Ru(bipyridine)2(thiourea)(NO) has Long Lasting Antihypertensive Effects in 2Kidney‐1Clip and Dahl‐Salt Sensitive Hypertensive Rats
Authors: Nascimento Nilberto Robson Falcão , Cabral Pedro Henrique Bezerra , Sousa Eduardo Henrique Silva , Lopes Luiz Gonzaga França , Paz Iury Araújo , Santos Cláudia Ferreira , Fonteles Manasses Claudino 
Published: November 2023

Ruthenium coordinated nitric oxide were synthesized as models for the development of better drugs to treat angina and pulmonary hypertension. The compound [Ru(bipyridine)2(thiourea)(NO)] – FOR0812, was synthesized and probed in vitro for its potential vasodilator activity and in vivo for its antihypertensive properties. First, we tested its effects on thoracic aortic rings, harvested from male Wistar rats (200–250g). The rings were mounted in 5 ml organ baths in Krebs‐Henseleit solution warmed to 37°C and gassed with 5%CO2 in 95%O2. The tissues were coupled to isometric force transducers under a 1g passive tension and coupled to a data acquisition system and recorded by using LabChart 7.0. FOR0812 was added cummulatively (10−12 a 10−4M) in aortic rings precontracted with phenylephrine or high potassium (60mM). On the other hand, in order to test the potential antihypertensive effects of FOR0812 the drug was administered at 1mg/kg by the oral route during 15 days to 2kidney‐1clip hypertensive rat model (2K‐1C) or to Dahl salt‐sentitive rats (DS). In addition, the acute effects of intravenous bolus injections of 0.1;1 or 5mg/Kg FOR0812 on systemic hemodynamics were also studied by using microtip pressure‐volume catheters inserted in the left ventricle. FOR 0812 induced a concentration‐dependent relaxation of 103±2.3 % with an IC50 of 0.24 μM[0.084 – 0.72] while the positive control sodium nitroprusside had a maximal relaxant effect of 108±5.3% with an IC50 of 0.05 μM[0.025 –0.12]. The vasorelaxant effect of FOR0812 was completely blunted by ODQ (10μM) (*p<0.05). The potency for the vasorelaxant of FOR0812 was reduced 5.8‐fold by glibenclamide, 5.4‐fold by apamin‐carybdotoxin and by 11‐fold by tetraethylammonium. The vasorelaxant response was greatly blunted by a nitric oxide scavenger, hydroxocobalamin (FOR0812=103±2.3 % vs. FOR0812+hydroxocobalamin=32.4%, *p<0.05). However, neither the removal of nitroxyl anions (NO−) with 3 mM L‐cystein, nor the blockade of RhoA/Rho kinase (ROCK) with fasudil (HA‐1077), nor the blockade of prostaglandin synthesis with indomethacin, did affect the vasorelaxant effect of FOR0812. Strikingly, FOR0812 reduced mean arterial blood pressure (MAP) of 2K‐1C rats from 181.5±3.6 mmHg to 149±3.1 mmHg after 4 days of treatment and continued to decrease MAP towards normal levels up to the end of the experimental period, i.e., 15th day the MAP of control rats was 171.1±3,2 mmHg while rats treated with FOR0812 had values of 111.4±6.9 mmHg. In the group treated only with vehicle (saline) the MAP continued high, during the whole experimental period (>160mmHg). FOR also reduced MAP of DS rats from 158.8± 5.6 mmHg to 122.6±6.7mmHg after six days of treatment and at the end the experimental period control rats treated with vehicle had MAP of 158.9±4.2 mmHg while DS rats treated with FOR0812 showed MAP of 118.1±5.8mmHg. The intravenous injection of FOR at 0.001; 0.01; 0.1 and 1 mg/Kg decreased vascular resistance (expressed in mmHg × ml/min) of normotensive rats from control values of 6.5±0.8 to 5.6±0.7;4.9±0.6; 4.8±0.6 and 2.6±0.6, respectively. In conclusion, FOR0812 has a clear antihypertensive effect, decreasing peripheral vascular resistance by inducing vasodilation. This effect is long lasting and does not have deleterious effect on the electrocardiogram or cardiac performance.

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