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Light irradiation has been used in clinical therapy for several decades. In this context, photobiomodulation (PBM) modulates signaling pathways via ROS, ATP, Ca 2+ , while photodynamic therapy (PDT) generates reactive oxygen species by excitation of a photosensitizer. NO generation could be an important tool when combined with both kinds of light therapy. By using a metal-based compound, we found that PBM combined with PDT could be a beneficial cancer treatment option. We used two types of ruthenium compounds, ([Ru(Pc)], Pc = phthalocyanine) and trans-[Ru(NO)(NO 2 )(Pc)]. The UV-vis spectra of both complexes displayed a band in the 660 nm region. In the case of 0.5 μM trans-[Ru(NO)(NO 2 )(Pc)], light irradiation at the Q-band reduced the percentage of viable human melanoma (A375) cells to around 50% as compared to [Ru(Pc)]. We hypothesized that these results were due to a synergistic effect between singlet oxygen and nitric oxide. Similar experiments performed with PDT (660 nm) combined with PBM (850 nm) induced more photocytotoxicity using both [Ru(Pc)] and trans-[Ru(NO)(NO 2 )(Pc)]. This was interpreted as PBM increasing cell metabolism (ATP production) and the consequent higher uptake of the ruthenium phthalocyanine compounds and more efficient apoptosis. The use of metal-based photosensitizers combined with light therapy may represent an advance in the field of photodynamic therapy., (Copyright © 2019 Elsevier B.V. All rights reserved.)

[Ru(terpy)(bdq)NO] 3+ (TERPY) is a nitric oxide (NO) donor that promotes relaxation of the mesenteric artery and aorta in rats. We sought to investigate whether it acts as both an NO donor and endothelial NO synthase (eNOS) activator, as shown previously for nitroglycerin. Human umbilical vein endothelial cells (HUVECs) and human embryonic kidney 293 cells transfected with empty vector (HEK) or eNOS cDNA (HEK-eNOS) were treated with TERPY (1µM) for different lengths of time. eNOS expression, dimerization, and Ser 1177 phosphorylation, caveolin-1 (Cav-1) oligomerization, Cav-1 Tyr 14 phosphorylation were evaluated by Western blotting. Studies also assessed the production of reactive oxygen/nitrogen species (ROS/RNS) in HUVECs and HEK-eNOS cells. In HEK cells devoid of eNOS, TERPY released NO without additional stimulus indicating that is an NO donor. Moreover, in HEK-eNOS cells, TERPY-induced NO production that was blocked by L-NAME. In addition, TERPY increased ROS and ONOO- production which were blocked by more than 80% by BH 4 (essential eNOS co-factor) and eNOS siRNA. These results suggest that TERPY-induced ROS and ONOO- production were originated from eNOS. HUVECs stimulated with TERPY showed increased eNOS Ser 1177 and Cav-1 Tyr 14 phosphorylation, and decreased eNOS dimerization, Cav-1 oligomerization, and Cav-1/eNOS interaction after 20min. It suggests that TERPY induces eNOS hyperactivation and uncoupling by disrupting Cav-1/eNOS interaction and depleting BH 4 . Endothelium-dependent vasodilation in response to NO donor TERPY is associated with eNOS activation and uncoupling, and thereby appears to be mediated, at least in part, via eNOS-dependent ROS/RNS production., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Ultradeformable liposomes (UDLs) as a drug delivery system (DDS), prepared from the unsaturated phospholipid, dioleylphosphocholine (DOPC), and containing the non-ionic surfactant Tween 20 as edge activator, have been explored as topical vehicles for zinc phthalocyanine (ZnPc) and the nitrosyl ruthenium complex [Ru(NH.NHq)(tpy)NO] 3+ (RuNO) as a photosensitizers for co-generation of 1 O 2 and NO as reactive species, respectively. However, in order to ensure that ZnPc was present in the UDLs in its monomeric form - essential for maximal ZnPc photophysical properties - it was necessary to replace 40wt% of the DOPC with the saturated phospholipid, dimyristoylphosphocholine (DMPC). The resultant ZnPc and complex [Ru(NH.NHq)(tpy)NO] 3+ containing UDLs were stable for at least a month when stored at 4°C, six times more elastic/deformable than conventional liposome (c-Ls), i.e. liposome prepared using the same weight ratio of lipids but in the absence of Tween 20, and to significantly enhance the in vitro permeation of ZnPc across fresh pig ear skin. The UDLs DDS incorporating ZnPc and [Ru(NH.NHq)(tpy)NO] 3+ were toxic (by the MTT assay) towards B16-F10 melanoma cells when irradiated with visible light at 670nm, the maximum absorption of ZnPc, and at a dose of 3.18J/cm 2 , but not when applied in the absence of light as expected. Based on these results it is proposed that the novel topical UDLs formulation developed is a suitable delivery vehicle for photodynamic therapy., (Copyright © 2017 Elsevier B.V. All rights reserved.)

