The flavonoid quercetin is metabolized into isorhamnetin, tamarixetin, and kaempferol, the vascular effects of which are unknown. In the present study, the effects of quercetin and its metabolites were analyzed on isometric tension in isolated rat thoracic and abdominal aorta, in isolated intact and ␤-escinpermeabilized iliac arteries, and on perfusion pressure in the isolated mesenteric resistance vascular bed. In noradrenalineprecontracted vessels, the four flavonoids produced a vasodilator effect, which was inversely correlated with the diameter of the vessel studied; i.e., quercetin, isorhamnetin, tamarixetin, and kaempferol were 5-, 25-, 4-, and 6-fold, respectively, more potent in the resistance mesenteric bed (Ϫlog IC 50 ϭ 5.35 Ϯ 0.15, 5.89 Ϯ 0.11, 5.34 Ϯ 0.10, and 5.66 Ϯ 0.06, respectively) than in the thoracic aorta (Ϫlog IC 50 ϭ 4.68 Ϯ 0.08, 4.61 Ϯ 0.08, 4.73 Ϯ 0.11, and 4.81 Ϯ 0.13, respectively; n ϭ 4 -6). The vasodilator responses of quercetin and isorhamnetin were not significantly modified after removal of the endothelium in the thoracic aorta or in the mesenteric bed. Furthermore, the guanylate cyclase inhibitor ODQ (1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one; 10 Ϫ6 M), the adenylate cyclase inhibitor SQ22536 [9-(tetrahydro-2-furanyl)-9H-purin-6-amine; 10Ϫ6 M], KCl (40 mM), or ouabain (10 Ϫ3 M) had no effect on isorhamnetin-induced vasodilation in the mesenteric bed. In permeabilized iliac arteries stimulated with Ca 2ϩ (pCa of 5.9), isorhamnetin was also significantly more potent (Ϫlog IC 50 ϭ 5.27 Ϯ 0.15) than quercetin (Ϫlog IC 50 ϭ 4.56 Ϯ 0.15). In conclusion, quercetin and its metabolites showed vasodilator effects with selectivity toward the resistance vessels. These effects are not due to or modulated by endothelial factors and are unrelated to changes in cytosolic Ca 2ϩ .Flavonoids comprise a large group of secondary metabolites widely distributed throughout the plant kingdom, including food plants. The daily flavonoid intake in the human diet (mainly from onions, apples, grapes, wine, tea, berries, herbs, and spices) is highly variable, with estimations ranging from 23 mg (flavonols plus flavones; Hertog et al., 1993b) to more than 500 mg (total flavonoids;

The flavonoid quercetin reduces blood pressure and endothelial dysfunction in animal models of hypertension. However, the results concerning the relationship between quercetin and NO present a complex picture. We have analyzed the mechanisms involved in the NO scavenging effects of quercetin and its repercussion on NO bioactivity in vascular smooth muscle. Quercetin scavenged NO with apparent zero-order kinetics with respect to NO. This effect was strongly dependent on the O 2 concentrations, so that NO decay at pH 7.4 could be fitted to the equation

A high calorie intake can induce the appearance of the metabolic syndrome (MS), which is a serious public health problem because it affects glucose levels and triglycerides in the blood. Recently, it has been suggested that MS can cause complications in the brain, since chronic hyperglycemia and insulin resistance are risk factors for triggering neuronal death by inducing a state of oxidative stress and inflammatory response that affect cognitive processes. This process, however, is not clear. In this study, we evaluated the effect of the consumption of a high-calorie diet (HCD) on both neurodegeneration and spatial memory impairment in rats. Our results demonstrated that HCD (90 day consumption) induces an alteration of the main energy metabolism markers, indicating the development of MS in rats. Moreover, an impairment of spatial memory was observed. Subsequently, the brains of these animals showed activation of an inflammatory response (increase in reactive astrocytes and interleukin1-β as well as tumor necrosis factor-α) and oxidative stress (reactive oxygen species and lipid peroxidation), causing a reduction in the number of neurons in the temporal cortex and hippocampus. Altogether, these results suggest that a HCD promotes the development of MS and contributes to the development of a neurodegenerative process and cognitive failure. In this regard, it is important to understand the relationship between MS and neuronal damage in order to prevent the onset of neurodegenerative disorders.

