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Biomedical subjects

E Borda

Publications and source records attributed to E Borda.

At least 73 records · Page 4Linked to original sources

Antilaminin IgG binds and interacts with cardiac cholinergic receptors.

Antilaminin IgG bound to cholinergic muscarinic receptors of normal mice heart and simulated the biological effect of a cholinergic agonist. Antilaminin IgG interfered with the binding of the radiolabelled muscarinic antagonist, (-)-[3H]quinuclidinyl benzilate, in a noncompetitive fashion. The interaction of antilaminin IgG with the muscarinic cholinergic receptor increased production of cGMP and decreased production of cAMP. Antilaminin IgG also decreased the contractile tension of mouse atria. Both the mechanical and enzymatic effect of antilaminin IgG required the activation of the muscarinic cholinergic system because they were blunted by atropine and mimicked by acetylcholine.

Acetylcholine↗

Stimulation of heart contractility by supernatants from lectin-activated lymphocytes. Role of IL-2.

The positive inotropic effect of cell-free supernatants from lectin-activated lymphocytes is lost by dialysis and can be partially restored by addition of arachidonic acid (AA). Interleukin-2 (IL-2) in the presence of AA could stimulate the response of the heart while the interferons (alpha-IFN or gamma-IFN) were ineffective. The activity of PHA-L-SN and that of IL-2 + AA was neutralized by anti-IL-2 MAb. These results suggest a key role for IL-2 in the stimulation of heart contractility by supernatants from activated lymphocytes.

Animals↗

Negative inotropic activity of antilaminin IgG: participation of cholinergic mechanisms.

1. Antilaminin IgG decreased the dF/dt of mouse isolated atria and inhibited the mechanical effect of acetylcholine in a non-competitive fashion. 2. Inhibitors of nicotinic and muscarinic cholinoceptors impaired the negative inotropic action of antilaminin IgG in mouse isolated atria. Hemicholinium and tetrodotoxin also reduced the response while the antihistamine, pyrilamine was without effect. 3. These results suggest that antilaminin IgG modulates cholinergic function in mouse isolated atria. Possible mechanisms are discussed.

Acetylcholine↗

Beta-adrenergic cardiac antibody in autoimmune myocarditis.

Balb/c mice were immunized with homologous heart in complete Freund's adjuvant to induce autoimmune myocarditis. The myocarditis was characterized by lymphomononuclear infiltration, electrocardiographic abnormalities and antimuscle antibodies by indirect immunofluorescence. In this paper, we demonstrate that the IgG present in autoimmune myocarditis mice is able to bind to beta-adrenoreceptors of the heart and also induce a biological effect inhibiting the contractile action of exogenous norepinephrine. Auto-immune IgG inhibited the binding of (3H)-dyhidroalprenolol to a beta-adrenergic receptor of purified myocardial membranes behaving as non-competitive inhibitor. This IgG also exerted a non-competitive inhibition upon the mechanical effect of exogenous norepinephrine. The recognition appears to be organ specific, because the autoimmune myocarditis IgG did not bind to beta-lymphocyte, lung and fat adrenoreceptors. The autoimmune IgG inhibited the stimulatory action of isoproterenol on cAMP levels, behaving as a beta-adrenergic antagonist.

Animals↗

[Interaction of antibodies with cardiac neurotransmitter receptors].

This paper demonstrates that antibodies against neurotransmitter receptors of the cardiac membrane are able to alter the physiology, pharmacology and biochemistry of the target organ. Sera from chagasic patients contain an antibody which binds to beta adrenoceptors of myocardium and modulates their activity. Chagasic IgG simulates a partial beta agonist by increasing contractility and diminishing reactivity to exogenous norepinephrine. Moreover, chagasic IgG inhibits the binding of the specific radioligand to purified cardiac membranes. The interaction of chagasic IgG with beta-adrenoceptors triggers signal transduction resulting in the stimulation of adenylate cyclase with an increased production of cAMP. Stimulation of Ca(++)-ATPase and inhibition of Na+ + K(+)-ATPase are also observed. These enzyme dysfunctions induce modifications of cellular thermodynamic equilibrium that trigger both morphological and functional alterations of the myocardium. Other immune sera can also trigger pharmacologic effects on isolated atria. Immune IgG directed against specific alloantigens and IgG from mice with autoimmune myocarditis are able to recognize the beta adrenergic receptor-coupled adenylate cyclase system and alter the function of target organs. The detection of antibodies against neurotransmitter receptors could be a useful marker during the early stages of development of autoimmune diseases.

Animals↗

[The effect of activated lymphocytes on cardiac contractility].

