IN VIVO AND IN VITRO TOLERANCE INDUCED BY NO DONORS, NITROGLYCERIN AND cis-[Ru (bpy) 2 (py) (NO2)](PF6) IN VENA CAVA

Abstract

NO donors are widely used as pharmacological tool to understand the physiological effect of NO, and the treatment of cardiovascular diseases. Among donors, nitroglycerin (glycerol Trinitate - NTG) and sodium nitroprusside (SNP) have been used to treat cardiovascular diseases. They have significant clinical limitations in their use. SNP releases cyanide and NTG induces tolerance, that is characterized by rapid loss of its anti-ischemic and hemodynamic effects during chronic and continued treatment. The cause of tolerance is still poorly understood, but it is believed that this process is multifactorial. The major clinical benefit of organic nitrates, including the NTG has been attributed to their potent venodilator effect, resulting in the reduction of venous return and cardiac preload and myocardial oxygen demand. Despite the selection of NTG through the venous system, most of tolerance studies are performed in arterial beds such as aorta and coronary. Our research group has studied nitrosyl ruthenium complex: - [RuCl ([15] aneN4] NO] 2 +, cis-[Ru (Cl) (bpy) 2 (NO)] 2 +, [Ru (terpy ) (BDQ) NO] 3 + and cis-[Ru (bpy) 2 (py) (NO2)] (PF6), as new NO donors. Several of these compounds are capable of releasing NO in vivo and in vitro in aorta and vena cava of wistar rats. Unlike the SNP, these compounds have low cytotoxicity. The hypotensive effect of NO donors was higher in renal hypertensive rats than in normotensive rats without altering heart rate, which would represent a therapeutic advantage. The hypothesis of this study is that the NTG and not the compound cis-[Ru(bpy)2(py)(NO2)](PF6) (pyridine) could induce the process of vascular tolerance in the inferior vena cava. This would be due to possible differences in biotransformation pathways and NO release from NO donor compounds and / or the signaling pathways involved in these venodilation activated by NO donors. This project aims to investigate whether NO donors NTG and pyridine, induce the phenomenon of tolerance and cross tolerance in vitro in the inferior vena cava and to investigate the cellular mechanisms involved in these processes. In the case of NTG we also investigate the phenomenon of tolerance and cross tolerance in vivo.