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PubMed2004

Actin-dependent tumour cell adhesion after short-term exposure to the antimetastasis ruthenium complex NAMI-A.

Imidazolium trans-imidazoledimethylsulphoxidetrachlororuthenate (NAMI-A) was tested in vitro on the pro-adhesive properties, evaluated as resistance to trypsin treatment, which is a bona fide measure of adhesion strength, of KB and HeLa carcinoma cell lines and on human polymorphonuclear neutrophils (HPMN). NAMI-A increased the pro-adhesive activity of KB cells at 0.001 mM concentration, after few minutes incubation and this effect was not influenced by the vehicle used for cell challenge, neither did it depend on NAMI-A concentration or on temperature. The same effect occurred on HeLa cells at 0.01 mM NAMI-A. This effect, detected at concentrations up to 100 times lower than those necessary to block cells at the G(2)-M premitotic phase of cell cycle, or to inhibit matrix metalloproteinase release or cell invasion, was not related to ruthenium uptake by tumour cells. HeLa cells and healthy HPMN, following short exposure to 0.1 mM NAMI-A, assumed a different shape, with the extrusion of filopodia (HeLa) and of large lamellopodia (HPMN), which increased their interactions with the substrate. This effect was attributed to stabilisation, altered turnover and sensitivity to cytochalasin D of actin filaments. Provided that adhesion is associated with cell motility and invasion, these data suggest that NAMI-A may exert antimetastatic properties at concentrations lower than those observed in the lungs at the end of a conventional intraperitoneal treatment in vivo.

Actin Cytoskeleton↗

PubMed2005

Exceptionally facile CO addition to a saturated ruthenium complex.

Synthesis and characterization of Cp*Ru[eta3-HC(PPh2NPh)2], 1, reveals it to have a "piano stool" structure with the ligand bound to Ru(II) via two N and the unique, sp3 hybridized carbon. While the analogous (cymene) Ru[eta3-HC(PPh2NPh)2]+ does not react with CO, under the same conditions, 1 adds one CO rapidly (25 degrees C, 1 atm CO). Characterization, including an X-ray structure determination, shows that CO has displaced one chelate ligand nitrogen, which then hangs off the molecule, free of Ru. DFT calculations reveal a possible mechanism via a remarkably low energy (+9.3 kcal/mol) intermediate, pendant N, but with one phenyl on phosphorus stabilizing Ru via donation from a C(ipso)=C(ortho) bond. DFT calculations show that the electronic energy change for binding CO is over 20 kcal/mol less favorable for cymene than for C5Me5- as ligand; the reactivity difference is thus thermodynamic in origin.

Carbon Monoxide↗

PubMed2006

Ru360, a specific mitochondrial calcium uptake inhibitor, improves cardiac post-ischaemic functional recovery in rats in vivo.

BACKGROUND AND PURPOSE: The mitochondrial permeability transition pore (mPTP), an energy-dissipating channel activated by calcium, contributes to reperfusion damage by depolarizing the mitochondrial inner membrane potential. As mitochondrial Ca(2+) overload is a main inductor of mPTP opening, we examined the effect of Ru(360), a selective inhibitor of the mitochondrial calcium uptake system against myocardial damage induced by reperfusion in a rat model. EXPERIMENTAL APPROACH: Myocardial reperfusion injury was induced by a 5-min occlusion of the left anterior descending coronary artery, followed by a 5-min reperfusion in anaesthetized open-chest rats. We measured reperfusion-induced arrhythmias and functions indicative of unimpaired mitochondrial integrity to evaluate the effect of Ru(360) treatment. KEY RESULTS: Reperfusion elicited a high incidence of arrhythmias, haemodynamic dysfunction and loss of mitochondrial integrity. A bolus intravenous injection of Ru(360) (15-50 nmol kg(-1)), given 30-min before ischaemia, significantly improved the above mentioned variables in the ischaemic/reperfused myocardium. Calcium uptake in isolated mitochondria from Ru(360)-treated ventricles was partially diminished, suggesting an interaction of this compound with the calcium uniporter. CONCLUSIONS AND IMPLICATIONS: We showed that Ru(360) treatment abolishes the incidence of arrhythmias and haemodynamic dysfunction elicited by reperfusion in a whole rat model. Ru(360) administration partially inhibits calcium uptake, preventing mitochondria from depolarization by the opening of the mPTP. We conclude that myocardial damage could be a consequence of failure of the mitochondrial network to maintain the membrane potential at reperfusion. Hence, it is plausible that Ru(360) could be used in reperfusion therapy to prevent the occurrence of arrhythmia.

