Nephroprotection from calcium channels blocking agents: a contribution to their probable mechanism of action

The prevalence and incidence of end-stage renal disease have progressively increased in the last 20 years and, both Hypertension (HT) and Diabetes Mellitus (DM) are the two most important causes of such a condition. Haemodynamic and metabolic perturbations contribute to the development and progression of renal disease and both HT and DM are key factors in the nephropathy. Blood pressure reduction alone is insufficient for maximal renal protection, hence the need for the knowledge of additional mechanisms for nephroprotection in order to establish preventive measures. To contribute to the knowledge of the nephroprotective mechanism of the calcium channel blocking agents (CB) of the dihydropiridine group, this prospective, experimental, longitudinal, and placebo-controlled clinical trial was performed in 55 non-diabetic normotensive and hypertensive adults receiving 3 CB drugs at antihypertensive doses and as monodoses. There were 3 groups. A: Normotensive (n = 25) receiving a single dose of Nitrendipine 20 mg; B: Type I and II hypertensive (n = 15) receiving Nifedipine for 12 weeks; and C: Type I and II hypertensive (n = 15) receiving Amlodipine 5 mg/day, for one week. Together with clinical and hemodynamic responses, biochemical parameters such as renal vasoactive hormones renin, prostaglandins and kallikreins, nitric oxide and cGMP were measured. The antihypertensive effect of CB drugs was confirmed and there was a significant increase in urinary kallikreins excretion related to an increase in nitric oxide. It is concluded that the nephroprotective effect of CB may be due to their capacity to increase urinary kallikreins which in turn, releases nitric oxide production. It is recommended to continue this research with larger number of hypertensive and diabetic patients with nephropathy and longer clinical trials.     

Serum lipoproteins, antioxidants and urine biochemical constituents in camel cystitis

The present study was undertaken to evaluate the serum and urine biochemical changes in camel cystitis. A total number of 25 male camels (3–12?years old) were subjected to study. Based on the histopathological findings, camels under investigation were classified into three groups: acute cystitis group (N?=?10), chronic cystitis group (N?=?8) and control group (N?=?7). Results revealed significant increases in serum total proteins and globulins in the chronic cystitis group compared with the control and acute cystitis group, significant decrease in serum vitamin C level in the chronic cystitis group compared with the acute cystitis group. In addition, serum β-carotene, α-tocopherol and LDL-C levels were significantly decreased in both the acute and chronic cystitis groups compared with the control group. Furthermore, urine GGT activity significantly increased in the acute cystitis group compared with the control and chronic cystitis groups. In conclusion, the most important biochemical changes in camels with acute and chronic cystitis are decreasing serum α-tocopherol, β-carotene and LDL-C. On the other hand, biochemical findings in chronic cystitis are hyperproteinaemia, hyperglobulinaemia and decrease serum vitamin C level.     

Immunosuppressive and anti-inflammatory action of antioxidants in rat autoimmune diabetes

Oxidative stress makes an important contribution to the development of autoimmune diabetes. We therefore tested the possible therapeutic value of two anti-oxidants, butylated hydroxyanisole (BHA) and pyrrolidine dithiocarbamate (PDTC), in the animal model of diabetes induced in susceptible DA rats by multiple low doses of streptozotocin (MLD-SZ, 20 mg/kg/day for 5 days). Administration of either BHA, or PDTC (50 mg/kg/day for 7 days), after finishing MLD-SZ injections, attenuated both the development of hyperglycemia and insulitis. Ex vivo analysis revealed that BHA treatment reduced the proliferation of autoreactive lymphocytes and down-regulated their adhesion to endothelium. In addition, BHA markedly attenuated the production of proinflammatory cytokines IL-1beta and TNF-alpha by both islets of pancreas and peritoneal macrophages. In parallel, macrophage release of cytotoxic oxygen and nitrogen intermediates superoxide anion (O(2)*(-)) and nitric oxide (NO*), respectively, was significantly inhibited. Finally, BHA treatment reduced intrapancreatic expression of inducible NO synthase (iNOS) and consequent production of NO* by pancreatic islets. Together, these data indicate that antioxidant agents might be a feasible therapeutic tools to interfere with development of autoimmune diabetes at multiple levels, including lymphocyte proliferation and adhesion, as well as the production of proinflammatory and cytotoxic mediators.     