Activated lymphocytes may have potent biologic effects outside the frame of the immune system. In these studies we analyzed the interaction of activated normal human lymphocytes and/or soluble products of lymphocyte activation on the contractile activity of isolated rat atria. The results indicate that phytohemagglutinin activated lymphocytes of the CD4 phenotype exert a positive inotropic effect on spontaneously beating atria. This effect is linked to steps of lymphocyte activation that precede cell division. Soluble factors released to the supernatant of stimulated lymphocytes can substitute for the intact cells. Interleukin-2 (IL-2) appears to be an important component of the active supernatants, as their activity can be reduced by monoclonal anti-IL-2 or by preincubation of the heart tissue with monoclonal anti-IL-2 receptor (anti-Tac). Highly purified IL-2 was active at 10 units/ml. In order to induce a positive inotropic effect at lower doses of natural or recombinant IL-2 (2-3 units/ml), synergic factors were required (2 x 10(-6) M arachidonic acid, AA, or Ca ionophore A 23187). Indirect evidence indicates that IL-2 exerts its biologic effect by turning on the phosphoinositide cycle and activating protein kinase C in the heart tissue target. It is postulated that similar mechanisms may be activated in inflammatory myocardiopathies or during the treatment of cancer with massive doses of IL-2.

Animals↗

Interleukin 2 stimulates heart contractility in the presence of exogenous arachidonate or the calcium ionophore A 23187.

An increase in the isometric developed tension (IDT) of isolated rat atria was observed shortly after the addition of human interleukin 2 (IL-2) to the organ preparation with subthreshold concentrations of either arachidonate (AA, 1.98 X 10(-6)M) or the calcium ionophore A 23187 (1.9 X 10(-6)M). Both natural purified IL-2 (nIL-2) and yeast recombinant IL-2 (rIL-2) were active in this experimental system. It was determined that this lymphokine was active at 2 X 10(-11)M, considering as a reference the specific activity of rIL-2. Anti-IL-2 monoclonal antibody (anti-IL-2 MAb) abolished this reaction. Inhibition of atrial phospholipase C activity by nitrocarboxyphenyl N,N-diphenylcarbamate (NCDC, 5 X 10(-6)M) prevented the development of the inotropic positive effect of IL-2 in the presence of either AA or A 23187. The synthetic diacylglyceride 1-oleoyl, 2-acetyl-glycerol (OAG) replaced the IL-2 as stimulatory signal but NCDC had no effect on the reaction. The results suggest that IL-2 can alter the physiologic behaviour of the heart and that its mechanism of action is probably similar to the one proposed for other IL-2 targets (IL-2 receptor-positive T lymphocytes, T cell lines).

Animals↗

Alloimmune B-lymphocytes modify the myocardium contractility-inducing release of SRS-A.

It has been previously demonstrated that murine alloimmune lymphoid cells were able to exert positive or negative inotropic effects on isolated mouse atria depending on the cellular type used. Here we show that BALB/c anti-C3H B-cells induced positive inotropic action on C3H mouse atria. Supernatants of alloimmunized B-cells co-cultivated with C3H myocardium exerted the same biological effect as alloimmune B-cells, indicating that a soluble factor is involved. Inhibitors of lipoxygenase(s) of arachidonic acid metabolism and a SRS-A blocker inhibited the positive effect of immune cells or its supernatants. The effect was prevented when we inhibited the atria lipoxygenase activity. On the other hand, when the inhibitors were applied to effector cells the response was not modified. In addition, supernatants of B-cells cultured with alloextracts were inactive. Supernatants from alloimmune B-cells plus myocardium release higher amounts of LTC4 than those from normal B-cells. It is proposed that SRS-A synthesis is induced in the atria by direct contact with alloimmune B-cells upon recognition of alloantigens expressed by atria cells; which in turn, triggers the positive inotropic effect.

Animals↗

Lymphocyte-induced stimulation of the contractile response of the heart.

In previous reports we have shown that phytohemagglutinin (PHA)-activated human lymphocytes had positive inotropic effects on spontaneously beating isolated rat atria. In this study, we demonstrated that the stimulatory effect on heart contractility induced by lymphocytes was linked to early events of lymphocyte activation by lectins. Active soluble factors were gradually released to the fluid phase. Similar results were obtained with both mitogenic (PHA) and nonmitogenic (WGA) lectins indicating that the stimulatory action of activated lymphocytes did not require cell division. Absence of Ca2+ inhibited both the generation of the stimulatory activity and lymphocyte proliferation. In contrast, verapamil, dexamethasone and low concentrations of cycloheximide eliminated only the appearance of the stimulatory effect.