Aconitate Hydratase↗

PubMed2004

Influence of the chemical form on the plasma clearance of ruthenium in humans.

The radioisotopes of ruthenium (103Ru and 106Ru) are abundant fission products and represent a radiological risk for the population in case of nuclear accidents. Few biokinetic studies have been performed on humans up to now and consequently the current model recommended by ICRP for ruthenium is derived mainly by extrapolation from animal data. The stable isotope 101Ru and proton activation analysis have been used to study the biokinetics of Ru in blood plasma samples taken during 8 studies in three healthy volunteers. The results obtained demonstrated that complexed Ru (in the form of citrate Ru(IV) complexes) is cleared from blood plasma very rapidly (characteristic half time of 17+/-2 min), while inorganic Ru remains longer in the systemic circulation, and is transferred to other organs and/or excreted with a biological half time of 23+/-2h. Good reproducibility of the clearance curves indicated no evidence of inter- or intra-individual variability when the same Ru solution was injected in repeated experiments to different subjects.

Adult↗

PubMed2005

Reversible colorimetric probes for mercury sensing.

The selectivity and sensitivity of two colorimetric sensors based on the ruthenium complexes N719 [bis(2,2'-bipyridyl-4,4'-dicarboxylate)ruthenium(II) bis(tetrabutylammonium) bis(thiocyanate)] and N749 [(2,2':6',2' '-terpyridine-4,4',4' '-tricarboxylate)ruthenium(II) tris(tetrabutylammonium) tris(isothiocyanate)] are described. It was found that mercury ions coordinate reversibly to the sulfur atom of the dyes' NCS groups. This interaction induces a color change in the dyes at submicromolar concentrations of mercury. Furthermore, the color change of these dyes is selective for mercury(II) when compared with other ions such as lead(II), cadmium(II), zinc(II), or iron(II). The detection limit for mercury(II) ions--using UV-vis spectroscopy--in homogeneous aqueous solutions is estimated to be approximately 20 ppb for N719 and approximately 150 ppb for N749. Moreover, the sensor molecules can be adsorbed onto high-surface-area mesoporous metal oxide films, allowing reversible heterogeneous sensing of mercury ions in aqueous solution. The results shown herein have important implications in the development of new reversible colorimetric sensors for the fast, easy, and selective detection and monitoring of mercuric ions in aqueous solutions.

Biosensing Techniques↗

PubMed2004

Cytotoxicity of the organic ruthenium anticancer drug Nami-A is correlated with DNA binding in four different human tumor cell lines.