Oxidation phenotype and the metabolism and action of beta-blockers

Summary Variability in response to some drugs such as debrisoquine can be attributed to genetic polymorphism of their oxidative metabolism. Most beta-adrenoceptor antagonists (beta-blockers) are extensively metabolised via oxidative routes. Anecdotal reports of high plasma concentrations of certain beta-blockers in poor metabolisers of debrisoquine (PM) have claimed that their oxidation is under polymorphic control. Controlled studies have shown that debrisoquine oxidation phenotype is a major determinant of the metabolism, pharmacokinetics and some of the pharmacological actions of metoprolol, bufuralol and timolol. The PM phenotype is associated with an increased drug bioavailability, a prolongation of elimination half-life and more intense and sustained betablockade. Phenotypic differences were also noted in the pharmacokinetics of the enantiomers of metoprolol. In vivo and in vitro work has identified some of the metabolic pathways which are subject to the defect, namely, the -hydroxylation and the 0-dealkylation of metoprolol and the 1'-hydroxylation of bufuralol. In contrast, the pharmacokinetics and pharmacodynamics of propranolol which is also extensively oxidised, are not related to debrisoquine polymorphism, although 4'-hydroxypropranolol formation is lowered in PM subjects. The clinical significance of impaired elimination of beta-blockers is unclear. If standard doses of beta-blockers are used in PM subjects, they may be susceptible to concentration-related adverse reactions and they may also require lower and less frequent dosing for control of angina pectoris.Abbreviations Beta-blocker Beta-adrenoceptor antagonist - EM Extensive metaboliser of debrisoquine - H117/04 4-(2-Hydroxy-3-isopropylaminopropoxy)-phenylacetic acid - PM Poor metaboliser of debrisoquine Presented in part at the Third International Symposium on Inborn Errors of Metabolism in Humans, Munich, March 1984.     

Tissue-selectivity: the mechanism of action of tibolone

Tibolone is effective in preventing bone loss and treating climacteric symptoms, without stimulating the endometrium. The effects on bone, brain and vagina can be accurately explained by the oestrogenic activity of tibolone, but oestrogenic activity is not expressed in the endometrium. Tibolone behaves differently from oestrogen plus progestogen combinations on the breast. Therefore, tibolone can be characterised as a selective oestrogen activity regulator. The objective of this review is to characterise the typical properties of tibolone in order to explain its tissue-selective action. Tibolone is rapidly converted into three major metabolites: 3 alpha- and 3 beta-hydroxy-tibolone, which have oestrogenic effects, and the Delta(4)-isomer, which has progestogenic and androgenic effects. The 3-hydroxy metabolites are present in the circulation, predominantly in their inactive sulphated form. The tissue-selective effects of tibolone are the result of metabolism, enzyme regulation and receptor activation that vary in different tissues. The bone preserving effects are the result of oestradiol receptor activation, whilst other steroid receptors, notably the progesterone and androgen receptor, are not involved. Breast tissue of monkeys is not stimulated, as occurs with oestrogen plus progestogen, because tibolone and its metabolites inhibit sulphatase and 17 beta-hydroxysteroid dehydrogenase (HSD) type I and stimulate sulphotransferase and 17 beta-HSD type II, the combined effects of which prevent conversion to active oestrogens. In addition, tibolone affects cellular homeostasis in the breast by inhibiting proliferation and stimulating apoptosis. Tibolone does not stimulate the endometrium because of the action of the highly stable progestogenic metabolite (Delta(4)-isomer) in combination with an effect on the sulphatase (inhibition)-sulphotransferase (stimulation) system. The oestrogenic metabolites of tibolone have direct favourable effects on the cardiovascular system and, in in vivo models, tibolone has shown no adverse consequences. In conclusion, tibolone shows oestrogenic effects in brain, vagina and bone and has direct oestrogenic effects on the cardiovascular system. In the endometrium, the progestogenic activity of the Delta(4)-metabolite and the effect on oestrogen-inactivating enzymes prevent oestrogenic stimulation. The mammary gland is not stimulated in currently used animal models. Tibolone appears to regulate estrogenic activity in the various tissues by influencing the availability of estrogenic compounds for the estradiol receptor in a tissue-selective manner.     

Intestinal contribution to secretion of very low density lipoproteins into plasma.

To resolve the question of the magnitude of the intestine's contribution to circulating very low density lipoproteins (VLDL), measurements of intestinal, hepatic, and total VLDL--triglyceride were made on the same animals or on animals studied under comparable conditions. Animals were examined in the fasted state and during infusion of a fat-free meal. Intestinal VLDL secretion was determined through timed collections of lymph from the mesenteric lymph duct; hepatic and total VLDL secretion rates were estimated by the accumulation of plasma VLDL after injections of Triton WR 1339. Results indicate that the intestine contributes only a minor portion (11%) of the amount of triglyceride entering into the plasma compartment in the fasted state. Although intestinal triglyceride production is increased by 50% (p less than 0.01) in fed rats, the overall contribution of the intestine is not significantly altered in fed rats and represents only 14--17% of total body VLDL secretion. Thus, although intestinal VLDL secretion can be modified experimentally, its total impact on endogenous triglyceride production in normotriglyceridemic rats is small.     

