Anthracyclines, such as doxorubicin and daunorubicin, continue to be widely used in the treatment of cancer, although they share the adverse effect of chronic, cumulative dose-related cardiotoxicity. ...The only approved treatment in prevention of anthracycline cardiotoxicity is dexrazoxane, a putative iron chelator. Previous in vitro studies have shown that disorders of iron metabolism, including altered IRP1-IRE binding, may be an important mechanism of anthracycline cardiotoxicity.
This study examined the role of IRP1-IRE binding ex vivo in a chronic model of daunorubicin cardiotoxicity in the Fischer 344 rat and whether dexrazoxane could prevent any daunorubicin-induced changes in IRP1 binding. Young adult (5-6 months) Fischer 344 rats received daunorubicin (2.5 mg/kg iv once per week for 6 weeks) with and without pretreatment with dexrazoxane (50 mg/kg ip). Other groups received saline (controls) or dexrazoxane alone. Rats were killed either 4 h or 2 weeks after the last dose of daunorubicin to assess IRP1-IRE binding.
Contractility (dF/dt) of atrial tissue, obtained from rats 2 weeks after the last dose of daunorubicin, was significantly reduced in daunorubicin-treated compared to control rats. Dexrazoxane pretreatment protected against the daunorubicin-induced decrease in atrial dF/dt. However, left ventricular IRP1/IRE binding was not affected by daunorubicin treatment either 4 h or 2 weeks after the last dose of daunorubicin.
IRP1 binding may not be altered in the rat model of chronic anthracycline cardiotoxicity.
Although beta-adrenoceptor agonists are primary agents in therapy of asthma, epidemiological studies have suggested that frequent or prolonged used of these drugs could be associated with ...exacerbation of disease. Mechanisms of any adverse effects remain unclear although in vitro studies have suggested that beta-adrenoceptor agonists can block glucocorticoid actions. Because asthma is an inflammatory disease characterized by eosinophil infiltration of the airways, actions of beta-agonists and corticosteroids that alter eosinophil survival and mediator generation may be of importance. Eosinophil generation of superoxide anion, a potent mediator that can damage respiratory epithelium, was markedly increased after 2-24 h of in vitro beta-adrenoceptor agonist exposure. These proinflammatory effects are in contrast to inhibition of superoxide generation, which is observed with acute beta-agonist exposure. Corticosteroid treatment to reduce inflammation is combined with beta-agonist therapy in current asthma guidelines. Although dexamethasone independently decreased eosinophil superoxide anion generation, in the presence of beta-adrenoceptor agonist dexamethasone inhibition was minimal and not statistically significant. Eosinophil survival is a relevant factor to pulmonary inflammation. Although beta-adrenoceptor agonists did not independently increase eosinophil survival, glucocorticoid actions that increase apoptosis were blocked. Thus, in vitro beta-agonists can independently increase inflammatory mediator generation and block anti-inflammatory actions of corticosteroid.
OBJECTIVE:--Nondiabetic patients were studied to determine whether modest elevations in blood glucose may be associated with a greater incidence of coronary artery disease (CAD). RESEARCH DESIGN AND ...METHODS--Baseline morning blood glucose determinations were evaluated with respect to subsequent coronary disease using records from 24,160 nondiabetic patients. CAD was identified from myocardial infarction, new diagnoses of angina, or new prescriptions for nitroglycerin that occurred more than a year after baseline glucose determinations. RESULTS:--Of 24,160 patients studied, 3,282 patients developed CAD over a total analysis time at risk of 77,048 years. Higher baseline morning glucose (100-126 vs. <100 mg/dl) was associated with a 53.9% greater myocardial infarction incidence rate, an 18.6% greater acute coronary syndrome incidence rate, and a 26.4% greater number of new prescriptions for nitrates (all P < 0.05). A Cox proportional hazards model with adjustment for age, BMI, sex, creatinine, lipids, smoking, and medications showed that elevated fasting glucose was associated with an increased hazard for new CAD (hazard ratio 1.13 95% CI 1.05-1.21, glucose >100 vs. <100 mg/dl). Kaplan-Meier analysis showed that elevated baseline glucose was associated with a progressive increase risk of CAD with time. CONCLUSIONS:--Patients with higher baseline blood glucose levels in the absence of diabetes and after adjustment for covariants have a significantly greater risk for development of CAD.
