Cardiovascular diseases include all types of disorders related to the heart or blood vessels. High blood pressure is an important risk factor for cardiac complications and pathological disorders. An increase in circulating angiotensin-II is a potent stimulus for the expression of reactive oxygen species and pro-inflammatory cytokines that activate oxidative stress, perpetuating a deleterious effect in hypertension. Studies demonstrate the capacity of NO to prevent platelet or leukocyte activation and adhesion and inhibition of proliferation, as well as to modulate inflammatory or anti-inflammatory reactions and migration of vascular smooth muscle cells. However, in conditions of low availability of NO, such as during hypertension, these processes are impaired. Currently, there is great interest in the development of compounds capable of releasing NO in a modulated and stable way. Accordingly, compounds containing metal ions coupled to NO are being investigated and are widely recognized as having great relevance in the treatment of different diseases. Therefore, the exogenous administration of NO is an attractive and pharmacological alternative in the study and treatment of hypertension. The present review summarizes the role of nitric oxide in hypertension, focusing on the role of new NO donors, particularly the metal-based drugs and their protagonist activity in vascular function.

A synthetic route was developed for the preparation of trans-[Ru(NH₃)₄(NO)X]^{n +}, where X = isonicotinamide (isn), pyrazine (pyz) or sulfite, and cis-[Ru(NH₃)₄(NO)(NO₂)]²⁺. The complexes have been characterized by elemental analysis, UV/VIS, infrared, ¹H NMR and ESR spectroscopies, molar conductance measurements and cyclic voltammetry. All showed ν(NO) in the range characteristic of metal-co-ordinated NO⁺ and do not exhibit any ESR signal, consistent with the formulation of Ru^II–NO⁺. The equilibrium constants K_eq for the reaction trans-[Ru(NH₃)₄(NO)X]³⁺ + 2OH^– ⇌ trans-[Ru(NH₃)₄(NO₂)X]⁺ + H₂O are 2.5 × 10⁸ and 6 × 10⁸ dm⁶ mol^–2 for X = isn or pyz. Cyclic voltammograms of the complexes in aqueous solution exhibited reversible one-electron waveforms in the potential range –0.13 to –0.38 V vs. SCE, which were assigned to the [Ru(NH₃)₄(NO)X]^{n +} → [Ru(NH₃)₄(NO)X]^{(n –1 )+} process. Nitric oxide and trans-[Ru(NH₃)₄(H₂O)X]²⁺ are the final products of the reaction between Eu^II and trans-[Ru(NH₃)₄(NO)X]³⁺, L = isn or pyz. Ab initio molecular orbital calculations performed for trans-[Ru(NH₃)₄(NO)(pyz)]³⁺ and trans-[Ru(NH₃)₄(NO)(pyz)]²⁺, and the products of the trans-[Ru(NH₃)₄(NO)(pyz)]³⁺ one-electron electrochemical or chemical reduction, strongly suggest the added electron is localized mainly on the nitrosyl ligand. A correlation was observed between ν(NO) and E_½ for the reversible reduction wave. These results indicate that the nitric oxide reduction is facilitated by strong π-acceptor ligands trans to the NO. Nitric oxide and trans-[Ru(NH₃)₄(H₂O)X]³⁺ were formed when solutions containing trans-[Ru(NH₃)₄(NO)X]³⁺ were irradiated in the range 310–370 nm.

Background and purpose:  The discovery of the pharmacological functions of nitric oxide has led to the development of NO donor compounds as therapeutic agents. A new generation of ruthenium NO donors, cis‐[Ru(NO)(bpy)₂L]X_n, has been developed, and our aim was to show that these complexes are able to lyse Trypanosoma cruzi in vitro and in vivo.Experimental approach:  NO donors were incubated with T. cruzi and their anti‐T. cruzi activities evaluated as the percentage of lysed parasites compared to the negative control. In vivo, trypanocidal activity was evaluated by observing the levels of parasitaemia, survival rate and elimination of amastigotes in mouse myocardial tissue. The inhibition of GAPDH was monitored by the biochemical reduction of NAD⁺ to NADH.Key results:  The NO donors cis‐[Ru(NO)(bpy)₂L]X_n presented inhibitory effects on T. cruzi GAPDH (IC₅₀ ranging from 89 to 153 µM). The crystal structure of the enzyme shows that the inhibitory mechanism is compatible with S‐nitrosylation of the active cysteine (cys166) site. Compounds cis‐[Ru(NO)(bpy)₂imN](PF₆)₃ and cis‐[Ru(NO)(bpy)₂SO₃]PF₆, at a dose of 385 nmol·kg⁻¹, yielded survival rates of 80 and 60%, respectively, in infected mice, and eradicated any amastigotes from their myocardial tissue.Conclusions and implications:  The ruthenium compounds exhibited potent in vitro and in vivo trypanocidal activities at doses up to 1000‐fold lower than the clinical dose for benznidazole. Furthermore, one mechanism of action of these compounds is via the S‐nitrosylation of Cys166 of T. cruzi GAPDH. Thus, these compounds show huge potential as candidates for the development of new drugs for the treatment of Chagas's disease.This article is commented on by Machado et al., pp. 258–259 of this issue. To view this commentary visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00662.x and to view a related paper in this issue by Guedes et al. visit http://dx.doi.org/10.1111/j.1476‐5381.2010.00576.x