NO is a potent bronchodilator and NO-donor compounds have demonstrated clinical significance for obstructive airway diseases. This study evaluated the relaxation mechanisms of two NO donors, a ruthenium compound (TERPY), and sodium nitroprusside (SNP), in rat tracheas with ovalbumin-induced asthma (OVA group) and in another control group. The effect of TERPY and SNP was evaluated in tracheal rings in an isolated organ chamber. The contribution of K(+) channels, sGC/cGMP pathway, phosphodiesterases, and extra and intracellular Ca(2+) sources were analyzed. The TERPY and SNP-induced tracheal smooth muscle relaxation in both groups. However, the maximum effect induced by TERPY was higher than that of SNP in both control (110.2 ± 3.2% vs 68.3 ± 3.1%, P < 0.001) and OVA groups (106.1 ± 1.5% vs 49.9 ± 2.7%, P < 0.001). In the control group, TERPY relaxation was induced by the activation of K(+) channels and reduction of the calcium influx, while in the OVA group, these same effects were also brought about by TERPY, but with participation of the sGC/cGMP pathway. In both groups, SNP-induced relaxation occurred through the activation of K(+) channels, sGC/cGMP pathway and reduction of calcium influx. However, the activation of sGC pathway and reticular Ca(2+) -ATPase seemed to be reduced in the OVA group. Furthermore, TERPY is capable of reversing the contraction of carbachol in asthmatic bronchioles. Finally, TERPY and SNP relaxation mechanisms were modified by asthma. SNP presented less relaxation than TERPY, which induced full relaxation with greater participation of K(+) and Ca(2+) fluxes through the membrane, thereby making TERPY a promising drug for reversing the narrowing of airways., (© 2016 John Wiley & Sons Australia, Ltd.)

We have previously demonstrated that the hypotensive effect of the ruthenium complex [Ru(terpy)(bdq)NO](3+) (TERPY) is slow, long lasting, and does not lead to reflex tachycardia. TERPY's hypotensive effect is increased in hypertensive rats (SHR or 2 kidney-1clip) compared with normotensive rats. We hypothesized that sexual differences could interfere in the hypotensive effects of nitric oxide (NO) donors in SHR. Therefore, here we aimed to investigate the role of sexual differences and endogenous NO in the hypotension induced by TERPY. In conscious, unrestrained animals, we evaluated the hypotensive effect of TERPY before and after the administration of N-nitro-L-arginine methyl ester (L-NAME) (nonselective NO synthase inhibitor), APOCYNIN (NADPH/NOX inhibitor), and TEMPOL (superoxide dismutase mimetic). The hypotensive effect of TERPY was higher in male than in female SHR, but this difference was not observed in the normotensive Wistar group. The effect of TERPY increased after administration of L-NAME in Wistar rats; however, this effect was not altered by L-NAME in SHR. In SHR, sexual dimorphism in TERPY effect was still observed in animals treated with L-NAME. TEMPOL increases the effect of TERPY only in female SHR. After TEMPOL, the sexual dimorphism in TERPY effect was abolished in the SHR group. APOCYNIN increased the effect of TERPY in male and female Wistar and SHR, but maintained the previously observed difference between male and female SHR. Thus, this study shows that TERPY's hypotensive effect increased in male compared with female SHR and indicates that sexual dimorphism in TERPY effect is associated with oxidative stress.