PURPOSE: The cytotoxicity, intracellular accumulation and DNA adduct formation of the ruthenium complex imidazolium trans-imidazoledimethylsulfoxide tetrachlororuthenate (ImH[ trans-RuCl(4)(DMSO)Im], Nami-A) were compared in vitro with those of cisplatin in four human tumor cell lines: Igrov-1, 2008, MCF-7, and T47D. METHODS: Cytotoxicity was assessed in vitro using a growth inhibition assay. Accumulation was determined by flameless atomic absorption spectroscopy (AAS). GG and AG intrastrand adducts were measured using the (32)P-postlabeling assay. RESULTS: Nami-A was on average 1053 times less cytotoxic than cisplatin. The cytotoxicity of cisplatin was linearly related to both intracellular platinum accumulation and DNA binding, while the cytotoxicity of Nami-A was significantly related only to DNA binding and not to intracellular ruthenium accumulation. The levels of accumulation of Nami-A measured as ruthenium and of cisplatin measured as platinum were correlated linearly with the incubation concentration over a concentration range of 0 to 600 micro M of both drugs. Ruthenium intracellular accumulation and DNA binding were on average 4.8 and 42 times less, respectively, than those of cisplatin. In addition, the numbers of GG and AG intrastrand adducts induced by Nami-A were 418 and 51 times fewer, respectively. Nami-A and cisplatin had the same binding capacity to calf thymus DNA. Nami-A was 25-40% less bound to cellular proteins than cisplatin. CONCLUSIONS: There was no saturation of the uptake and DNA binding capacity of either Nami-A or cisplatin. Furthermore, the low binding of Nami-A to cellular DNA cannot simply be explained by a lower capacity to bind to DNA, because the absolute level of binding in vitro to calf thymus DNA was the same for Nami-A and cisplatin. Finally, the lower cytotoxicity of Nami-A on a molar basis than that of cisplatin can at least partly be explained by its reduced reactivity to DNA in intact cells.

Animals↗

PubMed2002

Pharmaceutical development of a parenteral lyophilized formulation of the antimetastatic ruthenium complex NAMI-A.

This paper describes the development of a stable pharmaceutical dosage form for NAMI-A, a novel antimetastatic ruthenium complex, for Phase I testing. NAMI-A drug substance was characterized using several spectrometric and chromatographic techniques. In preformulation studies, it was found that NAMI-A in aqueous solution was not stable enough to allow sterilization by moist heat. The effect of several excipients on the stability of the formulation solution was investigated. None of them provided sufficient stability to allow long-term storage of an aqueous solution of NAMI-A. Therefore, a lyophilized product was developed. Five different formulations were prepared and subjected to thermogravimetric (TG) analysis and stability studies at various conditions for 1 year. Minimal degradation during the production process is achieved with a formulation solution of pH 3-4. Of the acids tested, only hydrochloric acid (HCl 0.1 mM) both stabilized the formulation solution and was compatible with the lyophilized product. This product was stable for at least 1 year when stored at -20 degrees C, 25 degrees C/60% relative humidity (RH) and 40 degrees C/75% RH, and was also photostable.

Antineoplastic Agents↗

PubMed2006

From bench to bedside--preclinical and early clinical development of the anticancer agent indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A).

Indazolium trans-[tetrachlorobis(1H-indazole)ruthenate(III)] (KP1019 or FFC14A) is just the second ruthenium-based anticancer agent after NAMI-A which was developed to the stage of clinical trials. Important steps in the mode of action of KP1019 are thought to be the binding to the serum protein transferrin and the transport into the cell via the transferrin pathway. Additionally, the selective activation by reduction in the tumor might contribute to the low side effects observed in in vivo studies. Apoptosis is induced at non-toxic levels via the mitochondrial pathway. These features distinguish it from the established platinum anticancer drugs and suggest that different types of cancer might be treatable with this drug. Indeed, promising activity against certain types of tumors, which are not successfully treatable with cisplatin, and only a very low incidence of acquired resistance has been observed in in vitro and in vivo studies. Recently, a clinical phase I trial was finished in which none of the treated patients experienced serious side effects, while disease stabilization in five of six evaluable patients was achieved. In this review, the preclinical and early clinical development of KP1019 - from bench to bedside - is recapitulated.

Antineoplastic Agents↗

PubMed2006

Ruthenium(II) complex of Hbopip: synthesis, characterization, pH-induced luminescence "off-on-off" switch, and avid binding to DNA.

