We have previously demonstrated that the hypotensive effect of the ruthenium complex [Ru(terpy)(bdq)NO](3+) (TERPY) is slow, long lasting, and does not lead to reflex tachycardia. TERPY's hypotensive effect is increased in hypertensive rats (SHR or 2 kidney-1clip) compared with normotensive rats. We hypothesized that sexual differences could interfere in the hypotensive effects of nitric oxide (NO) donors in SHR. Therefore, here we aimed to investigate the role of sexual differences and endogenous NO in the hypotension induced by TERPY. In conscious, unrestrained animals, we evaluated the hypotensive effect of TERPY before and after the administration of N-nitro-L-arginine methyl ester (L-NAME) (nonselective NO synthase inhibitor), APOCYNIN (NADPH/NOX inhibitor), and TEMPOL (superoxide dismutase mimetic). The hypotensive effect of TERPY was higher in male than in female SHR, but this difference was not observed in the normotensive Wistar group. The effect of TERPY increased after administration of L-NAME in Wistar rats; however, this effect was not altered by L-NAME in SHR. In SHR, sexual dimorphism in TERPY effect was still observed in animals treated with L-NAME. TEMPOL increases the effect of TERPY only in female SHR. After TEMPOL, the sexual dimorphism in TERPY effect was abolished in the SHR group. APOCYNIN increased the effect of TERPY in male and female Wistar and SHR, but maintained the previously observed difference between male and female SHR. Thus, this study shows that TERPY's hypotensive effect increased in male compared with female SHR and indicates that sexual dimorphism in TERPY effect is associated with oxidative stress.

The hypotensive effect of the new NO donor TERPY was evaluated in Wistar (WST) and SHR after pre‐infusion with an in bolus injection of Tempol (superoxide dismutase mimetic; 30 mg/Kg) and Apocynin (NADPH oxidase inhibitor; 30mg/Kg) and the effects were compared to sodium nitroprusside (SNP) effects (35 μg/Kg). The hypotensive effect of both NO donors was increased in SHR, but only SNP increased the HR (heart rate). The Tempol infusion decreased the mean arterial pressure (MAP) in WST and SHR, but did not alter the HR and reduced the TERPY effect. In the presence of Tempol, the hypotension evoked by TERPY is not different between WST and SHR, and the SNP effect was increased in SHR. Apocynin induced hypotension was more significant in SHR, but it decreased the HR in both groups. In apocynin infused rats, the hypotension induced by TERPY was higher in SHR, but there was no difference in the effect of SNP. These results indicates that superoxide anions is involved in the difference of the hypotensive effect between Wistar and SHR and that NADPH oxidase participates in the hypotensive response of SNP but not to TERPY.