Effects of BQ-123 on renal function and acute cyclosporine-induced renal dysfunction

Effects of BQ-123 on renal function and acute cyclosporine-induced renal dysfunction. Cyclosporin A (CsA) is widely used to suppress graft rejection following transplantation and in the treatment of a variety of autoimmune diseases. Therapy with CsA is often accompanied by adverse effects which include hepatotoxicity, hypertension, and nephrotoxicity. The role of endothelin (Et) in CsA-induced nephrotoxicity has been the subject of recent investigations. BQ-123 is a recently discovered Et receptor antagonist which is selective for the Et A receptor. In the present study, BQ-123 was used to further characterize the role of Et in CsA-induced nephrotoxicity. All experiments were performed in Inactin (100 mg/kg, i.p.) anesthetized male Munich-Wistar rats (250 to 350 g). Animals were prepared for the recording of blood pressure (MAP) and heart rate (HR) as well as the measurement of urine volume (UV), U Na V, U K V, GFR and effective renal plasma flow (ERPF). GFR and ERPF were estimated from the clearance of 14 C-inulin and 3 H-PAH, respectively. On the day of the experiment, animals were randomly assigned to one of three groups and treated according to the following protocols: Group 1, pretreatment with BQ-123 (1 mg/kg, i.v. bolus with 0.1 mg/kg/hr i.v. infusion) followed by treatment with vehicle (cremophor; 0.15 ml, i.v.); Group 2, pretreatment with normal saline (1.0 ml/kg; plus 25 µl/min infusion) followed by treatment with CsA (20 mg/kg, i.v.); and Group 3, pretreatment with BQ-123 (same as group 1) followed by CsA (20 mg/kg, i.v.). BQ-123 administration alone produced transient changes in several of the measured parameters. These transient changes included reductions in both ERPF (-1.1 ml/min/100 g, P ≤ 0.01 vs. baseline=2.7 ± 0.1) and GFR (-0.3 ml/min/100 g, P ≤ 0.01 vs. baseline=0.9 ± 0.04). In contrast, filtration fraction (FF) and U Na V were increased. By forty minutes after administration of BQ-123, the measured parameters of renal function returned to control values and remained stable for the experimental period. CsA alone significantly increased MAP (+14 mm Hg, P ≤ 0.05 vs. baseline=127 ± 3) and reduced ERPF (-0.9 ml/min/100 g, P ≤ 0.01 vs. baseline=2.6 ± 0.2) and GFR (-0.2 ml/min/100 g, P ≤ 0.01 vs. baseline=0.9 ± 0.05). Administration of CsA also produced reductions in UV and U K V, and there was a tendency toward reduction in U Na V. In the presence of BQ-123, the effects of CsA on MAP, ERPF and GFR were completely prevented. However, BQ-123 failed to prevent CsA-induced changes in UV, U Na V and U K V. The present data demonstrate that BQ-123 itself causes transient changes in ERPF, GFR and tubular function which may be explained by a partial agonist effect of this compound. Additionally, systemic pretreatment with BQ-123 prevented CsA-induced changes in MAP, ERPF and GFR but did not prevent changes in UV, U Na V and U K V. Therefore, when given intravenously prior to CsA BQ-123 can prevent the hypoperfusion and hypofiltration associated with CsA-induced nephrotoxicity; however, tubular mediated processes appear to remain at risk.