The new nitric oxide donor is a potential vasodilator that similarly relaxes aorta from normotensive and renal hypertensive rats.

LMPC Araújo, RS Da Silva, LM Bendhack. Phaculty of Pharmaceutical Sciences - University of São Paulo, Physics and Chemistry, Brazil

Introduction: Nitric oxide (NO) is the main endogenous vasodilator that regulates vascular tone. There is a great interest in the development of compounds that may serve as vehicle to NO release in biological systems, mainly when the endogenous NO production is impaired, such as in hypertension. The nitrosyl ruthenium compounds are a new class of NO donors which are attractive as potential therapeutic agents due to its low toxicity. [Ru(bpy)2(pyNO2](PF6) (RuBPY) is a new nitrosyl ruthenium complex synthesized in our laboratory that releases NO in the presence of the vascular tissue only. Aim: Thus, the aim of present work was to investigate the effects of the NO donor RuBPY in isolated aorta from normotensive (2K) and renal hypertensive rats (2K-1C). Methods: The RuBPY complex was synthesized as previously reported and characterized by UV-Visible spectroscopy as well as cyclic voltammetry experiments. Male Wistar rats (180–200 g) were used in the present study. Renovascular hypertension (2K-1C) was produced by placing a silver clip on the left renal artery while rats were under anaesthesia (tribromoethanol, 25 mg/kg prepared in deionized water). Control rats (2K) were subjected only to laparotomy. Rats were considered to be hypertensive when systolic arterial pressure was higher than 160 mmHg at 6 weeks after surgery. Following arterial pressure recordings, rats were killed by decapitation. The thoracic aorta was isolated, cut into rings and mounted between two steel hooks to measure the isometric tension. The rings were placed in organ chambers containing Krebs’ solution maintained at pH 7.4 and gassed with 95% O2 and 5% CO2 at 37 ºC. The maximal relaxation (Emax), potency (pEC50) and time course of RuBPY were analyzed. To avoid interference of endogenous NO, the experiments were performed on endothelium-denuded aortas. Aortic rings were pre-contracted with EC50 of phenylephrine (100 nmol/L, diluted in deionized water). When the contractions reached a plateau, the RuBPY, prepared in pH 7.4 phosphate buffer (1 mmol/L), were added cumulatively (0.1 nmol – 10 μmol/L) to the organ bath. The time-course for the relaxation induced by RuBPY was evaluated when RuBPY (10 μmol/L) was added to the organ chamber after a stable contraction in response to EC50 of phenylephrine. Statistical significance was determined by using the Student’s t test. In all cases, probability levels of less than 0.05 (P<0.05) were taken to indicate statistical significance. All pharmacological studies were performed in accordance with the Ethical Animal Committee of the University of São Paulo (11.1.1050.53.5). Results: Vascular reactivity experiments showed that the RuBPY induced relaxation in denuded aortic rings, and the Emax and potency triggered by RuBPY were similar between 2K (Emax:112.7 ± 34.6%, pEC50: 7.37 +0.11, n=8) and 2K-1C rats (Emax: 114.6 ± 6.3%, pEC50: 7.19 +0.12, n=5). The time to RuBPY reach maximum relaxation was similar in 2K and 2K-1C (4 min, n= 5). Conclusion: Taken together, our results demonstrated that RuBPY is a potential vasodilator with relaxation above 100% and that this effect is similar in isolated aortic rings from normotensive 2K and hypertensive 2K-1C rats.

Supported by FAPESP and CNPq.