Study of tolerance in vitro and in vivo and clinical effects induced by new nitric oxide donors

• Grant number: 05/00663-3
• Support Opportunities: Scholarships in Brazil - Post-Doctoral
• Start date: January 01, 2006
• End date: December 31, 2008
• Field of knowledge: Biological Sciences - Pharmacology - General Pharmacology
• Principal Investigator: Lusiane Maria Bendhack
• Grantee: Daniella Bonaventura
• Host Institution: Faculdade de Ciências Farmacêuticas de Ribeirão Preto (FCFRP). Universidade de São Paulo (USP). Ribeirão Preto , SP, Brazil

Abstract

Nitric oxide donors (NO) are used to better understand the physiologic role of NO, as well as, to treat cardiovascular diseases. Among the existing donors, nitroglycerin (GTN) and sodium nitroprusside (SNP) are the most used. The NTG, chronically used, lead to the development of tolerance that is characterized by a dramatically reduction of its vasodilator function and loss of the hemodynamic effects impairing its clinical benefits. The SNP has a high toxicity because of the production of cyanide during its metabolization, besides generating a severe and quickly drop of the arterial blood pressure, leading to the activation of baroreceptors. New NO donors have been synthesized in order to minimize these GTN and SNP side effects. Ruthenium macrocyclic compounds have been studied as possible NO donors. We previously characterized the vascular relaxation induced by two of these ruthenium compounds, trans-[RuCl([15]aneN4)NO]2+ e [Ru(terpy)(bdq)NO+]3. The results showed that these new NO donors have different mechanisms of action. Both of them activate guanylyl cyclase and potassium channels. However, the activation of these pathways seems to be more relevant for the relaxation effect induced by trans-[RuCl([15]aneN4)NO]2+ than for [Ru(terpy)(bdq)NO+]3+. The compound trans-[RuCl([15]aneN4)NO]2+ is able to activate ATP dependent potassium channels (KATP), higher and slower calcium conductance potassium channels (KCa) and voltage-dependent potassium channels (Kv). The compound [Ru(terpy)(bdq)NO+]3+ is able to activate only the high calcium conductance potassium channels (KCa) e Kv. In relation to the sarcoplasmic reticulum Ca2+-ATPase activation, it seems to be involved in the relaxation of just the trans-[RuCl([15]aneN4)NO]2+. Our results show that the compound trans-[RuCl([15]aneN4)NO]2+ promotes its relaxation by the production of the radicalar NO while the same effect promoted by [Ru(terpy)(bdq)NO+]3+ is due to both, radicalar NO and nitroxil ions. Moreover, these NO donors do not have toxic effects in vascular smooth muscle cells, representing an advantage for their therapeutic application when compared to SNP. In this regard, knowing the vasorelaxation mechanisms of these new NO donors and their advantages with respect to the SNP, this project has the aim to investigate if the compounds trans-[RuCl([15]aneN4]NO]2+ and [Ru(terpy)(bdq)NO+]3+ are able to develop the in vitro and in vivo tolerance phenomenon, and also verify if they are able to reduce the arterial blood pressure of renal hypertension animals, in a similar way of GTN and SNP. (AU)