Comparison of the tolerance on the venous relaxation induced by nitroglycerin and by the new nitrite donor cis‐[Ru(bpy)2(py)(NO2)](PF6)

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Organic nitrates such as nitroglycerin (GNT, glycerol trinitrate), are commonly used in clinical cardiovascular medicine in the acute treatment of angina and severe arterial hypertension. The development of tolerance due to the continuous treatment with high doses leads to a decrease of the magnitude of the vasodilatation induced by GNT. It is a major limitation for the chronic clinical use of GNT. The present study aimed to verify if the new nitrite donor cis‐[Ru(bpy)2(py)(NO2)](PF6) (Rubpy) induces in vitro tolerance in the rat cava vein and to compare this effect with GTN. We have analyzed the maximum relaxing effect (ME) and the potency (EC50) induced by GNT and Rubpy in concentration‐effect curves constructed in vein rings pre‐contracted with endothelin‐1. The experiments were performed on intact endothelial rings following pre‐incubation for 30 min with GTN (EC100: 0.1mmol/L or EC50: 4 μmol/L) or Rubpy (EC100: 0.1μmol/L or EC50: 2 μmol/L). After pre‐incubation with GTN (EC100), the ME was reduced (from 57.5±2.5%, n=4 to 28.1±0.8%, n=4, p<0.001). Pre‐incubation with the EC50 of GTN had no effect. Rubpy induced relaxation in a concentration‐dependent way, that has not been changed by pre‐incubation for 30 min with RuBPY in the EC50 or EC100 (78.6±2.8%, n=4). In conclusion, prior exposure with GTN reduces the relaxation induced by GTN whereas it does not occur with Rubpy. Supported by FAPESP/CNPq.