The cis-[Ru(bpy)(2)(py)NO(2)](PF(6)) specie (RuBPY) has been used as nitric oxide (NO) delivery agent. It is an NO reservoir and it is thermodynamically stable in aqueous solution. This study aimed to evaluate the NO specie generated by RuBPY as compared to NO released from sodium nitroprusside (SNP) and to study the cellular mechanisms specially focusing the activation of soluble guanylyl-cyclase (sGC), K(+) channels and the cell membrane hyperpolarization, which are the main targets for NO-inducing vascular relaxation. NO generated by RuBPY and the vascular smooth muscle cell (VSMC) membrane potential were measured by confocal microscopy. The cellular mechanisms of aorta relaxation were investigated using K(+) channel blockers and sGC inhibitor. NO released from RuBPY was higher than NO released from SNP. RuBPY released only radicalar NO(0) and SNP released both NO(-) and NO(0). The concentration-effect curves for RuBPY-induced relaxation was shifted to the right by inhibition of sGC with ODQ and by the non-selective blockade of K(+) channels with TEA. The simultaneous combination of ODQ and TEA abolished the vasorelaxation induced by RuBPY. The membrane potential measured by the sensitive dye 4-Di-ANNEPS demonstrated that RuBPY induces cell membrane hyperpolarization. Taken together, our results indicate that the large amount of NO(0) specie generated by RuBPY induces vasorelaxation due to activation of sGC, K(+) channels sensitive to TEA, and cell membrane hyperpolarization. These results indicate that NO(0) generated from RuBPY can also directly activate the K(+) channels in an independent way of sGC., (Crown Copyright © 2013. Published by Elsevier B.V. All rights reserved.)

Aims: To examine the vasodilatation induce by the NO donors, [Ru(terpy)(bdq)NO](3+) (TERPY) and sodium nitroprusside (SNP), and to compare their effects in aortic rings from hypertensive 2K-1C and normotensive 2K rats., Main Methods: Vascular reactivity was performed in aortic rings pre-contracted with phenylephrine (Phe 100nM). We have analyzed the maximal relaxation (Emax) and potency (pD(2)) of NO donors., Key Findings: Potency of SNP was greater than TERPY in both arterial groups. The vasodilatation induced by TERPY was greater in 2K than in 2K-1C, and it was inhibited by sGC inhibitor ODQ in 2K and in 2K-1C aortic rings. ODQ did not alter the efficacy to SNP, but it reduced its potency in 2K and 2K-1C. The blockade of K(+) channels reduced the potency of TERPY only in aortic rings of 2K. On the other hand, the potency of SNP was reduced in both 2K and 2K-1C. The combination of ODQ and TEA reduced the relaxation induced by TERPY and SNP in 2K and reduced the efficacy to SNP in 2K-1C aortic rings but it had no additional effect on the TERPY relaxation in 2K-1C aortas. The production of cGMP induced by TERPY was greater than that produced by SNP, which was similarly increased in 2K and 2K-1C. Sarcoplasmic reticulum Ca-ATPase inhibition only impaired the relaxation induced by SNP in 2K aortic rings., Significance: Taken together, our results provide evidences that in this model of hypertension, impaired K(+) channels activation by TERPY and SERCA activation by SNP may contribute to decreased vasodilatation., (Copyright © 2011 Elsevier Inc. All rights reserved.)

The synthesis, structural aspects, pharmacological assays, and in vitro photoinduced cytotoxic properties of [Ru(NO)(ONO)(pc)] (pc=phthalocyanine) are described. Its biological effect on the B16F10 cell line was studied in the presence and absence of visible light irradiation. At comparable irradiation levels, [Ru(NO)(ONO)(pc)] was more effective than [Ru(pc)] at inhibiting cell growth, suggesting that occurrence of nitric oxide release following singlet oxygen production upon light irradiation may be an important mechanism by which the nitrosyl ruthenium complex exhibits enhanced biological activity in cells. Following visible light activation, the [Ru(NO)(ONO)(pc)] complex displayed increased potency in B16F10 cells upon modifications to the photoinduced dose; indeed, enhanced potency was detected when the nitrosyl ruthenium complex was encapsulated in a drug delivery system. The liposome containing the [Ru(NO)(ONO)(pc)] complex was over 25% more active than the corresponding ruthenium complex in phosphate buffer solution. The activity of the complex was directly proportional to the ruthenium amount present inside the cell, as determined by inductively coupled plasma mass spectroscopy. Flow cytometry analysis revealed that the photocytotoxic activity was mainly due to apoptosis. Furthermore, the vasorelaxation induced by [Ru(NO)(ONO)(pc)], proposed as NO carrier, was studied in rat isolated aorta. The observed vasodilation was concentration-dependent. Taken together, the present findings demonstrate that the [Ru(NO)(ONO)(pc)] complex induces vascular relaxation and could be a potent anti-tumor agent. Nitric oxide release following singlet oxygen production upon visible light irradiation on a nitrosyl ruthenium complex produces two radicals and may elicit phototoxic responses that may find useful applications in photodynamic therapy., (Crown Copyright © 2011. Published by Elsevier Inc. All rights reserved.)

