Inhibition of nitric oxide-stimulated vasorelaxation by carbon monoxide-releasing molecules.

Carbon monoxide (CO) is a weak soluble guanylyl cyclase stimulator, leading to transient increases in cGMP and vasodilation. The aim of the present work was to measure the effect of CO-releasing molecules (CORMs) on the cGMP/nitric oxide (NO) pathway and to evaluate how selected CORMs affect NO-induced vasorelaxation. METHODS AND RESULTS: Incubation of smooth muscle cells with some but not all of the CORMs caused a minor increase in cGMP levels. Concentration-response curves were bell-shaped, with higher CORMs concentrations producing lower increases in cGMP levels. Although exposure of cells to CORM-2 enhanced cGMP formation, we observed that the compound inhibited NO-stimulated cGMP accumulation in cells and NO-stimulated soluble guanylyl cyclase activity that could be reversed by superoxide anion scavengers. Reactive oxygen species generation from CORMs was confirmed using luminol-induced chemiluminescence and electron spin resonance. Furthermore, we observed that NO is scavenged by CORM-2. When used alone CORM-2 relaxed vessels through a cGMP-mediated pathway but attenuated NO donor-stimulated vasorelaxation. CONCLUSION: We conclude that the CORMs examined have context-dependent effects on vessel tone, as they can directly dilate blood vessels, but also block NO-induced vasorelaxation

An N-Acetyl Cysteine Ruthenium Tricarbonyl Conjugate Enables Simultaneous Release of CO and Ablation of Reactive Oxygen Species.

We have designed and synthesised a [Ru(CO)3 Cl2 (NAC)] pro-drug that features an N-acetyl cysteine (NAC) ligand. This NAC carbon monoxide releasing molecule (CORM) conjugate is able to simultaneously release biologically active CO and to ablate the concurrent formation of reactive oxygen species (ROS). Complexes of the general formulae [Ru(CO)3 (L)3 ](2+) , including [Ru(CO)3 Cl(glycinate)] (CORM-3), have been shown to produce ROS through a water-gas shift reaction, which contributes significantly, for example, to their antibacterial activity. In contrast, NAC-CORM conjugates do not produce ROS or possess antibacterial activity. In addition, we demonstrate the synergistic effect of CO and NAC both for the inhibition of nitric oxide (formation) and in the expression of tumour-necrosis factor (TNF)-α. This work highlights the advantages of combining a CO-releasing scaffold with the anti-oxidant and anti-inflammatory drug NAC in a unique pro-drug.We thank the EU (Marie Curie CIG to G.J.L.B.), FCT Portugal (FCT Investigator to G.J.L.B.; SFRH/BPD/95253/2013 to J.D.S.) and the EPSRC for funding. The NMR spectrometers are part of The National NMR Facility, supported by Fundação para a Ciência e a Tecnologia (RECI/BBB-BQB/0230/2012). G.J.L.B. is a Royal Society University Research Fellow.This is the final version of the article. It first appeared from Wiley via http://dx.doi.org/10.1002/chem.20150247

Efeitos hemorreológicos e cardiovasculares da eritropoietina num modelo de rato em exercício físico sob a acção de drogas

Recombinant human erythropoietin (rhEPO) has been therapeutically used for correction of anaemia. However, due to the increase in circulating red blood cells (RBCs) it promotes, thus increasing oxygen delivery to muscles and improving performance in sport, it has been also illegally used as sports doping. Besides the well known increase of hematocrit and blood viscosity; which might cause serious complications for the athletes, other disturbances could occur, whose mechanisms remain to be fully elucidated. This study aimed to evaluate the hemorheological and cardiovascular effects of administration of rhEPO to rats under chronic aerobic exercise. A ten week-protocol was performed in four male Wistar rat groups: control — sedentary; rhEPO — 50 IV/kg, 3 times/wk; exercised (EX) — swimming for 1 hr, 3 times/ wk; EX+rhEPO. rhEPO in trained rats promoted erythrocyte count increase, hypertension, heart hypertro-phy, sympathetic and serotonergic overactivation, as well as a trend to increased oxidative stress. In conclusion, rhEPO doping in rats under chronic exercise promotes not only the expected increased hematocrit, but also other serious deleterious cardiovascular and thromboembolic modifications, including live risk, which might be known and assumed by all sports authorities, including athletes and their physicians.info:eu-repo/semantics/publishedVersio