Tolerance induced in vitro by the nitrite donor [Ru(bpy)2(py)NO2](PF6)(RuBPY)

• Grant number: 11/22569-0
• Support Opportunities: Scholarships in Brazil - Doctorate
• Start date: March 01, 2012
• End date: February 29, 2016
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Lusiane Maria Bendhack
• Grantee: Tamy Midori Banin
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil
• Associated scholarship(s): 14/15364-0 - Biotransformation of RuBPY, BE.EP.DR

Abstract

Nitrite has been considered a metabolite of the nitric oxide (NO) pathway. However, evidences in the literature has been shown that nitrite is present in large concentrations in the blood and tissues. It can be the intravascular and tissue source of stored NO. Nitric oxide is a small and simple biosinthetic molecule with high permeability between cells, and it is classified as a messenger that does not depend on specific transporters. Its endogenous production plays an important role on the control of the vascular tone, arterial pressure, inhibition of platelet aggregation and immunological responses. The ruthenium nytrosil compounds are studied as NO-donors. These compounds present therapeutic potential as vasodilators. They are not toxic for the vascular cells, which could be explained by the similarities between iron and ruthenium. Although several compounds were synthesized in our laboratory, the complex [Ru-(bpy)2(py)NO2](PF6), (RuBPY) seems to be more useful as vasodilator because it is a nitrite donor and it is intracellularly converted to NO. Nitric oxide donors have important therapeutic limitations because they induce tolerance after continuous use. The mechanisms that lead to tolerance to nitrates is still unclear. However, it should be due to multifactorial causes that involves reactive oxygen species (ROS) production, decreased activity of the enzyme soluble guanylyl-cyclase and increased expression of phosphodiesterases that produces cyclic GMP degradation. The tolerance phenomenon has been clearly associated to organic nitrates. However, no informations are avaialble about nitrite tolerance. Therefore, the aim of the present work is to evaluate whether the compound RuBPY induces tolerance in the denuded or with intact endothelium rat aorta. If it is true, the cellular mechanisms involved in this process will be studied. We have previously shown that other ruthenium-derived compounds induce tolerance. If this nitrite donor does not induce tolerance, it will be very important to investigate why it does not occur. In this case, we will investigate if the sGC and phosphodiesterases involved in the cGMP pathway are activated and also IF the production of ROS is normalized.