Because β-adrenoceptor agonists are commonly used in the treatment of disease states associated with eosinophil activation, β-adrenergic regulation of the eosinophil respiratory burst (as monitored ...with lucigenin-dependent luminescence) was evaluated. Normodense, nonprimed eosinophils from healthy volunteer subjects were potently inhibited by very low concentrations of isoproterenol. The inhibitory concentration of 50% for isoproterenol was approximately 2 nmol/L. The β-agonist was able to inhibit the eosinophil respiratory burst induced by receptor-mediated (chemotactic peptide) and nonreceptor-mediated (calcium ionophore and phorbol ester) stimuli. Thus β-agonist inhibition was unlikely to be isolated to an effect at the receptor or G protein linkage. To determine whether cyclic adenosine 3',5' monophosphate (cAMP) may mediate β-agonist effects, studies were performed with the type IV cAMP phosphodiesterase inhibitor Ro-201724. β-Agonist inhibition of the respiratory burst was clearly synergistic with effects of Ro-201724. We conclude that β-adrenoceptor agonists can regulate the eosinophil respiratory burst at least partially through an effect mediated by cAMP. Because regulation of the eosinophil by isoproterenol was observed at very low concentrations, these results may be relevant to pharmacologic effects of β-agonists in disease states complicated by eosinophil activation during asthma. (J A
LLERGY C
LIN I
MMUNOL 1995;95:735-41.)
Impairments in the respiratory burst and stimulus-response coupling were studied with respect to the increased rate of cell replication that occurred in HL60 cells during repetitive passages in cell ...culture. During a 45-week period of culture, HL60 cells developed a progressive increase in rate of replication. Concomitantly, undifferentiated cells developed an impairment in ATP-induced calcium mobilization. The percentage of cells that could be differentiated with dimethyl sulfoxide progressively diminished. Differentiated cells developed an impairment in both the respiratory burst and secretion of beta-glucuronidase. In addition, regulation of the respiratory burst by cAMP agonists including isoproterenol, adenosine, and prostaglandin E2 was reduced in rapidly proliferating cells. Thus, multiple changes in stimulus-response coupling occur during cell culture in association with an increase in rate of cell replication. It may be important to recognize progressive impairments in cell function in studies using repetitive samples of HL60 cells from a continuously maintained cell population. The observed impairments in stimulus-response coupling may be relevant to unregulated cell growth in neoplastic disease.
We investigated the role of cellular calcium pools in angiotensin II-stimulated aldosterone synthesis in bovine adrenal glomerulosa cells. Angiotensin II decreased the size of the exchangeable cell ...calcium pool by 34%, consistent with previous observations that angiotensin II causes decreased uptake of 45Ca+2 into cells and increased efflux of 45Ca+2 from preloaded cells. Atomic absorption spectroscopy showed that angiotension II caused a decrease of 21% in total cellular calcium. Angiotensin II caused efflux of 45Ca+2 in the presence of EGTA and retarded uptake of 45Ca+2 when choline was substituted for sodium, suggesting that hormone effects on calcium pools do not involve influx of trigger calcium or sodium. Cells incubated in calcium-free buffer and 0.1 mM or 0.5 mM EGTA synthesized reduced (but still significant) amounts of the steroid in response to hormone. Cells incubated in increasing concentrations of extracellular calcium contained increasing amounts of intracellular calcium and synthesized increasing amounts of aldosterone in response to angiotensin II. These results point to the participation of intracellular calcium pools in angiotensin II-stimulated steroidogenesis and the importance of extracellular calcium in maintaining these pools.
PIII-12 Cusack, B. J.; Gambliel, H.; Musser, B. ...
