cyclic-gmp and Arthritis--Rheumatoid

Rheumatoid arthritis (RA) is a chronic autoimmune disorder characterized by inflammatory synovitis and progressive joint. Although the etiology is extremely complex, overwhelming evidence suggests that dysregulation or imbalance of the immune system plays a central role in disease pathogenesis. The bone loss and joint destruction are immunological insults mediated by infiltration and abnormal activation of various immune cells. Since pharmacological inhibition of cyclic nucleotide phosphodiesterases (PDEs), which degrade cyclic AMP and cyclic GMP, can regulate the activity of multiple immune cells, which are considered as a potential strategy for treating RA. Therefore, this review attempted to summarize the modulating effects of PDEs on immune cells and described the molecular underpinnings and potential clinical application of PDEs inhibitors for RA.

Topics: Animals; Antirheumatic Agents; Arthritis, Rheumatoid; Cyclic AMP; Cyclic GMP; Humans; Joints; Phosphodiesterase Inhibitors; Second Messenger Systems; Treatment Outcome

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Calcium; Cartilage; Cell Membrane; Connective Tissue; Cyclic AMP; Cyclic GMP; Epinephrine; Glucocorticoids; Humans; Hydrogen-Ion Concentration; In Vitro Techniques; Inflammation; Kinetics; Leukocytes; Lysosomes; Neutrophils; Osmotic Fragility; Phagocytosis; Prostaglandins

A controlled cross over study on the effect of fasting on cyclic nucleotide and catecholamine excretion was carried out in 12 female RA patients. They were hospitalized during a control and fasting period. The fasting period started with 3 days of habituation to hospital conditions, followed by 7 days of total fasting. Thereafter followed 3 days of realimentation. The control period was in every respect identical with the fasting period, with the exception of food intake. All medication was stopped when the patients were admitted to the hospital. The urinary concentrations of cAMP, cGMP, E and NE were monitored daily. The clinical status of the subjects was evaluated every second day using Ritchie's clinical index. Clinical and laboratory measures of inflammatory activity remained unaltered during the control period, but improved significantly during fasting. Excretion of cAMP and cGMP was low during the control period when compared with published normal levels. The cAMP/cGMP ratio in urine was normal, however. The urinary levels of E and NE were normal in the control period, but increased significantly during fasting. Excretion of cAMP decreased during fasting, while urinary cGMP levels decreased initially, but rose to prefasting levels towards the end of the fast. The cAMP/cGMP ratio increased during the first days of the fast, with a maximum on days 2 and 3. This increment coincided in time with the greatest rate of improvement in clinical joint activity.

Topics: Adult; Arthritis, Rheumatoid; Blood Sedimentation; Cyclic AMP; Cyclic GMP; Epinephrine; Fasting; Female; Humans; Middle Aged; Norepinephrine; Radioimmunoassay

The content of cyclic nucleotides in blood plasma was measured in 151 patients suffering from rheumatoid arthritis. As compared to the control, the patients demonstrated a significant decrease of the cAMP content and a rise of the cGMP content. The disease standing was found to produce an appreciable effect on the cAMP content. RA patients untreated with glucocorticoids manifested significant correlations between the content of cyclic nucleotides and some characteristics of inflammation and of the immune status. At the same time the majority of such correlations may be lost under conditions of hormonal dependence, which is likely to attest to dysregulation of inflammatory process. In the course of the treatment, the content of cAMP in the plasma increase is attended by a reduction increases in 63.8% of the patients. In the majority of them, that of the level of circulating immune complexes, thereby supporting the relationship between immunopathological and metabolic disorders at the cellular level.

Topics: Antigen-Antibody Complex; Arthritis, Rheumatoid; beta 2-Microglobulin; Cyclic AMP; Cyclic GMP; Dinoprost; Epoprostenol; Humans; Immunoglobulin E; Prostaglandins E; Thromboxanes

Levels of cAMP were decreased and cGMP increased in progressive systemic sclerosis (PSS) fibroblasts compared with normal fibroblasts. PSS cells took up unusually large quantities of Ca++. The epinephrine-induced increases in cAMP were diminished sixfold and epinephrine-induced Ca++ uptake was abnormal in PSS cells. Considerable heterogeneity was observed in rheumatoid arthritis fibroblasts. Membrane-bound abnormalities in (PSS) cells may be of importance in the defective control of collagen production in progressive systemic sclerosis.

Topics: Adolescent; Adult; Arthritis, Rheumatoid; Biological Transport; Calcium; Cells, Cultured; Collagen; Cyclic AMP; Cyclic GMP; Epinephrine; Female; Fibroblasts; Humans; Male; Middle Aged; Propranolol; Scleroderma, Systemic; Skin

20 patients with active rheumatoid arthritis were treated for 12 weeks with the prostaglandin E1 precursors cis-linoleic acid and gamma-linolenic acid in the form of primrose evening oil (Efamol) and the co-factors zinc, ascorbic acid, niacin, and pyridoxin (Efavit). There was a slight fall in skin reactivity to UV light during the treatment, but no effect on plasma or urine concentrations of PGE1, cAMP or cGMP. There was no effect of the treatment on ESR, P-fibrinogen, number of tender joints, number of swollen joints, the duration of morning stiffness, or on the patient's estimation of pain.

