Although the anti-inflammatory actions of glucocorticoids (GCs) are well established in the periphery, these stress hormones can increase inflammation under some circumstances in the brain. The transcription factor nuclear factor-B (NF-B), which is inhibited by GCs, regulates numerous genes central to inflammation. In this study, the effects of stress, GCs, and NMDA receptors on lipopolysaccharide (

Neutrophils act as first-line-of-defense cells and the reduction of their functional activity contributes to the high susceptibility to and severity of infections in diabetes mellitus. Clinical investigations in diabetic patients and experimental studies in diabetic rats and mice clearly demonstrated consistent defects of neutrophil chemotactic, phagocytic and microbicidal activities. Other alterations that have been reported to occur during inflammation in diabetes mellitus include: decreased microvascular responses to inflammatory mediators such as histamine and bradykinin, reduced protein leakage and edema formation, reduced mast cell degranulation, impairment of neutrophil adhesion to the endothelium and migration to the site of inflammation, production of reactive oxygen species and reduced release of cytokines and prostaglandin by neutrophils, increased leukocyte apoptosis, and reduction in lymph node retention capacity. Since neutrophil function requires energy, metabolic changes (i.e

Baroreflex dysfunction, oxidative stress and inflammation, important hallmarks of hypertension, are attenuated by exercise training. In this study, we investigated the relationships and time-course changes of cardiovascular parameters, pro-inflammatory cytokines and pro-oxidant profiles within the hypothalamic paraventricular nucleus of the spontaneously hypertensive rats (SHR). Basal values and variability of arterial pressure and heart rate and baroreflex sensitivity were measured in trained (T, low-intensity treadmill training) and sedentary (S) SHR at weeks 0, 1, 2, 4 and 8. Paraventricular nucleus was used to determine reactive oxygen species (dihydroethidium oxidation products, HPLC), NADPH oxidase subunits and pro-inflammatory cytokines expression (Real time PCR), p38 MAPK and ERK1/2 expression (Western blotting), NF-κB content (electrophoretic mobility shift assay) and cytokines immunofluorescence. SHR-S vs. WKY-S (Wistar Kyoto rats as time control) showed increased mean arterial pressure (172±3 mmHg), pressure variability and heart rate (358±7 b/min), decreased baroreflex sensitivity and heart rate variability, increased p47phox and reactive oxygen species production, elevated NF-κB activity and increased TNF-α and IL-6 expression within the paraventricular nucleus of hypothalamus. Two weeks of training reversed all hypothalamic changes, reduced ERK1/2 phosphorylation and normalized baroreflex sensitivity (4.04±0.31 vs. 2.31±0.19 b/min/mmHg in SHR-S). These responses were followed by increased vagal component of heart rate variability (1.9-fold) and resting bradycardia (−13%) at the 4th week, and, by reduced vasomotor component of pressure variability (−28%) and decreased mean arterial pressure (−7%) only at the 8th week of training. Our findings indicate that independent of the high pressure levels in SHR, training promptly restores baroreflex function by disrupting the positive feedback between high oxidative stress and increased pro-inflammatory cytokines secretion within the hypothalamic paraventricular nucleus. These early adaptive responses precede the occurrence of training-induced resting bradycardia and blood pressure fall.

Our data show that intrauterine undernutrition: (1) induces hypertension both in the male and female offspring, hypertension being more severe in male than in female rats; (2) alters endothelium-dependent responses in aortas from the resulting offspring. The endothelial dysfunction is associated with a decrease in activity/expression of eNOS in aortas from male offspring. The mechanism involved in altered response to ACh in female offspring might be a consequence of reduction in estrogen levels leading to reduced eNOS activity.

The inter-and intracellular regulator nitric oxide (NO) has been suggested to play a role in the modulation of cellular excitability, but the mechanism(s) by which this occurs remain unclear. Using the kidney as a model system, we report here evidence that NO, produced in response to various hormones and cytokines, can effect long-term alterations in the activity of the membrane sodium pump. This regulation of Na,K-ATPase, which occurs in a system of NO-containing renal tubules, involves cGMP and cGMP-dependent protein kinase. Na,K-ATPase can also be regulated by alterations of cGMP initiated through NO-independent factors, such as atriopeptin, and in nonrenal tissues, such as cerebellum. Regulation of the membrane sodium pump by NO and cGMP, therefore, represents a mechanism for hormonal modulation of ion gradients, not only in kidney but also in other organs, including brain, where NO and cGMP play a prominent role in cellular function.Nitric oxide (NO) is a key paracrine and autocrine regulator in a number oftissues, including blood vessels, immune cells, and the nervous system (1). In this latter tissue, NO has been implicated in mechanisms of cell injury and in long-term physiological changes in cellular excitability. While considerable progress has been made in elucidating the regulation of NO synthesis and in identifying NO's immediate second messenger effectors [e.g., soluble guanylyl cyclase (GC)], much less is known about the downstream biochemical targets of NO.In the kidney, acetylcholine (ACh), bradykinin (BK), and certain other endothelium-dependent factors promote salt and water loss through a mechanism involving formation of NO and production of cGMP (2, 3). Prior reports have suggested that these hormonal effects occur in renal blood vessels and result from an alteration of renal or glomerular hemodynamics. In the kidney-like choroid plexus and ciliary process, however, cGMP [formed from activation of atriopeptin (ANF) receptors] alters fluid secretion and stimulates protein phosphorylation through a direct effect on secretory epithelium (4-6). Because NO is a potent stimulus to cGMP production, these latter observations raise the possibility that NO (and hormones stimulating its production) might be capable of altering membrane ion movement through direct (i.e., nonvascular) effects on transporting epithelium. An intriguing target for such regulation in secretory (as well as excitable) cells would be the membrane sodium pump Na,KATPase, which has been shown (7, 8) to be regulated by dopamine and cAMP. The present study investigates this possible role for NO and cGMP. METHODS NO Synthase (NOS). NOS activity was measured (9) in high-speed supernatants from rat cerebellum, kidney medulla and cortex, porcine LLC-PK1 epithelial cells, and purified cultured tubules incubated with 0.2 mM L-arginine/10 mM Hepes/0.425 mM EDTA/0.45 mM CaCl2/80 units of calmodulin/1 gM tetrahydrobiopterin/4 1LM FAD/4 pM FMN/0.5 mM dithiothreitol/0.16 M sucrose/±1 mM NADPH. For Ca2+/calmodulin-free activity, EDTA w...