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

Abstract

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 14C-inulin and 3H-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.