Topics: Adult; Aged; Arthritis, Rheumatoid; Ascorbic Acid; Cyclic AMP; Cyclic GMP; Drug Combinations; Fatty Acids, Essential; Fatty Acids, Unsaturated; Female; gamma-Linolenic Acid; Humans; Linoleic Acids; Male; Middle Aged; Niacin; Oenothera biennis; Plant Oils; Prostaglandins E; Pyridoxine; Radioimmunoassay; Skin; Ultraviolet Rays; Zinc; Zinc Compounds

The effects of agents used in RA treatment, various drugs, RF, rheumatoid nodule and synovial fluid was studied on chemotaxis of PMNs. NSAIDS, corticosteroids, theophylline, colchicine, SOD, RF, rheumatoid nodule and synovial fluid were found to inhibit the chemotactic responsiveness while AMPc, GMPc, PGEI and immunodulator drugs enhanced chemotaxis. The results support the hypothesis that drugs tested may modulate chemotactic function by affecting cellular microtubules assembly and/or GMPc accumulation.

Topics: Alprostadil; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Chemotaxis, Leukocyte; Cyclic AMP; Cyclic GMP; Humans; Immunosuppressive Agents; Neutrophils; Prostaglandins E

Topics: Adrenal Cortex Hormones; Alprostadil; Anti-Inflammatory Agents, Non-Steroidal; Arthritis, Rheumatoid; Cyclic AMP; Cyclic GMP; Humans; Neutrophils; Oxygen; Prostaglandins E; Superoxides; Theophylline

Topics: Adult; Arthritis, Rheumatoid; Ascorbic Acid; B-Lymphocytes; Chediak-Higashi Syndrome; Concanavalin A; Cyclic GMP; Humans; Hypersensitivity, Delayed; Immunity, Cellular; Immunoglobulins; In Vitro Techniques; Lymphocytes; Middle Aged; Monocytes; Pokeweed Mitogens; T-Lymphocytes, Regulatory

Topics: Anti-Inflammatory Agents; Antineoplastic Agents; Arthritis, Rheumatoid; Cyclic AMP; Cyclic GMP; Disease Models, Animal; Humans; Metallothionein; Receptors, Drug; Structure-Activity Relationship; Tissue Distribution

Levels of cyclic adenosine 3',5'-monophosphate (cAMP) and cyclic guanosine 3',5'-monophosphate (cGMP) have been investigated in joint fluid in inflammatory arthropathies. A disturbed balance between cAMP and cGMP due to a depressed level of cAMP was found in rheumatoid arthritis (RA) and Reiter's syndrome, in comparison with patients with osteoarthritis. No correlation could be demonstrated between the absolute levels of cAMP or cGMP and the degree of local inflammatory activity, white cell count, or lysosomal enzyme activity in the joint fluid. Intra-articular injection of epinephrine showed just as good an effect on local pain as betamethasone (Cellestona), but the steriod reduced the swelling more effectively. An increase in intracellular levels of cAMP at 20 min was observed following injection of epinephrine with a slight change in cGMP. Intra-articular injection of dibutyryl-cAMP (db-cAMP) produced a marked easing of local pain and swelling in each of the 4 patients so treated. It is concluded that stimulation of the beta-adrenergic system or injection with db-cAMP may be beneficial in rheumatoid inflammation.

Topics: Anti-Inflammatory Agents; Arthritis, Reactive; Arthritis, Rheumatoid; Betamethasone; Bucladesine; Cyclic AMP; Cyclic GMP; Epinephrine; Humans; Injections, Intra-Articular; Osteoarthritis; Synovial Fluid

Topics: Anti-Inflammatory Agents; Arthritis, Rheumatoid; Cell Differentiation; Cyclic AMP; Cyclic GMP; Humans; Immunosuppressive Agents; Lymphocyte Activation; Lymphocytes; T-Lymphocytes

The purpose of this investigation was to examine the effects of autonomic neurohormones, cyclic nucleotides, and related agents on the immunologic discharge of lysosomal enzymes from, and phagocytosis by, purified human neutrophils. In order to discern the possible intracellular mechanisms by which certain neurohormones influence neutrophil function, the concentrations of cyclic AMP and cyclic GMP in neutrophils were assessed during cell contact with phagocytizable particles and autonomic agents. The model system employed for study was the interaction of purified human neutrophils with rheumatoid arthritic (RA) serum-treated zymosan particles at 37 degrees C in a neutral, balanced salt solution containing glucose. Neutrophils ingested the particles and discharged beta-glucuronidase but not lactate dehydrogenase activity during 30 min of incubation. Treatment of zymosan particles with RA serum was more effective than treatment with normal serum with regard to the extent of both particle uptake and lysosomal enzyme release. During contact of neutrophils with RA serum-treated zymosan particles epinephrine, isoproterenol, and cyclic AMP inhibited both particle ingestion and beta-glucuronidase discharge. These actions of epinephrine were associated with a concomitant elevation of cyclic AMP levels. In contrast to the actions of catecholamines and cyclic AMP, acetylcholine and cyclic GMP accelerated lysosomal enzyme release without affecting particle uptake. The actions of acetylcholine were associated with a concomitant elevation of cyclic GMP levels. Increases in neutrophil levels of cyclic GMP but not of cyclic AMP were associated also with the discharge of beta-glucuronidase provoked by particles in the absence of added cholinergic agents. The data suggest that the immunologic release of lysosomal enzymes from human neutrophils can be regulated by autonomic neurohormones, perhaps via the selective formation of appropriate nucleotides.

Topics: Arthritis, Rheumatoid; Catecholamines; Cell Separation; Cyclic AMP; Cyclic GMP; Glucuronidase; Humans; Immune Sera; In Vitro Techniques; L-Lactate Dehydrogenase; Lysosomes; Neutrophils; Nucleotides, Cyclic; Parasympathomimetics; Phagocytosis; Zymosan