Elizabeth Slade

Ruthenium complexes as nitric oxide scavengers: a potential therapeutic approach to nitric oxide-mediated diseases

1 Ruthenium(III) reacts with nitric oxide (NO) to form stable ruthenium(II) mononitrosyls. Several Ru(III) complexes were synthesized and a study made of their ability to bind NO, in vitro and also in several biological systems following expression of the inducible isoform of nitric oxide synthase (iNOS). Here we report on the properties of two, related polyaminocarboxylate‐ruthenium complexes: potassium chloro[hydrogen(ethylenedinitrilo)tetraacetato]ruthenate (=JM1226; CAS no.14741‐19‐6) and aqua[hydrogen(ethylenedinitrilo)tetraacetato]ruthenium (=JM6245; CAS no.15282‐93‐6). 2 Binding of authentic NO by aqueous solutions of JM1226 yielded a product with an infrared (IR) spectrum characteristic of an Ru(II)‐NO adduct. A compound with a similar IR spectrum was obtained after reacting JM1226 with S‐nitroso‐N‐acetylpenicillamine (SNAP). 3 The effect of JM1226 or JM6245 on nitrite (NO2−) accumulation in cultures of macrophages (RAW 264 line) 18 h after stimulating cells with lipolysaccharide (LPS) and interferon‐γ (IFNγ) was studied. Activation of RAW264 cells increased NO2− levels in the growth medium from (mean±1 s.e.mean) 4.9±0.5  μM to 20.9±0.4 μM. This was blocked by actinomycin D (10 μM) or cycloheximide (5 μM). The addition of JM1226 or JM6245 (both 100 μM) to activated RAW264 cells reduced NO2− levels to 7.6±0.2 μM and 8.8±0.6 μM, respectively. NG‐methyl‐L‐arginine (L‐NMMA; 250 μM) similarly reduced NO2− levels, to 6.1±0.2 μM. 4 The effect of JM1226 or JM6245 on NO‐mediated tumour cell killing by LPS+IFNγ‐activated macrophages (RAW 264) was studied in a co‐culture system, using a non‐adherent murine mastocytoma (P815) line as the ‘target’ cell. Addition of JM1226 or JM6245 (both 100 μM) to the culture medium afforded some protection from macrophage‐mediated cell killing: target cell viability increased from 54.5±3.3% to 93.2±7.1% and 80.0±4.6%, respectively (n=6). 5 Vasodilator responses of isolated, perfused, pre‐contracted rat tail arteries elicited by bolus injections (10 μl) of SNAP were attenuated by the addition of JM1226 or JM6245 (10−4 M) to the perfusate: the ED50 increased from 6.0 μM (Krebs only) to 1.8 mM (Krebs+JM6245) and from 7 μM (Krebs only) to 132 μM (Krebs+JM1226). Oxyhaemoglobin (5 μM) increased the ED50 value for SNAP from 8 μM to 200 μM. 6 Male Wistar rats were injected with bacterial LPS (4 mg kg−1; i.p.) to induce endotoxaemia. JM1226 and JM6245 (both 100 μM) fully reversed the hyporesponsiveness to phenylephrine of tail arteries isolated from animals previously (24 h earlier) injected with LPS. Blood pressure recordings were made in conscious LPS‐treated rats using a tail cuff apparatus. A single injection of JM1226 (100 mg kg−1, i.p.) administered 20 h after LPS (4 mg kg−1, i.p.) reversed the hypotension associated with endotoxaemia. 7 The results show that JM1226 and JM6245 are able to scavenge NO in biological systems and suggest a role for these compounds in novel therapeutic strategies aimed at alleviating NO‐mediated disease states.

Use of luminescent gold compounds in the design of thin-film oxygen sensors

The use of two gold compounds incorporated into thin plastic films as luminescence quenching oxygen sensors is described. The films are sensitive both to gaseous oxygen and to oxygen dissolved in nonaqueous media such as ethanol. The luminescence quenching of these sensors by oxygen obeys the Stern−Volmer equation and Stern−Volmer constants of 5.35 × 10-3 and 0.9 × 10-3 Torr-1 are found, respectively, for the two dyes in a polystyrene polymer matrix. The sensitivity of the films is strongly influenced by the nature of the polymer matrix, and greatest sensitivity was found in systems based on the polymers polystyrene or cellulose acetate butyrate. Sensitivity was not found to be temperature dependent though raising the temperature from 15 to 50 °C did result in a slight decrease in emission intensity and a hypsochromic shift in the emission wavelength. The rate of response and recovery of the sensors can be increased either by decreasing film thickness or by increasing the operating temperature. The operat...

Kinetics of nitric oxide scavenging by ruthenium(iii)polyaminocarboxylates: novel therapeutic agents for septic shock

The reaction of two representative ruthenium(III) polyaminocarboxylates with nitric oxide are rapid (k > 10 7 M - 1 s - 1 at pH 7.4 and 7.3 °C) forming tight (K = 10 8 M - 1 ) ruthenium(II) mononitrosyls.

Luminescent Gold Compounds in Optical Oxygen Sensors

The use of luminescent gold(I) phosphine complexes as oxygen sensors is reported. Room temperature phosphorescent-based sensors have advantages over those based on fluorescence, and they have significant potential for development in clinical applications.