A novel ruthenium(II) complex of [Ru(bpy)2(Hbopip)](ClO4)2 (in which bpy=2,2'-bipyridine, Hbopip=2-(4-benzoxazolyl)phenylimidazo[4,5-f][1,10]phenanthroline) was synthesized and characterized. The spectrophotometric pH titrations of the complex showed that it acted as a pH-induced luminescence "off-on-off" switch: a luminescence off-on switch with a luminescence enhancement factor of IpH=3.0/IpH=1.0=20 occurring over a narrow pH range of 1.00-3.00 plus a luminescence on-off switch with a luminescence enhancement factor of 3 over a pH range of 3.20-9.40. The excited-state ionization constant of the complex derived, pKa1*=3.06, is 1.36 pKa units greater than the ground-state pKa1=1.70, and pKa2*=5.01 and pKa3*=8.22 are comparable to the ground-state pKa2=5.23 and pKa3=8.22, respectively. The complex avidly bound to calf thymus DNA with a large binding constant of (1.2+/-0.3)x10(7) M-1 in buffered 50 mM NaCl, as evidenced by UV-vis and luminescence titrations, steady-state emission quenching by [Fe(CN)6]4-, DNA competitive binding with ethidium bromide, viscosity measurements, and DNA melting experiments.

Binding, Competitive↗

PubMed2004

TGFbeta1 regulation and collagen-release-independent connective tissue re-modelling by the ruthenium complex NAMI-A in solid tumours.

PURPOSE: The objective of this study is to evaluate the fibrotic process induced in vivo by NAMI-A in mice with solid tumours. In addition, the in vitro effects of NAMI-A on collagen fibres and the expression of TGFbeta1 in TS/A adenocarcinoma cells, NIH/3T3 fibroblasts and co-culture of fibroblasts and tumour cells have also been studied. METHODS: Collagen fibres release was assayed in supernatant of culture cells treated with 0.1 and 0.01 mM NAMI-A. TGFbeta1 was detected by RT-PCR and immunoblot on cellular lysates. RESULTS: NAMI-A, given to mice bearing MCa mammary carcinoma at advanced stages of growth, increased the thickness of connective tissue and induced recruitment of leukocytes, particularly in the peritumour capsule. In vitro NAMI-A stimulated collagen production by NIH/3T3 fibroblasts and decreased collagen release by TS/A tumour cells after prolonged exposure, either after single cell treatment or in co-cultures. In co-cultures, NAMI-A, in a dose-dependent manner, down-regulated the expression of TGFbeta1 mRNA and protein in tumour cells and up-regulated it in fibroblasts. The isoform of this cytokine is involved in fibrosis, invasion and metastatic processes. CONCLUSIONS: These data emphasize the ability of NAMI-A to evoke beneficial effects from healthy cells against tumour growth and metastases. The contribution of fibroblasts to the fibrosis arising in tumour masses is due to TGFbeta1, and its down-regulation in tumour cells might explain the documented reduction of gelatinase release.

Animals↗

PubMed2001

Validated method for the determination of the novel organo-ruthenium anticancer drug NAMI-A in human biological fluids by Zeeman atomic absorption spectrometry.

NAMI-A is a novel ruthenium-containing experimental anticancer agent. We have developed and validated a rapid and sensitive analytical method to determine NAMI-A in human plasma, plasma ultrafiltrate and urine using atomic absorption spectrometry with Zeeman correction. The sample pretreatment procedure is straightforward, involving only dilution with an appropriate hydrochloric acid buffer-solution. Because the response signal of the spectrometer depended on the composition of the sample matrix, in particular on the amount of human plasma in the sample, all unknown samples were diluted to match the matrix composition in which the standard line was prepared (plasma-buffer 1:10 v/v). This procedure enabled the measurement of samples of different biological matrices in a single run. The validated range of determination was 1.1-220 microM NAMI-A for plasma and urine, and 0.22-44 microM for plasma ultrafiltrate. The lower limit of detection was 0.85 microM in plasma and urine and 0.17 microM in plasma ultrafiltrate. The lower limit of quantitation was 1.1 and 0.22 microM, respectively. The performance of the method, in terms of precision and accuracy was according to the generally accepted criteria for validation of analytical methodologies. The applicability of the method was demonstrated in a patient who was treated in a pharmacokinetic phase I trial with intravenous NAMI-A.