SAP signaling: a dual mechanism of action

In this issue of Immunity, Kageyama et?al. (2012), Zhao et?al. (2012), and Dong et?al. (2012) show that the adaptor protein SAP regulates both positive and negative signals through SLAM receptors to stabilize intercellular contacts.     

Cancer therapeutics: understanding the mechanism of action

An intended consequence of the significant investment to characterize the mammalian genome, and its alterations in neoplastic diseases, has been the discovery and commercialization of new approaches to anticancer therapy. As a result, the list of available targets, formerly directed against the processes of DNA replication and mitosis, or in hormonal regulation of growth of tissue, has been dramatically extended. Many of the newer targets represent normal or aberrant signaling pathways, and are present within the cancer cell as second messengers, on its surface (as receptors), or in the external milieu (as ligands). These targets are, therefore, important to the cancer cell phenotype, and affect proliferation, differentiation, and death options for the cell. Another group of targets encompass the cancer cell's relationship to the tissue environment (both stroma and nonneoplastic cells). These targets involve interactions with blood supply (angiogenesis), immune function (evasion), and matrix (invasion and metastasis). Thus, most targets are directly or indirectly critical to some aspect of cancer cell physiology, although a few additional targets are being approached as localization signals for the delivery of otherwise less specific chemotherapeutic or radiotherapeutic agents. The development of new therapeutic approaches has expanded the scope of research required to characterize the mechanism of action for anticancer agents in preclinical models and in clinical trials. In preclinical research, mechanism of action studies have supported the selection of therapeutic agents, appropriate models of efficacy, and experimental design, as well as rational characterization and prediction of nontumor (host) effects. In clinical research, mechanism of action studies have supported the identification of surrogate markers of efficacy (critical for determining adequacy of dose and latency of response), and the selection of patient subpopulations and tumor subtypes most likely to exhibit clinical responses. Finally, information on mechanism of action may suggest strategies for combination therapies and predict potential mechanisms of disease resistance to therapy.     

Cryptococcus neoformans melanin and virulence: mechanism of action.

Black melanin-like pigments are produced by several neurotropic fungi, including Cryptococcus neoformans. Pigment production is associated with virulence. In media containing phenolic substrates such as L-dopa, C. neoformans cells become black as a result of pigment accumulation. Pigmented and nonpigmented C. neoformans cells were studied with transmission electron microscopy and electron spin resonance (ESR) spectroscopy. Transmission electron microscopy showed electron-dense cell walls, and ESR spectroscopy revealed a stable free-radical population in pigmented cells. The ESR signals of pigmented cells were increased by light, alkaline pH, and Zn2+ and decreased by acid pH, indicating that the black pigment was a type of melanin. A mutant deficient in melanin synthesis (mel) generated by UV radiation lacked ESR-detectable radicals, was less virulent for mice, was more susceptible to killing by nitrogen- and oxygen-derived radicals, and had 100-foldless phenoloxidase activity than the parent strain. The interaction of melanized C. neoformans, nonmelanized C. neoformans, and the hypomelanotic mel mutant with J774.16 murine macrophage-like cells was studied. Melanized cells were more resistant to antibody-mediated phagocytosis and the antifungal effects of murine macrophages than nonmelanized cells. Small increases in the intensity of the ESR signals of melanized cells in solutions containing chemically generated oxygen- and nitrogen-derived radicals indicated electron transfer to or from melanin. Melanin appears to contribute to virulence by protecting fungal cells against attack by immune effector cells.     

Inhibiting effect and mechanism of action of 5'-deoxy-5'-fluorothymidine on vaccinia virus reproduction]

5'-deoxy-5'-fluorothymidine in concentrations 2.5 times 10-4 to 2 times 10-3 M was found capable of inhibiting vaccinia virus reproduction in tissue culture. Its inhibiting effect was associated with the primary capacity to inhibit biosynthesis of thymidylic nucleotides in the stage of TDP and TTP synthesis which appears to be the consequence of inhibition of thydidylate kinase activity. Under these conditions accumulation of TMP is observed. The data obtained permit to consider 5'-deoxy-5'-fluorothymidine to be an "early" inhibitor of vaccinia virus reporduction, and its mechanism of action to be a new type of directed interference with vaccinia virus reproduction.     

Immunobiology of IL-37: mechanism of action and clinical perspectives

This article provides an overview of the biological function of a recently discovered cytokine, IL-37, formerly referred to as IL-1F7, and its role in chronic inflammation and autoimmune disease. Much has been discovered about IL-37 in the past decade, including its ability to down-regulate systemic and local inflammation by lowering levels of pro-inflammatory molecules. Here, we critically review the published reports. Future research is necessary to understand the receptor-dependent effects of IL-37, its intracellular and extracellular functions in both normal and diseased states and its potential role as a biomarker and pharmacological target in human disease.     

