Abstract 297: Increased ETA Receptor-Mediated Contractility of Thoracic Aorta by Endothelin-1 in High-Fat-Diet--Fed Insulin-Resistant Rats
Abstract: Increased incidences of cardio-vascular complications in diabetic conditions are a major concern. Endothelin-1 (ET-1) is an important regulator of vascular contractility, and its effects are mediated through ETA and ETB. Previous data from the lab indicates that GPCR mediate contractile responses are enhanced and the present study is aimed to extend the hypothesis that ETA receptor mediated contractile responses of ET-1 under insulin-resistant condition are enhanced.
Methods: Male Sprague-Dawley (SD) rats were kept on high-fat diet (HFDIRR, 8 weeks) for inducing insulin-resistance. Further, b-cell specific toxin streptozotocin (STZ, 50 mg/kg; i.p.) was used to induce hypoinsulinemia in rats. The responses of ET-1, ACh, KCl and Ang -II were recorded in the concentration-dependent manner in the thoracic aorta of rats. Specific ETA receptor antagonist, BMS182874 was used to confirm the findings. Specific binding of [3H]-BQ123 was performed to determine the characteristics of ETA receptors. Biochemical parameters were measured and induction of insulin-resistance was confirmed by intra-peritoneal glucose tolerance test (IPGTT).
Results: ET-1 mediated contractile response (4541 ± 274 mg/mm2 (mean ± s.e.m. (n=8)) was significantly higher in insulin-resistant rats, while that of KCl unchanged. Tempol (100μM) restored the ET-1 mediated contractions in HFDIRR (4541 ± 274 vs 3406 ± 252.8 mg/mm2; p < 0.001; (n=5)). BMS182874 restored NO-mediated endothelium-dependent ACh relaxation in HFDIRR. The specific binding of [3H]-BQ123 to ETA receptors (112.35 ± 5.19 vs. 39.74 ± 4.04 f mol/mg; P < 0.001; (n=5)) was increased in HFDIRR.
Conclusions: Insulin-resistance up-regulates ETA receptor may be responsible enhanced ET-1 mediated contractility of the thoracic aorta.
- © 2012 by American Heart Association, Inc.