Animals↗

Molecular and biological interaction between major histocompatibility complex class I antigens and luteinizing hormone receptors or beta-adrenergic receptors triggers cellular response in mice.

Purified IgG from BALB/c mouse anti-C3H serum exerts positive inotropic and chronotropic effects in C3H mouse atria and induces testosterone synthesis in C3H mouse Leydig cells. The effect depends on IgG concentration and can be abolished by beta-adrenergic-receptor and luteinizing hormone-receptor antagonists. IgG interferes with the binding of dihydroalprenolol and luteinizing hormone. Monoclonal antibodies against major histocompatibility complex class I antigens were active on the Leydig cells of C3H and BALB/c mice. There was a parallelism between the effect of each individual monoclonal antibody with specificity for a particular haplotype and the response of the target cell from the strains carrying such haplotypes. These antibodies could precipitate the soluble luteinizing hormone-receptor complex. The results suggested that bound hormone triggers the association of major histocompatibility class I antigen with the receptor, thereby activating the respective target cells.

Animals↗

Hypersensitivity to calcium associated with an increased sarcolemmal Ca2+-ATPase activity in diabetic rat heart.

Sarcolemmal Ca2+-dependent ATPase activity and the mechanical response to calcium and verapamil were studied in myocardium from normal rats and those with diabetes induced by streptozotocin. Sarcolemmal Ca2+-ATPase activity was increased in diabetic animals, depending on the duration of the diabetes. Both the maximal velocity and the affinity were greater in hearts of diabetic rats compared with normal controls. In insulin treated diabetic hearts the affinity of the enzyme for calcium decreased but the maximal velocity was not modified. The enzyme activity was stimulated maximally by millimolar concentrations of calcium and inhibited by lanthanum chloride. Calcium induced a concentration dependent increase in dF/dt in normal and diabetic hearts, but in diabetes the dose-response curve to calcium chloride was shifted to the left. Verapamil depressed the dF/dt in a concentration dependent manner in normal and diabetic hearts; but the drug was more effective in diabetic than in normal rats. These results suggest that an increase in sarcolemmal Ca2+-ATPase activity may be of critical importance in the hypersensitivity of diabetic heart in the presence of low extracellular calcium and calcium blockade.

Animals↗

Antibodies to beta 1 and beta 2 adrenoreceptors in Chagas' disease.

Evidence accumulated over the last decade concerning human and experimental models suggests that an immunopathological mechanism may be involved in the pathogenesis of chronic Chagas' disease. In this paper we demonstrate the existence of two different circulating IgG in chagasic patients which bind with myocardial beta 1 and spleen cell beta 2 adrenoceptors, acting as non-competitive inhibitors. Both chagasic IgG against beta 1 and beta 2 adrenoceptor increased intracellular levels of cAMP that could be blocked by specific beta 1 and beta 2 adrenoceptor antagonists. The specificity for beta 1 and beta 2 adrenoceptors and the independence of other tissue reactive antibodies was demonstrated by IgG absorption with turkey red blood cell (TRBC), human lymphocytes (HL) or guinea pig red blood cells (GPRBC). The F(ab')2 fraction acted similarly. This supports the specificity of beta 1 and beta 2 adrenoceptors to the chagasic IgG and the independence of the other tissue reactive antibodies, such as EVI system. The probable pathogenic role of both beta 1 and beta 2 adrenergic chagasic antibody is discussed.

Antibody Specificity↗

Dual effects of alpha-adrenoceptor agonist on contractility of mice isolated atria.

Contractility responses of mice atria to alpha-adrenergic agonists (methoxamine and clonidine) were studied. The alpha-adrenergic agonists increased the rate of force development (dF/dt) and decreased contractile frequency. The positive inotropic effect was mediated through cardiac alpha-adrenoceptors, while the negative chronotropic effect involved parasympathetic activation. Blockers of phospholipase C inhibited both the positive inotropic and the negative chronotropic effects of the alpha-adrenergic agonists. Inhibitors of phospholipase A2 and cyclooxygenase activity attenuated the positive inotropic effect of the agonists without modifying the negative chronotropic effect.

Animals↗

Chagasic IgG modifies the activity of sarcolemmal ATPases through a beta adrenergic mechanism.

The effect of anti beta adrenoceptor IgG from chagasic sera upon Ca2+-ATPase and Na++K+-ATPase of myocardial membrane was studied. Chagasic IgG stimulated Ca2+-ATPase and inhibited Na++K+-ATPase activities. Both enzymatic effects of the IgG could be prevented after beta adrenoceptor blockade or after the absorption of chagasic IgG with turkey red blood cells. Isoproterenol acted similarly. These results provide information concerning to the biochemical mechanism, by which an antibody, known to activate adenylate cyclase system coupled to cardiac beta adrenoceptor, produces stimulation of myocardial contractility.