Antineoplastic Agents↗

PubMed2003

Dinuclear versus mononuclear ruthenium(II) and osmium(II) complexes as potent mediators of glucose oxidase; crystal structure of [OsCl(4,4'-bpy)(bpy)2]BF4.

New and known homo- and heterodinuclear Ru(II) and Os(II) complexes with 4,4'-bipyridine (4,4'-bpy), pyrazine, and 4-pyCH=CHpy-4' as bridging ligands (LL) of the type [Cl(bpy)(2)M(LL)MCl(bpy)(2)]X(2) (bpy=2,2'-bipyridine; X=PF(6) or BF(4)) have been studied in their capacity to exchange electrons with a reduced active site of glucose oxidase (GO) from Aspergillus niger. Cyclic voltammograms (CVs) of the dimers in the aqueous buffered solution, when compared with CVs of the parent monomeric species [MCl(LL)(bpy)(2)]BF(4) and [MCl(2)(bpy)(2)] which could be generated at pH approximately 7, if the dimers undergo monomerization, indicate that the dimers are the dominating species under such conditions. All electrochemically oxidized dinuclear complexes studied show high rates of oxidation of GO reduced by D-glucose and the corresponding observed second-order rate constants are in the range (5-64)x10(5) M(-1) s(-1) at 25 degrees C. However, these values are lower than that for the mononuclear complex [OsCl(4,4'-bpy)(bpy)(2)]BF(4) (1.1x10(7) M(-1) s(-1)), suggesting that potentially two-electron dimeric mediators have no advantage compared with corresponding monomeric complexes of Ru(II) and Os(II). The structure of [OsCl(4,4'-bpy)(bpy)(2)]BF(4) was confirmed by X-ray crystallography. The monodentate 4,4'-bpy ligand is coordinated cis to the chloride. Its higher reactivity toward reduced GO is accounted for in terms of the antenna effect of the monodentate 4,4'-bpy ligand. The antenna length equals 9.2 A and matches the depth of the enzyme active site pocket of ca. 10 A. The mechanism of the antenna effect is discussed.

2,2'-Dipyridyl↗

PubMed2005

Inhibition of B16 melanoma metastases with the ruthenium complex imidazolium trans-imidazoledimethylsulfoxide-tetrachlororuthenate and down-regulation of tumor cell invasion.

The antimetastatic ruthenium complex imidazolium trans-imidazoledimethylsulfoxide-tetrachlorouthenate (NAMI-A) is tested in the B16 melanoma model in vitro and in vivo. Treatment of B6D2F1 mice carrying intra-footpad B16 melanoma with 35 mg/kg/day NAMI-A for 6 days reduces metastasis weight independently of whether NAMI-A is given before or after surgical removal of the primary tumor. Metastasis reduction is unrelated to NAMI-A concentration, which is 10-fold lower than on primary site (1 versus 0.1 mM), and is correlated to the reduction of plasma gelatinolitic activity and to the decrease of cells expressing CD44, CD54, and integrin-beta(3) adhesion molecules. Metastatic cells also show the reduction of the S-phase cells with accumulation in the G(0)/G(1) phase. In vitro, on the highly metastatic B16F10 cell line, NAMI-A reduces cell Matrigel invasion and its ability to cross a layer of endothelial cells after short exposure (1 h) to 1 to 100 microM concentrations. In these conditions, NAMI-A reduces the gelatinase activity of tumor cells, and it also increases cell adhesion to poly-L-lysine and, in particular, to fibronectin, and this effect is associated to the increase of F-actin condensation. This work shows the selective effectiveness of NAMI-A on the metastatic melanoma and suggests that metastasis inhibition is due to the negative modulation of tumor cell invasion processes, a mechanism in which the reduction of the gelatinolitic activity of tumor cells plays a crucial role.

Animals↗

PubMed2003

Antiangiogenic properties of selected ruthenium(III) complexes that are nitric oxide scavengers.

