chain expression. Expression of the 5 chain was up-regulated significantly by co-stimulation through IL-1 together with TGF- or TNF-. Thus, the 1 integrin profile of cytokine activated synoviocytes in vitro resembled that of synoviocytes in synovitis in situ. These data suggest that IL-1, TNF-, IFN-, and TGF- are likely to be among the effectors regulating 1 integrin expression in synoviocytes in vivo.     

Effect of amino acid derivatives of β-carboline-3-carboxylate on behavior in rats

Brain Research Institute, All-Union Mental Health Research Center, Academy of Medical Sciences of the USSR, Moscow. (Presented by Academician of the Academy of Medical Sciences of the USSR O. S. Adrianov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 107, No. 5, pp. 586–587, May, 1989.     

Flow Cytometric Analysis of In Vitro Proinflammatory Cytokine Secretion in Peripheral Blood from Multiple Sclerosis Patients

The cytokines, interferon- (IFN-), tumor necrosis factor- (TNF-rpar;, and interleukin-2 (IL-2) are important endogenous proinflammatory proteins and have been linked to disease activity in multiple sclerosis. In this study, we use flow cytometric methodology to compare the secretion of IFN-, IL-2, and TNF- from peripheral blood-derived T cells of multiple sclerosis patients to the secretion in healthy controls. The percentages of IFN-, IL-2, and TNF- secreting cells are not significantly different between multiple sclerosis patients and controls. However, the TNF- secreting CDS cell percentage is correlated with the IFN- and IL-2 secreting CD3 cell percentages in multiple sclerosis patients. In the controls, only the TNF- secreting CD3 cell percentage is correlated with IFN-. These findings show that correlated secretion of cytokines occurs in multiple sclerosis and suggest that concerted intercytokine interactions may play an important role in the disease.     

Physical activity decreases the number of β-adrenergic receptors on human lymphocytes

Summary On intact human lymphocytes a specific binding site (BS) for¹²⁵I-Cyanopindolol (¹²⁵I-CYP), a derivative of the -blocking drug pindolol, was characterized. Inhibition of binding for catecholamines in the following order of potency: l-isoprenaline > l-adrenaline > l-noradrenaline proves the BS as a ₂-receptor subtype. In 77 healthy persons (36 females, 41 males) the number of BS amounted to 2,639±125 BS/cell without any significant correlation to age (17–86 years) or sex. The dissociation constant (K_D) indicating the affinity of iodocyanopindolol to the BS on intact lymphocytes was K _d =1.9±1.1×10^–10 M. A change of the number of -adrenergic receptors on intact human lymphocytes has been measured previously in asthmatics and in the myocardium of patients with congestive heart failure. We investigated a possible change in the -receptors on lymphocytes by physical and mental activity (stress) in physicians going about their daily routine work. Persons left alone in a hospital room reading or sleeping were defined as inactive controls. The number of BS on intact lymphocytes was significantly higher in inactive persons at 8 a.m. (2,230±482 BS) compared to active persons (1,743±285 BS;P<0.05) and at 1 p.m. (2,394±253 BS vs 1,733±556;P<0.05) but not different at 6 p.m. (1,634±578 BS vs 1,768±588 BS;P<0.1). The K _d remained unchanged under all conditions. The serum noradrenaline and adrenaline levels were also measured during the day. The serum adrenaline levels were higher in the active group than in the inactive group at 8 a.m. (46±11 pg/ml vs 22±8 pg/ml;P<0.01) and at 1 p.m. (36±13 pg/ml vs 13±5 pg/ml;P<0.01) but not at 6 p.m. (37±28 pg/ml vs 13±6 pg/ml;P<0.1). Our data clearly show higher serum adrenaline levels but fewer BS on intact human lymphocytes in active persons than in inactive persons at 8 a.m. and 1 p.m. The high catecholamine serum levels may cause a down-regulation of the number of -receptors in the active persons.Abbreviations ¹²⁵I-CYP ¹²⁵Iodocyanopindolol - BS binding site - K _d dissociation constant - cAMP cyclic adenosine monophosphate With support of Deutsche Forschungsgemeinschaft Kr 679/3-I     

Inhibitor of β-Hydroxy-β-Methylglutaryl Coenzyme A Reductase Decreases Energy Supply to the Myocardium in Rats

Hypocholesterolemic preparations, inhibitors of the key enzyme of cholesterol biosynthesis -hydroxy--methylglutaryl coenzyme A reductase (statins), block the synthesis of ubiquinone Q10, intermediate electron carrier in the mitochondrial respiratory chain. This should decrease energy supply to tissues. Daily peroral administration of -hydroxy--methylglutaryl coenzyme A reductase inhibitor simvastatin (24 mg/kg perorally) for 30 days had no effect on the contents of macroergic phosphates (ATP and creatine phosphate) in the liver, but decreased these parameters in the myocardium.