Muscarinic cholinergic antibody in experimental autoimmune myocarditis regulates cardiac function

Evidence is presented showing that in experimental autoimmune myocarditis, there are certain components in IgG fraction of the sera that bind to myocardium muscarinic cholinergic receptors. The autoimmune IgG simulated the biologic effect of cholinergic agonists because (i) it increased cGMP levels, (ii) it decreased cAMP stimulated levels, and (iii) it reduced heart contractility and diminished reactivity to exogenous acetylcholine. Autoimmune IgG inhibited the binding of specific muscarinic cholinergic radioligand to purified myocardial membranes behaving as noncompetitive inhibitors. The recognition appears to be organ specific because the autoimmune IgG did not bind to muscarinic cholinergic receptors of urinary bladder. The presence of antibodies against antigens expressed in an accessible form to antibody in living myocardial cells might be related to some of the immunopathologic mechanisms participating in the pathogenesis of the experimental autoimmune myocarditis.     

Neuroendocrine regulation of cardiac activity in the snail Strophocheilus oblongus

• 1.1. Cardio-accelerator substances are present both in the brain and heart tissue of the snail Strophocheilus.
• 2.2. The excitatory effect of organ extracts is due not only to the presence of ACh and 5-HT but probably to another substance of neuroendocrine nature as well.
• 3.3. Structural modifications of stainable neurosecretory-like material were found in heart tissue submitted to electrical stimulation through its nerve, and the new excitor substance was found in the blood stream.
• 4.4. The unidentified excitor substance is: (a) heat-stable in different pH; (b) soluble in 50% acetone; (c) inactivated by pronase; (d) non-dialysable and (e) does not migrate with paper electrophoresis.

     

Role of the hypothalamus in the reflex regulation of cardiac activity

A review of literary and own experimental data is given. More adequate method in the study of the hypothalamic heart regulation is the investigation of the hypothalamic influences on the cardiac reflexes. The necessity of the experiments on the unanesthetized unrestrained animals is underlined. The dual modulating hypothalamic influences existing already in fishes having been revealed on the unanesthetized animals. The character of the modulating influence is determinated to a certain extent by the cardiac reflex intensity: small responses are increased, larger ones are reduced. The extension of system regions involved into the reflex response pattern at the increase of the degree of temperature effect of venous blood on heart has been discovered in unanesthetized unrestrained cats.     

Evaluation of the phagocytic activity of peripheral blood neutrophils in patients with hyperthyroidism

In 80 women with hyperthyroidism (40 with diagnosed Graves disease and 40 with hyperactive nodular goiter) the following tests related to the function of peripheral blood neutrophils have been carried out: 1. nitrotetrazolium blue (NRT) reduction test. 2. evaluation of phagocyting activity by using latex particles and living bacteria cells, and 3. determination of immunoglobulin concentration and the C3 component of the complement in blood serum. The following features were found in the patients with hyperthyroidism: 1. the elevated values of the index of spontaneous NBT reduction which return to normal following the treatment with propranolol or metizol lasting 14 days, 2. a decrease in the phagocyting activity of neutrophils occurring with stimulation of phagocytosis by both the latex particles and bacteria cells. 3. the return to normal values of the index of neutrophils phagocyting the latex particles following two-week treatment with propranolol or metizol. It was concluded that in patients with hyperthyroidism the changes in NRT reduction and phagocyting activity of peripheral blood neutrophils return to normal following the two-week treatment of these patients with both propranolol and metizol.     

Roles played by lymphocyte function-associated antigen-1 in the regulation of lymphocytic cholinergic activity

Lymphocytes possess the essential components of a cholinergic system, including acetylcholine (ACh); choline acetyltransferase (ChAT), its synthesizing enzyme; and both muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively). Stimulation of lymphocytes with phytohemagglutinin, which activates T cells via the T cell receptor/CD3 complex, enhances the synthesis and release of ACh and up-regulates expression of ChAT and M(5) mAChR mRNAs. In addition, activation of protein kinase C and increases in intracellular cAMP also enhance cholinergic activity in T cells, and lymphocyte function associated antigen-1 (LFA-1; CD11a/CD18) is an important mediator of leukocyte migration and T cell activation. Anti-CD11a monoclonal antibody (mAb) as well as antithymocyte globulin containing antibodies against CD2, CD7 and CD11a all increase ChAT activity, ACh synthesis and release, and expression of ChAT and M(5) mAChR mRNAs in T cells. The cholesterol-lowering drug simvastatin inhibits LFA-1 signaling by binding to an allosteric site on CD11a (LFA-1 alpha chain), which leads to immunomodulation. We found that simvastatin abolishes anti-CD11a mAb-induced increases in lymphocytic cholinergic activity in a manner independent of its cholesterol-lowering activity. Collectively then, these results indicate that LFA-1 contributes to the regulation of lymphocytic cholinergic activity via CD11a-mediated pathways and suggest that simvastatin exerts its immunosuppressive effects in part via modification of lymphocytic cholinergic activity.     