Adrenergic beta-Agonists↗

The release of phosphate from contracting atria as a parameter of (Na+ + K+)-ATPase activity. Effect of ouabain.

An experimental situation that permits simultaneous evaluation of the mechanical activity and inorganic phosphate (Pi) release by beating atria was developed. It concerned cell membrane integrity and compartmentalization of the cells. The Pi released by isolated rat and guinea pig atria was measured in a physiological salt solution. The preparations were incubated under preload for the simultaneous recording of dF/dt and Pi. The substrate of this reaction was the endogenous ATP. Pi release by atria increased with time. It was stimulated at high K+ concentrations (30 mmol/l) and inhibited at very low ones (1.2 mmol/l). The lack of Mg2+ in the incubation media did not affect it. Ouabain induced different effects upon Pi release; at low concentrations it was increased while at higher ones it was inhibited. The relationship between ouabain concentrations, mechanical responses and liberation of Pi by isolated atria from rat and guinea pig showed that at low concentrations ouabain simultaneously increased dF/dt and Pi release. On the contrary, at high concentrations of ouabain dF/dt decreased, contracture occurred and the Pi release decreased. Isoproterenol, norepinephrine and calcium, at concentrations that increased dF/dt, did not modify Pi release. Different concentrations of potassium and ouabain also modulated the 32P Pi efflux in a fashion similar to that with the Pi released by beating atria. We propose that Pi release by living cells appears to be correlated with manipulations which either stimulate or inhibit (Na+ + K+)-ATPase activity.

Animals↗

Modification of sarcolemmal enzymes by chagasic IgG and its effect on cardiac contractility.

It has been shown that sera from chagasic patients contain an antibody which binds to beta-adrenoceptors of myocardium and modulates their activity. Chagasic IgG triggered a marked stimulation of myocardial contractility with an increase in intramyocardial cyclic AMP and inhibition of (Na+ + K+)-ATPase activity. Both the mechanical and enzymatic effects of the IgG could be prevented by beta-adrenoceptor blockade or after the absorption of chagasic IgG with turkey red blood cells. In contrast, guinea pig red blood cells were unable to remove the beta-reactivity of chagasic IgG. These findings suggest that the IgG from chagasic patients increases myocardial contractility by behaving as a beta-agonist. This effect is likely related to stimulation of the adenylate cyclase coupled to the cardiac beta-adrenoceptor.

Adenylyl Cyclase Inhibitors↗

Chagasic IgG binds and interacts with cardiac beta adrenoceptor-coupled adenylate cyclase system.

It has been previously shown that sera from chagasic patients have an antibody specific for beta adrenoceptors, independently of other tissue-reactive antibodies as the EVI (endocardium, blood vessels, interstitium) system, and it is highly specific to other heart diseases. In this paper we demonstrate that the IgG present in chagasic sera was able to bind to beta adrenoceptors of the heart and also to interact with the membrane bound adenylate cyclase complex, inducing stimulation of enzymatic activity. Moreover, this antibody stimulated contractile activity of guinea pig myocardium, that could be blocked by a specific beta adrenoceptor antagonist. Chagasic IgG inhibited the binding of (-)-(3H)-dyhidroalprenolol to a beta-adrenergic receptor of purified guinea pig myocardial membranes behaving as non-competitive inhibitor. This IgG also exerted a non-competitive inhibition upon the mechanical effect of exogenous norepinephrine.

Adenylyl Cyclases↗

Modification of the contractile activity of isolated atria by T4 lymphocytes from patients with Chagas' disease: effect of soluble factors.

The results of this study show that peripheral blood mononuclear leukocytes of patients with Chagas' disease (Ch-PBMC) respond to challenge with homologous as well as with heterologous heart antigens releasing active soluble factors capable of increasing the contractile tension and frequency of beating rat atria. The reaction was related to T. cruzi infection rather than to the presence of cardiomyopathy. Indirect evidence suggests that supernatants of Ch-PBMC activated with heart tissue homogenates involved the generation of arachidonic acid metabolites by the lipoxygenase system of rat atria. Active effector cells were present in Ch-PBMC that had been depleted of T8-lymphocytes by lysis with OKT8 and rabbit complement (C) and not in those depleted of T4-lymphocytes with OKT4 and C. Therefore, the positive inotropic and chronotropic effects of Ch-PBMC were due to the action of cells from the T4 subset.

Animals↗