Nitric oxide (NO) is a gaseous molecule that has specific functions dictated by its localization and its kinetics of release. As NO-donors have a range of potential uses in the skin, much attention has been paid to the development of topical NO delivery systems. The aim of this work was to study the release rate and the skin penetration of the NO-donor cis-[Ru(NO(2))(bpy)(2)(4-pic)](+) from different gel formulations and their potential as topical NO delivery systems under light stimuli. Among the formulations developed, the anionic gel retarded the nitro-ruthenium complex diffusion and also obstructed NO release after light irradiation. On the other hand, NO release before light irradiation was observed when the complex was dispersed in the cationic chitosan gel, possibly due to oxi-redox reactions between the amino groups of the polymer and the drug molecule. Finally, the non-ionic gel released the NO after light irradiation to the same extent as a drug aqueous solution at the same pH. The drug dispersed in this gel also penetrated into the stratum corneum skin layer, and the nitro-ruthenium complex present in the skin was able to release the NO after light stimuli, suggesting the potential use of this formulation as a topical NO delivery system., (Copyright (c) 2010 Elsevier B.V. All rights reserved.)

Background and Purpose: Benznidazole (Bz) is the therapy currently available for clinical treatment of Chagas' disease. However, many strains of Trypanosoma cruzi parasites are naturally resistant. Nitric oxide (NO) produced by activated macrophages is crucial to the intracellular killing of parasites. Here, we investigate the in vitro and in vivo activities against T. cruzi, of the NO donor, trans-[RuCl([15]aneN(4))NO](2+)., Experimental Approach: Trans-[RuCl([15]aneN(4))NO](2+)was incubated with a partially drug-resistant T. cruzi Y strain and the anti-proliferative (epimastigote form) and trypanocidal activities (trypomastigote and amastigote) evaluated. Mice were treated during the acute phase of Chagas' disease. The anti-T. cruzi activity was evaluated by parasitaemia, survival rate, cardiac parasitism, myocarditis and the curative rate., Key Results: Trans-[RuCl([15]aneN(4))NO](2+) was 10- and 100-fold more active than Bz against amastigotes and trypomastigotes respectively. Further, trans-[RuCl([15]aneN(4))NO](2+) (0.1 mM) induced 100% of trypanocidal activity (trypomastigotes forms) in vitro. Trans-[RuCl([15]aneN(4))NO](2+) induced permanent suppression of parasitaemia and 100% survival in a murine model of acute Chagas' disease. When the drugs were given alone, parasitological cures were confirmed in only 30 and 40% of the animals treated with the NO donor (3.33 micromol.kg(-1).day(-1)) and Bz (385 micromol.kg(-1).day(-1)), respectively, but when given together, 80% of the animals were parasitologically cured. The cured animals showed an absence of myocarditis and a normalisation of cytokine production in the sera. In addition, no in vitro toxicity was observed at the tested doses., Conclusions and Implications: These findings indicate that trans-[RuCl([15]aneN(4))NO](2+)is a promising lead compound for the treatment of human Chagas' disease.

A new nitrosyl ruthenium complex [Ru(NH.NHq)(terpy)NO](3+) nitric oxide donor was recently developed and due to its excellent vasodilator activity, it has been considered as a potential drug candidate. Drug metabolism is one of the main parameters that should be evaluated in the early drug development, so the biotransformation of this complex by rat hepatic microsomes was investigated. In order to perform the biotransformation study, a simple, sensitive and selective HPLC method was developed and carefully validated. The parameters evaluated in the validation procedure were: linearity, recovery, precision, accuracy, selectivity and stability. Except for the stability study, all the parameters evaluated presented values below the recommended by FDA guidelines. The stability study showed a time-dependent degradation profile. After method validation, the biotransformation study was accomplished and the kinetic parameters were determined. The biotransformation study obeyed the Michaelis-Menten kinetics. The V(max) and K(m) were, respectively, 0.1625+/-0.010 micromol/mg protein/min and 79.97+/-11.52 microM. These results indicate that the nitrosyl complex is metabolized by CYP450.