The nitric oxide synthase (NOS) pathway has been clearly demonstrated to regulate angiogenesis. Increased levels of NO correlate with tumour growth and spreading in different experimental and human cancers. Drugs interfering with the NOS pathway may be useful in angiogenesis-dependent tumours. The aim of this study was to pharmacologically characterise certain ruthenium-based compounds, namely NAMI-A, KP1339, and RuEDTA, as potential NO scavengers to be used as antiangiogenic/antitumour agents. NAMI-A, KP1339 and RuEDTA were able to bind tightly and inactivate free NO in solution. Formation of ruthenium-NO adducts was documented by electronic absorption, FT-IR spectroscopy and (1)H-NMR. Pretreatment of rabbit aorta rings with NAMI-A, KP1339 or RuEDTA reduced endothelium-dependent vasorelaxation elicited by acetylcholine. This effect was reversed by 8-Br-cGMP. The key steps of angiogenesis, endothelial cell proliferation and migration stimulated by vascular endothelial growth factor (VEGF) or NO donor drugs, were blocked by NAMI-A, KP1339 and RuEDTA, these compounds being devoid of any cytotoxic activity. When tested in vivo, NAMI-A inhibited angiogenesis induced by VEGF. It is likely that the antitumour properties previously observed for ruthenium-based NO scavengers, such as NAMI-A, are related to their NO-related antiangiogenic properties.

Angiogenesis Inhibitors↗

PubMed1999

Spectrophotometric kinetic study and analytical implications of the glucose oxidase-catalyzed reduction of [MIII(LL)2Cl2]+ complexes by D-glucose (M = Os and Ru, LL = 2,2'-bipyridine and 1,10-phenanthroline type ligands).

Glucose oxidase-catalyzed reduction of cis-[MIII(LL)2Cl2]+ (M = Os and Ru) complexes to cis-[MII(LL)2Cl2] (LL = 2,2'-bipyridine and 1,10-phenanthroline type ligands) by D-glucose is a first-order process in the complex and the enzyme in aqueous buffered solution. The reaction follows Michaelis-Menten kinetics in D-glucose and the rate is independent of D-glucose concentration above 0.03 M. The reactivity decreases in the series [Ru(bpy)2Cl2]+ > [Os(phen)2Cl2]+ > [Os(4,4'-Me2bpy)2Cl2]+ > [Os(4,7-Me2phen)2Cl2]+. The measured second-order rate constant for the oxidation of reduced glucose oxidase by [Os(phen)2Cl2]+ in air equals 1.2 x 10(5) M-1 s-1 at pH 6,7, [D-glucose] 0.05 M, and 25 degrees C, which is ca. 20% less than that when the reaction solutions are purged with argon. In the case of [Ru(bpy)2Cl2]+ the rate constant equals 1.8 x 10(5) M-1 s-1 under similar conditions in air, showing higher reactivity of Ru complexes compared with Os ones. The reduction is pH-dependent with a maximum around 7. Added for solubilization of poorly soluble metal complexes, surfactants decrease the rates of the enzymatic reaction. The retardation effect increases in the series: cetyltrimethylammonium bromide < Triton X-100 << sodium dodecyl sulfate, i.e. on going from positively charged to neutral and then to negatively charged surfactants. The behavior of the OsIII and RuIII complexes toward reduced glucose oxidase contrasts to that of recently studied ferricenium cations. As opposed to the latter, the former do not show kinetically meaningful binding with the enzyme, and the Michaelis kinetics typical of the ferricenium case is not realized for the OsIII, and RuIII species. The systems OsIII- or RuIII-glucose oxidase are convenient for routine "one pot" spectrophotometric monitoring of the D-glucose content in samples, since the metal reduction to MII is accompanied by a strong increase in absorbance in the visible spectral region.

Aspergillus niger↗

PubMed2006

Sulphur mustard vapor breakthrough behaviour on reactive carbon systems.

