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 EtA 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), UNaV, UKV, 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 microliters/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.(ABSTRACT TRUNCATED AT 250 WORDS)
Kivlighn
S D
SD
Department of Cardiovascular Pharmacology, Merck Research Laboratories, West Point, Pennsylvania.
Gabel
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RA
Siegl
P K
PK
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D016572:Cyclosporine / Q000494:pharmacology; D065128:Endothelin Receptor Antagonists; D007668:Kidney / Q000187:drug effects* / Q000503:physiopathology; D007674:Kidney Diseases / Q000139:chemically induced* / Q000503:physiopathology*; D007677:Kidney Function Tests; D008297:Male; D010456:Peptides, Cyclic / Q000494:pharmacology*; D014677:Pharmaceutical Vehicles; D011092:Polyethylene Glycols / Q000494:pharmacology; D051381:Rats; D011919:Rats, Inbred Strains; D012016:Reference Values
D065128:Endothelin Receptor Antagonists; D010456:Peptides, Cyclic; D014677:Pharmaceutical Vehicles; C022131:cremophor; D011092:Polyethylene Glycols; D016572:Cyclosporine; C072247:cyclo(Trp-Asp-Pro-Val-Leu)