Clinical pharmacology and therapeutics,
02/2006, Letnik:
79, Številka:
2
Journal Article
Recenzirano
BACKGROUND/AIMS
Anthracyclines, such as doxorubicin and daunorubicin, can cause chronic, cumulative dose‐related cardiotoxicity. This can be prevented by dexrazoxane, a putative iron chelator. ...Disorders of iron metabolism, including altered IRP1‐IRE binding may be an important mechanism of anthracycline cardiotoxicity. This study was designed to examine the role of IRP1‐IRE binding in a chronic model of daunorubicin cardiotoxicity and whether dexrazoxane could prevent such changes in IRP1‐IRE binding due to daunorubicin.
METHODS
Young adult, Fischer 344 rats received daunorubicin 2.5 mg/kg iv once per week for 6 weeks with (N, 9) and without(N, 11) pretreatment with ip dexrazoxane 50 mg/kg. Other groups received saline (controls; N, 8) or dexrazoxane alone (N, 9). Rats were sacrificed either 4h (for IRP1/IRE binding) or 2 weeks (for IRP1/IRE binding and atrial functional studies) after the last dose of daunorubicin.
RESULTS
Contractility (dF/dt) in atrial tissue was significantly reduced in daunorubicin‐treated compared to control rats (dF/dt 10.1 +/− 1.0 vs. 32.9 +/− 3.1 g/sec; P < 0.001). dF/dt was unchanged in rats given daunorubicin with dexrazoxane pretreatment (dF/dt 26.9 +/− 2.9 g/sec). Left ventricular IRP1/IRE binding was not significantly affected by daunorubicin treatment either 4h or 2 weeks after treatment.
CONCLUSIONS
IRP1/IRE binding may not be altered in chronic anthracycline cardiotoxicity. Dexrazoxane protects against chronic anthracycline cardiotoxicity in the rat.
Clinical Pharmacology & Therapeutics (2005) 79, P61–P61; doi: 10.1016/j.clpt.2005.12.220
Ouabain (1 microM and below) inhibited both basal and angiotensin II-stimulated aldosterone synthesis in bovine adrenal glomerulosa cells. Ouabain had no effect on binding of 125I-labeled ...angiotensin, on angiotensin's effects on 45Ca2+ fluxes, or on 32PO4 incorporation into phosphatidylinositol. This spectrum of activities resembles that of the protein synthesis inhibitor cycloheximide, which also blocks aldosterone synthesis. Ouabain was, therefore, tested for its effect on protein synthesis, as measured by uptake of 3Hleucine into acid-precipitable material. Ouabain inhibited protein synthesis at concentrations similar to those that depressed aldosterone synthesis, but did not block uptake of the nonmetabolized amino acid carboxyl-14Caminocyclopentane-1-carboxylic acid, nor the entrance of 3Hleucine into cells. When cells previously loaded with 86Rb+ were treated with 1 microM ouabain, they lost approximately half of the accumulated radioactivity in 30 min. When cells were incubated in potassium-free buffer, both protein and aldosterone synthesis were severely inhibited. Increased extracellular potassium reversed ouabain's inhibition of protein and aldosterone synthesis in parallel. Pregnenolone synthesis was inhibited by ouabain, and elevated potassium overcame that blockade. Ouabain did not block aldosterone synthesis from exogenous progesterone. These data fit a model in which ouabain causes loss of cell potassium, which, in turn, depresses protein synthesis. Since protein synthesis is necessary for angiotensin II stimulation of cholesterol side-chain cleavage, ouabain depresses that step, pregnenolone synthesis, and thus, aldosterone synthesis.
We screened potassium channel agonists and antagonists in a search for pharmacologic probes of the channels that mediate potassium's effects on adrenal zona glomerulosa cells. Suspensions of bovine ...cells were tested, and aldosterone was measured by radioimmunoassay. The most potent inhibitors were pinacidil, capsaicin, glyburide, and quinine. These reagents were more potent against aldosterone production than against cortisol production. Aldosterone produced under basal conditions, as well as that stimulated by potassium, angiotensin II, or dibutyryl cyclic AMP, was antagonized. The vasodilatory and aldosterone-inhibiting potencies of potassium channel reagents were very different. Candidate antihypertensives with potassium channel activity should be tested for adrenal inhibition.
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