Effect of Pretreatment With Atenolol and Nifedipine on ZD6126-Induced Cardiac Toxicity in Rats

medical-grade air and was maintained with 1.5% – 2.5% isofl urane throughout the pro-cedure. The abdominal cavity of each rat was opened, and the descending ab dominal aorta was located and cleared of connective tissue. A tie placed underneath the vessel was lifted to occlude the vessel while the catheter of a DSI TA11PA-C40 radiote-lemetry implant (Data Sciences International, St Paul, MN) was inserted into the aorta along the bevel of a bent 21-gauge needle. The catheter was held in place by suturing it to the inside of the abdominal wall. The surgical abdominal wound was then closed with dissolving sutures, and the outer skin was closed with autoclips. The rats were allowed to recover from surgery and accli-matized to the handling procedures required for dosing, and they were randomly assigned to one of three groups (n = 3 rats per group). Group 1 (the control group) received 1% polysorbate 80 by mouth at 150 minutes and, 1 hour later (i.e., at 210 minutes), 0.9% sodium chloride solution (physiological saline) by intravenous injection. Time zero (0 minutes) was arbitrarily defi ned as 6:00 am. Group 2 received 1% polysorbate 80 by mouth at 150 minutes and ZD6126 (12.5 mg in physiological saline/kg) by intrave-nous injection at 210 minutes. Group 3 received atenolol (6 mg/kg) and nifedipine (10 mg/kg) (Sigma – Aldrich, Poole, U.K.), both by mouth at 150 minutes, each in 1% polysorbate 80, and ZD6126 (AstraZeneca) (12.5 mg/kg) by intravenous injection at 210 minutes. Blood pressure and heart rate data were collected via the radiotelemetry implant every 5 minutes beginning at 0 minutes for 24 hours. For each rat, data were collected as a moving point average over a 30-second period within each 5-minute interval. Vascular disrupting agents selectively destroy the existing tumor vasculature by inducing morphologic changes in tumor endothelial cells that lead to vessel occlu-sion and massive central tumor necrosis ( 1 – 3 ). ZD6126, a soluble prodrug of