We have described a new compound (trans-[RuCl([15]aneN(4))NO](2+)), which in vitro releases NO by the action of a reducing agent such as catecholamines. We investigated the effect of this NO donor in lowering the mean arterial pressure (MAP) in severe and moderate renal hypertensive 2K-1C rats. MAP was measured before and after intravenous in bolus injection of the compound in conscious 2K-1C and normotensive (2K) rats. In the hypertensive rats (basal 196.70+/-8.70mmHg, n=5), the MAP was reduced in -34.25+/-13.50mmHg (P<0.05) 6h after administration of 10mmol/L/Kg of the compound in bolus. In normotensive rats the compound had no effect. We have also studied the effect of the injection of 0.1mmol/L/Kg in normotensive (basal 118.20+/-11.25mmHg, n=4), moderate (basal 160.90+/-2.30mmHg, n=6), and severe hypertensive rats (basal 202.46+/-16.74 mmHg, n=6). The compound at the dose of 0.1mmol/L/Kg did not have effect (P>0.05) on MAP of normotensive and moderate hypertensive rats. However, in the severe hypertensive rats (basal 202.46+/-16.70mmHg, n=6) there was a significant reduction on the MAP of -28.64+/-12.45mmHg. The NO donor reduced the MAP of all hypertensive rats in the dose of 10mmol/L/Kg and in the severe hypertensive rats at the dose of 0.1mmol/L/Kg. The compound was not cytotoxic to the rat aortic vascular smooth muscle cells in the concentration of 0.1mmol/L/Kg that produced the maximum relaxation.

The synthesis of [Ru(NO(2))L(bpy)(2)](+) (bpy = 2,2'-bipyridine and L = pyridine (py) and pyrazine (pz)) can be accomplished by addition of [Ru(NO)L(bpy)(2)](PF(6))(3) to aqueous solutions of physiological pH. The electrochemical processes of [Ru(NO(2))L(bpy)(2)](+) in aqueous solution were studied by cyclic voltammetry and differential pulse voltammetry. The anodic scan shows a peak around 1.00 V vs. Ag/AgCl attributed to the oxidation process centered on the metal ion. However, in the cathodic scan a second peak around -0.60 V vs. Ag/AgCl was observed and attributed to the reduction process centered on the nitrite ligand. The controlled reduction potential electrolysis at -0.80 V vs. Ag/AgCl shows NO release characteristics as judged by NO measurement with a NO-sensor. This assumption was confirmed by ESI/MS(+) and spectroelectrochemical experiment where cis-[Ru(bpy)(2)L(H(2)O)](2+) was obtained as a product of the reduction of cis-[Ru(II)(NO(2))L(bpy)(2)](+). The vasorelaxation observed in denuded aortic rings pre-contracted with 0.1 mumol L(-1) phenylephrine responded with relaxation in the presence of cis-[Ru(II)(NO(2))L(bpy)(2)](+). The potential of rat aorta cells to metabolize cis-[Ru(II)(NO(2))L(bpy)(2)](+) was also followed by confocal analysis. The obtained results suggest that NO release happens by reduction of cis-[Ru(II)(NO(2))L(bpy)(2)](+) inside the cell. The maximum vasorelaxation was achieved with 1 x 10(-5) mol L(-1) of cis-[Ru(II)(NO(2))L(bpy)(2)](+) complex.

Impaired relaxation induced by the new nitric oxide (NO) donor [Ru(NH.NHq)(terpy)NO(+)](3+) (TERPY) has been observed in the aortic rings from renal hypertensive rats (2K-1C). An increased production of reactive oxygen species (ROS) in the aortas from 2K-1C rats are capable of reducing NO bioavailability. Therefore, this study aimed at investigating the effects of an antioxidant (vitamin C) on the relaxant effect of NO released from TERPY on the 2K-1C rat aorta. As for vascular reactivity, the potency of TERPY is greater in the control rats (2K) than in 2K-1C whereas the maximum relaxation (ME) is not significantly different between the 2K and 2K-1C rat aortas. The relaxation of TERPY is potentiated only in the 2K-1C aortic ring treated with vitamin C. TERPY has a lower effect in decreasing cytosolic Ca(2+) concentration ([Ca(2+)]c) in vascular smooth muscle cells (VSMCs) from 2K-1C rats. This effect is also potentiated in 2K-1C aortic cells treated with vitamin C, but it is not altered in 2K cells. The basal cytosolic NO concentration ([NO]c) is lower in 2K-1C than in 2K cells, and the bioavailability of the NO released from TERPY is larger in 2K than in 2K-1C VSMCs. The superoxide radical concentration ([O(2)(*-)]) is higher in the 2K-1C aorta, and vitamin C reduces the [O(2)(*-)] in the 2K-1C aorta. Taken together, these results show that in the aortas of renal hypertensive 2K-1C rats, released NO from the new NO donor is not available to produce a similar effect in 2K aorta due to increased [O(2)(*-)].