The lymphocytic cholinergic system and its contribution to the regulation of immune activity

Lymphocytes express most of the cholinergic components found in the nervous system, including acetylcholine (ACh), choline acetyltransferase (ChAT), high affinity choline transporter, muscarinic and nicotinic ACh receptors (mAChRs and nAChRs, respectively), and acetylcholinesterase. Stimulation of T and B cells with ACh or another mAChR agonist elicits intracellular Ca2+ signaling, up-regulation of c-fos expression, increased nitric oxide synthesis and IL-2-induced signal transduction, probably via M3 and M5 mAChR-mediated pathways. Acute stimulation of nAChRs with ACh or nicotine causes rapid and transient Ca2+ signaling in T and B cells, probably via alpha7 nAChR subunit-mediated pathways. Chronic nicotine stimulation, by contrast, down-regulates nAChR expression and suppresses T cell activity. Activation of T cells with phytohemagglutinin or antibodies against cell surface molecules enhances lymphocytic cholinergic transmission by activating expression of ChAT and M5 mAChR, which is suggestive of local cholinergic regulation of immune system activity. This idea is supported by the facts that lymphocytic cholinergic activity reflects well the changes in immune system function seen in animal models of immune deficiency and immune acceleration. Collectively, these data provide a compelling picture in which lymphocytes constitute a cholinergic system that is independent of cholinergic nerves, and which is involved in the regulation of immune function.     

Regeneration of the parathyroid glands in experimental hyperthyroidism

By means of morphological, morphometric and radioautographic methods, regeneration of mechanically traumatized parathyroid glands has been studied in 22 euthyroid and 22 hyperthyroid rats on the 1st-20th days after the operation. The thyroid gland is stimulated by daily injection of thyrotropin (1 ME/100 g of body mass). Twelve non-operated animals (6 hyperthyroid and 6 euthyroid rats) serve as control. In the regenerating parathyroid glands of the hyperthyroid animals in comparison with the euthyroid ones, certain increase of proliferative activity is noted in parathyrocytes and in cells of the granular tissue on the 2d-6th days, a more pronounced hypertrophy of epitheliocytes on the 2d-20th days, hyperplasia of their nucleolar apparatus on the 2d-5th days. The experimental hyperthyroidism stimulates manifestation of restorative processes in the regenerating parathyroid glands during development of active inflammatory reaction in them; however, it does not influence the parameters of the organ's structure studied in the nonoperated animals.     

Effects of modulation of the cholinergic system activity on the experimental tumor growth and antitumor activity of chlofiden

We studied the influence of an anticholinesterase agent, proserine, and an m-cholinoblocker, atropine, on the growth of Pliss lymphosarcoma in rats and on the antitumor activity of a cytotoxic drug, chlofiden. It has been demonstrated that proserine stimulates tumor growth and decreases the antitumor efficacy of chlofiden. Injections of atropine evoked opposite effects: inhibition of the tumor growth and an increase in the, antitumor activity of chlofiden. Possible mechanisms of the above effects are discussed.     

Structural changes in the gastric mucosa in experimental hyperthyroidism

Using a structural and functional analysis experiments on rats have shown the morphological substrate of the impaired pepsin secretion in experimental hyperthyroidism. It has been established that enhancement of the proteolytic activity of gastric juice at early times of hyperthyroidism is linked with activation of biosynthetic processes in the chief gastric cells. Under the conditions of prolonged hyperthyroidism, the reduced proteolytic activity of gastric juice is caused by inhibition of both bioenergetic and biosynthetic processes in the chief cells.     

Microglial regulation of cholinergic differentiation in the basal forebrain

Because inflammation during pregnancy can lead to neurodevelopmental anomalies, we investigated the role of inflamed microglia on cholinergic precursors in the rat embryonic basal forebrain (BF) cultured on embryonic day 15. Conditioned medium (CM) taken from microglia stimulated variously (microglial CM; MCM) increased activity of choline acetyltransferase (ChAT), the enzyme responsible for acetylcholine biosynthesis and a phenotypic hallmark of the cholinergic neuron. There was a concomitant decline in glutamic acid decarboxylase expression. Of stimulators tested, only β-amyloid failed to produce effective MCM. Infection with a Lac-Z-containing retrovirus revealed that MCM promoted cholinergic differentiation from undifferentiated precursors in the population. Several candidates were tested for their ability to mimic MCM. Mature nerve growth factor (NGF) did not mimic MCM, but acted synergistically with it to promote enormous increases in ChAT activity. However, a microglial cell line produced high-molecular weight forms of NGF (pro-NGF) that were lethal to mature cholinergic neurons. Although bone morphogenetic proteins (BMP) 2, 4, and 9 increased ChAT activity dose-dependently, noggin did not inhibit the effects of the MCM, suggesting that BMPs were not the only active factor(s) in the MCM. Embryonic microglia isolated following maternal inflammation produced a variety of immune system cytokines and chemokines. One of these, interleukin-6 (IL-6), was tested for its ability to promote cholinergic differentiation. Although IL-6 alone did not mimic the action of MCM, neutralization of it inhibited MCM effectiveness. Thus, following maternal inflammation, a complex microglial-derived cocktail of factors can promote excess cholinergic differentiation in the embryonic BF.