Breakthrough behaviour of sulphur mustard, the deadliest of persistent chemical warfare agents, on carbon systems such as NaOH/CrO(3)/C, NaOH/CrO(3)/EDA/C and RuCl(3)/C has been studied and the data were compared with that of active carbon. Effects of bed lengths of carbons on breakthrough time have also been correlated. Thereafter, the effects of flow rate of air-sulphur mustard mixture, concentration and temperature on the kinetic parameters such as rate constant (k(v)) and kinetic saturation capacity (W(e)) were analyzed and interpreted by means of modified Wheeler equation. Rate constant was found to be increasing while W(e) was found to be invariable with the increase in air flow rate. Both k(v) and W(e) decreased with the increase of temperature, however, no significant effect on W(e) and k(v) was observed due to concentration change (0.3-0.6 mg/l). The values of kinetic saturation capacity were used to predict the service lives/breakthrough times of carbon beds (when used in filtration systems).

Air Pollutants↗

PubMed1998

Solution studies of the antitumor complex dichloro 1,2-propylendiaminetetraacetate ruthenium (III) and of its interactions with proteins.

A mixed complex of ruthenium (III) with 1,2-propylendiaminetetraacetate (PDTA) and chloride--RAP hereafter--has been found to exhibit favorable anticancer properties in vivo. To get some insight into the possible mechanism of action of this ruthenium (III) complex, its solution behavior and reactivity with proteins were investigated through absorption, circular dichroism and 1H NMR spectroscopies. Under physiological conditions RAP slowly looses the two coordinated chlorine atoms to produce a number of ruthenium (III) reactive species; a description of the distribution of these species on the dependence of pH has been obtained through 1H NMR studies of the hyperfine shifted signals. Remarkably, through the different solution conditions employed in this study, the ruthenium ion always remains in the 3+ oxidation state and the PDTA ligand is always bound to the metal. Upon reaction with albumin, apotransferrin or diferric transferrin, at a 1:1 ratio, RAP rapidly binds to these proteins to produce substantially equivalent and relatively stable adducts. This behavior is tentatively interpreted in terms of a tight interaction between RAP and surface residues of these proteins. The implications of these findings for the biological action of this novel ruthenium (III) compound are discussed.

Antineoplastic Agents↗

PubMed2002

A new inorganic vasodilator, trans-[Ru(NO)(NH(3))(4)(POEt)(3)](PF(6))(3): hypotensive effect of endothelium-dependent and -independent vasodilators in different hypertensive animals models.

The hypotensive effect of RuNO was investigated in acute and chronic hypertensive rats, as well as in normotensive rats. Acute hypertension rats were used with 30% increase on basal BP (phenylephrine, angiotensin II (Ang II), N(G)-nitro-L-arginine methyl ester (L-NAME), and adult spontaneously hypertensive rats (SHR) (basal BP 168 +/- 3 mm Hg) were used as models for chronic hypertension. Rats were implanted with catheters (iv/ia) for BP measurements and for in bolus administration of RuNO, sodium nitroprusside (SNP), and acetylcholine (Ach) (10, 20, 40 nmol/kg, iv). The principal findings of this study were: (i) The hypotensive response to RuNO was 150% higher in acutely (phenylephrine and Ang II) and chronically (SHR) hypertensive rats than in normotensive rats, except in the case of L-NAME-induced hypertension (deltaMAP = 10 +/- 1.4 mm Hg). Chronic SHR showed 60% increase (deltaMAP = 19 +/- 0.8 mm Hg) in the effect compared to normotensive rats. (ii) The hypotensive response to SNP was lower (60%) in hypertensive rats than in normotensive rats, when compared to RuNO. However, the responses were similar in L-NAME-induced hypertension (deltaMAP = 30 +/- 2 mm Hg). (iii) The vasodilator response to Ach was increased in rats with Ang II-induced hypertension (deltaMAP = 53 +/- 1 mm Hg) and in SHR (deltaMAP = 67 +/- 3 mm Hg). RuNO response was more potent than SNP in hypertensive models and the increment in relation to normotensive was observed in the phenylephrine- and L-NAME-treated rats. This response could be correlated to the different endothelial dysfunction present in each model.

Acetylcholine↗