No abstract

Energy drinks (EDs) are often consumed in combination with alcohol because they reduce the depressant effects of alcohol. However, different researches suggest that chronic use of these psychoactive substances in combination with alcohol can trigger an oxidative and inflammatory response. These processes are regulated by both a reactive astrogliosis and an increase of proinflammatory cytokines such as IL-1β, TNF-α, and iNOS, causing cell death (apoptosis) at the central and peripheral nervous systems. Currently, mechanisms of toxicity caused by mixing alcohol and ED in the brain are not well known. In this study, we evaluated the effect of chronic alcohol consumption in combination with ED on inflammatory response and oxidative stress in the temporal cortex (TCx) and hippocampus (Hp) of adult rats (90 days old). Our results demonstrated that consuming a mixture of alcohol and ED for 60 days induced an increase in reactive gliosis, IL-1β, TNF-α, iNOS, reactive oxygen species, lipid peroxidation, and nitric oxide, in the TCx and Hp. We also found immunoreactivity to caspase-3 and a decrease of synaptophysin in the same brain regions. The results suggested that chronic consumption of alcohol in combination with ED causes an inflammatory response and oxidative stress, which induced cell death via apoptosis in the TCx and Hp of the adult rats.

1 We have compared the mechanisms involved in sodium nitroprusside (SNP)-induced relaxation and [Ca 2+ ] i reduction in isolated piglet pulmonary (PA) and mesenteric (MA) arteries. 2 SNP (10 M7361075 M) evoked a concentration-dependent relaxation of PA and MA (pD 2 =6.66+0.06 and 6.74+0.14, respectively) stimulated by noradrenaline, which was markedly reduced by the guanylate cyclase inhibitor ODQ. In fura 2-incubated PA and MA, SNP produced a parallel reduction in contractile force and in [Ca 2+ ] i , expressed as the ratio of emitted¯uorescence at 340 and 380 nm (F340/F380).

Acetylcholine (ACh) and N-methyl-D aspartate receptors (NMDARs) interact in the regulation of multiple important brain functions. NMDAR activation is indirectly modulated by ACh through the activation of muscarinic or nicotinic receptors. Scant information is available on whether ACh directly interacts with the NMDAR. By using a cortical brain slice preparation we found that the application of acetylcholine as well of other drugs acting on muscarinic or nicotinic receptors induces an acute and reversible reduction of NMDAR-mediated currents (I NMDA ), ranging from 20% to 90% of the control amplitude. The reduction displayed similar features in synaptic INMDA in brain slices, as well as in currents evoked by NMDA application in brain slices or from acutely dissociated cortical cells, demonstrating its postsynaptic nature. The cholinergic inhibition of INMDA displayed an onset-offset rate in the order of a second, was resistant to the presence of the muscarinic antagonist atropine (10 μM) in the extracellular solution, and of G-protein blocker GDP β S (500 μM) and activator GTP γ S (400 μM) in the intracellular solution, indicating that it was not G-protein dependent. Recording at depolarized or hyperpolarized holding voltages reduced NMDAR-mediated currents to similar extents, suggesting that the inhibition was voltageindependent, while the reduction was markedly more pronounced in the presence of glycine (20 μM). A detailed analysis of the effects of tubocurarine suggested that at least this drug interfered with glycine-dependent NMDAR-activity.We conclude that NMDAR-mediated currents can be inhibited directly by cholinergic drugs, possibly by direct interaction within one or more subunits of the NMDAR. Our results could supply a new interpretation to previous studies on the role of ACh at the glutamatergic synapse.

Activation of the growth hormone (GH)-secretagogue receptor (GHS-R) by synthetic GH-releasing peptides (GHRP) or its endogenous ligand (ghrelin) stimulates GH release. Though much is known about the signal transduction underlying short-term regulation, there is far less information on mechanisms that produce long-term effects. In the current report, using whole-cell patch-clamp recordings, we assessed the long-term actions of such regulatory factors on voltage-activated Ca(2+) currents in GH-secreting cells derived from a rat pituitary tumour (GC cell line). After 96 h in culture, all recorded GC somatotropes exhibited two main Ca(2+) currents: a medium voltage-activated (MVA; T/R-type) and a high voltage-activated (HVA; mostly dihydropyridine-sensitive L-type) current. Interestingly, L- and non-L-type channels were differentially up-regulated by GHRP-6 and ghrelin. Chronic treatment with the GHS induced a significant selective increase on Ba(2+) current through HVA Ca(2+) channels, and caused only a modest increase of currents through MVA channels. Consistent with this, in presence of D-(Lys(3))-GHRP-6, a specific antagonist of the GHS-R, the increase in HVA Ca(2+) channel activity after chronic treatment with the GHS was abolished. The stimulatory effect on HVA current density evoked by the secretagogues was accompanied by an augment in maximal conductance with no apparent changes in the kinetics and the voltage dependence of the Ca(2+) currents, suggesting an increase in the number of functional channels in the cell membrane. Lastly, in consistency with the functional data, quantitative real-time RT-PCR revealed that the expression level of transcripts encoding for the Ca(V)1.3 pore-forming subunit of the L-type channels was significantly increased after chronic treatment of the GC cells with ghrelin.