The mechanism of insulin action

Summary Variations in the concentration of blood glucose are not above or below the level of the physiological changes during electrosleep induced by weak rhythmical electric impulses. Electrosleep has no effect on the hypoglycemic action of insulin. However, when massive doses of insulin are introduced the characteristic symptoms of hyperinsulinlsm do not appear. A new design for a more stable apparatus for inducing electrosleep is presented.Presented by Active Member Acad. Med. Sci. USSR V. N. Chernigovskii     

Reticuloendothelial-depressing substance: studies on the mechanism of action

This study was carried out to evaluate the mechanism of action of a reticuloendothelial (RE)-depressing substance. This RE-depressing substance was obtained from the plasma of dogs subjected to 3 hr of intestinal ischemia. RE-depressing substance was partially purified by dialysis and reverse-phase column chromatography. The assay of RE-depressing activity was based on the depression of the rate of clearance of colloidal carbon from the blood of rats or mice. The effect of RE-depressing substance on three other RE system (RES) test particles (gelatinized lipid emulsion, formalinized sheep erythrocytes, and IgM-coated erythrocytes) was determined. RE-depressing substance did not affect the clearance rate or the organ localization of these three test particles. Therefore, RE-depressing substance affected only the clearance of colloidal carbon. Since platelet aggregation has been shown to contribute to the clearance of colloidal carbon, the effect of RE-depressing substance on platelet aggregation was evaluated. RE-depressing substance depressed in vitro platelet aggregation induced by ADP or collagen. It was concluded that the effect of RE-depressing substance on the clearance of colloidal carbon was due to a depression of platelet aggregation rather than to a depression of hepatic macrophage phagocytic function.     

Inhaled furosemide: a whole new mechanism of action

The use of aerosolized furosemide has been increasing throughout Mexico, primarily because of its mechanism and site of action as well as its local and systemic effect. We hypothesize that its effect on the respiratory system is totally independent from its diuretic activity and that it is primarily caused by its interaction with the chlorine channels. Furthermore, there is also evidence that furosemide induces prostaglandin synthesis, blocks the sodium-calcium pump, producing relaxation of the smooth muscle that narrows the airway and causes reduced nerve responsiveness to the Neurokinin A produced in acute asthma attacks.     

Oxidation of biological systems: oxidative stress phenomena,antioxidants, redox reactions,and methods for their quantification

Reactive oxygen species (ROS) and other radicals are involved in a variety of biological phenomena, such as mutation, carcinogenesis, degenerative and other diseases, inflammation, aging, and development. ROS are well recognized for playing a dual role as deleterious and beneficial species. The objectives of this review are to describe oxidative stress phenomena, terminology, definitions, and basic chemical characteristics of the species involved; examine the biological targets susceptible to oxidation and the defense mechanisms of the organism against these reactive metabolites; and analyze methodologies, including immunohistochemical markers, used in toxicological pathology in the visualization of oxidative stress phenomena. Direct detection of ROS and other free radicals is difficult, because these molecules are short-lived and highly reactive in a nonspecific manner. Ongoing oxidative damage is, thus, generally analyzed by measurement of secondary products including derivatives of amino acids, nuclei acids, and lipid peroxidation. Attention has been focused on electrochemical methods based on voltammetry measurements for evaluating the total reducing power of biological fluids and tissues. This approach can function as a tool to assess the antioxidant-reducing profile of a biological site and follow changes in pathological situations. This review thus includes different topics essential for understanding oxidative stress phenomena and provides tools for those intending to conduct study and research in this field.     

Rabbit tumor necrosis factor: mechanism of action.

Rabbit tumor necrosis factor (TNF) was examined for effects on normal and transformed cells in culture. Several assays for killing of L-929 cell targets were developed, and their sensitivities were compared. Normal cells were not killed by TNF, and the discrimination between normal and transformed cells was shown not to be due to a cell cycle-dependent mechanism. TNF killing of L-929 cells was delayed for 10 to 12 h and thereafter showed concentration and time-dependent increases in cytolysis. Actinomycin D or cycloheximide treatment of L-929 cells resulted in an enhancement of the rate of cell killing as well as a shortening of the preceding lag period. TNF killing of L-929 cells was temperature dependent; cells were considerably more resistant to lysis at 25 degrees C and showed enhanced killing at 39 degrees C as compared to 37 degrees C controls. The slope of the dose curve showed less than single-hit kinetics. A model for cell killing whose general features incorporate both the specificity and catalytic properties of an enzymatic reaction is proposed for TNF action.