We investigated the effects of selective K(+) channel blockers and guanylyl cyclase inhibitor on the rat aorta relaxation induced by the new NO donor cis-[Ru(Cl)(bpy)(2)(NO)](PF(6)) (RUNOCL), following endothelium removal. NO release from RUNOCL was obtained by photo-induction using a visible light system lambda > 380 nm. RUNOCL induced relaxation of phenylephrine contracted aortic rings under light with the maximum effect (ME) of 101.2+/-3.7% and pD(2): 6.62+/-0.16 (n=7), but not in the absence of light. Relaxation stimulated with RUNOCL was also studied on 60 mM of KCl-contracted arteries or after incubation with the non-selective K(+) channel blocker (1 mM TEA) or the selective K(+) channel blockers (3 microM glibenclamide (K(ATP)), 1 mM 4-aminopyridine (K(V), 4-AP), 1 microM apamin (SK(Ca)-APA) or 0.1 microM iberiotoxin (BK(Ca) IBTX). Relaxation induced by RUNOCL was lower in KCl-contracted aortic rings with ME of 68.6+/-10.0% and pD(2): 3.92+/-0.60 (n=4). As compared to Phe-contracted arteries the potency of RUNOCL in inducing rat aorta relaxation was reduced by K(+) channel blockers as demonstrated by the pD(2) values from 6.62+/-0.16 (n=7) (control) to (TEA: 5.32+/-0.108, n=5; IBTX: 5.63+/-0.02 (n=5), APA: 5.73+/-0.13 (n=5)). But the ME was reduced only by IBTX (60.7+/-3.4%). 4-AP and glibenclamide had no effect on the relaxation induced by RUNOCL. The aortic tissue cGMP content increased with RUNOCL under light irradiation from 63.13+/-0.45 fmol/microg to 70.56+/-4.64 fmol/microg of protein (n=4) and the inhibition of guanylyl cyclase with ODQ reduced the ME: 30.1+/-1.6% and pD(2): 6.35+/-0.05 (n=4). Our results suggest that the NO released by photo-induction from RUNOCL induces rat aorta relaxation by activation of K(Ca) by a cGMP-dependent pathway.

The aim of the present study was to investigate the possible endogenous storage of photosensitive nitric oxide, and also to examine the relaxant effect of NO released from the compound by UV light irradiation. Aorta was isolated from rats and the endothelium was mechanically removed. Denuded aortic rings pre-contracted with prostaglandin F(2alpha) responded with relaxation to UV light irradiation. The first stimulation produced the greatest response that decreased until complete disappearance. After this, the addition of the compound in the absence of light did not produce any response. However, in the presence of UV light irradiation, the complex trans-[RuCl([15]aneN4)NO]2+ induced 100% relaxation. After incubation with the nitric oxide scavenger, oxyhaemoglobin, this relaxation was completely abolished. In PGF2(2alpha)-pre-contracted aortas, the time to reach maximum relaxation was only 50s. Taken together, these results suggest that preformed endogenous nitric oxide stores exist in the denuded rat aorta, and that they are sensitive to UV light. The photo-induction of the complex trans-[RuCl([15]aneN4NO]2+ induces complete aorta relaxation, which is due to release of nitric oxide in the extracellular medium.

The vasorelaxation induced by a nitrosyl macrocyclic ruthenium complex, proposed as a new nitric oxide (NO) carrier, was studied in rat isolated aorta. The compound trans-[RuCl([15]aneN4)NO]2+ was characterized by elemental analysis, UV-visible spectrum, and infrared spectrum. Based on the electrochemical process, the reduction of the compound was followed by NO release, which was also observed using norepinephrine as a reducing agent and NO released was analyzed by a sensor. Vasorelaxation induced by this NO donor was studied and compared to those obtained with sodium nitroprusside (SNP). The relaxation induced by the compound was concentration-dependent in denuded rat aortas and occurred only in pre-contracted arteries with norepinephrine. The macrocyclic compound induced relaxation with a similar efficacy as SNP, although the potency of SNP was slightly greater. The time to reach maximum relaxation (595 s) was longer than that of SNP (195 s). Relaxation was completely abolished by oxyhemoglobin, a known NO scavenger., (Copyright 2004 Elsevier Inc.)