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(PP165) Whole brain irradiation reduces insulin, leptin and body weight in Fisher 344 rats one year post-treatment: effects of AT1-receptor blockade.
Robbins, Mike*,1, Gilliam-Davis, Shea2, Payne, Valerie1, Tommasi, Ellen2, Diz, Debra2, 1 Department of Radiation Oncology, Brain Tumor Center of Excellence, Winston-Salem, NC2 Hypertension & Vascular Disease Center, General Surgery, Winston-Salem, NC
ABSTRACT- Blockade of the renin-angiotensin system (RAS) protects against radiation-induced deficits in lung and kidney function. To determine whether angiotensin (Ang) II contributes to development of late effects of whole brain irradiation (WBI), we assessed hemodynamic, RAS and metabolic profiles of AT1 receptor blocked rats one year post-WBI. The AT1 receptor blocker L158809 (L) was given orally (20 mg/L, starting at 13-14 wks of age, during exposure to 40 Gy in 8 fractionated doses over four wks). Systolic blood pressure (SBP) was not different among sham-irradiated (IR)-vehicle (n = 7), WBI-vehicle (n = 3), or sham-IR-L (n = 6) rats, but was slightly higher in WBI-L (n = 6) rats vs sham-IR-L rats (110 ± 10 vs 92 ± 4 mm Hg; p < 0.05). WBI lowered body weight (BWT) ∼30% in vehicle and L-treated rats, while food intake was double that of sham-IR rats. BWT was 10% lower in sham-IR-L relative to sham-IR-vehicle rats in spite of similar food intake. Serum insulin and leptin were ∼60-80% lower in both WBI groups, and 30-40% lower in sham-IR-L than sham-IR-vehicle rats (Insulin - sham-IR-vehicle: 3 ± 0.4 vs sham-IR-L: 2 ± 0.3 ng/ml; p<0.05; Leptin - sham-IR-vehicle: 12 ± 1 vs sham-IR-L: 7 ± 1 ng/ml; p<0.05). Glucose was lower in sham-IR-L than sham-IR-vehicle rats but comparable in other groups. Sham-IR-L rats showed expected increases in plasma Ang peptides [(1-7), II] relative to untreated groups. Ang II was not elevated in WBI-L rats, which was also not different from WBI-vehicle rats. Thus, long-term blockade of AT1 receptors in Fischer 344 rats improves metabolic parameters independent of effects on SBP. WBI also profoundly lowered BWT and serum insulin and leptin, while food intake was elevated. WBI-vehicle or WBI-L rats were comparable with respect to all variables studied, suggesting that the effects of AT1 receptor blockade in WBI can be studied in the absence of differences in key systemic indicators of cardiovascular and metabolic function. That WBI increased overall body metabolism suggests that brain mechanisms may be involved in the initiation of these systemic effects. Support: HL-51952 and CA82722
Key words: Whole body brain radiation, angiotensin II type I receptor blocker, insulin, leptin
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