Effects of selective endothelin (ET)-A receptor antagonist versus dual ET-A/B receptor antagonist on hearts of streptozotocin-treated diabetic rats

• Published in: Life sciences (1973) Vol. 111; no. 1-2; pp. 6 - 11
• Main Authors: Miyauchi, Yumi, Jesmin, Subrina, Sakai, Satoshi, Kamiyama, Junko, Shimojo, Nobutake, Rahman, Arifur, Islam, Majedul, Zaedi, Sohel, Maeda, Seiji, Maruyama, Hidekazu, Mizutani, Taro, Homma, Satoshi, Aonuma, Kazutaka, Miyauchi, Takashi
• Format: Journal Article
• Language: English
• Published: Netherlands Elsevier Inc 28.08.2014
• Subjects: Animals; Blood Glucose - analysis; Blood Pressure - drug effects; Diabetes Mellitus, Experimental - drug therapy; Diabetes Mellitus, Experimental - metabolism; Diabetes Mellitus, Experimental - physiopathology; Diabetic heart; Echocardiography; Endothelin A Receptor Antagonists; Endothelin B Receptor Antagonists; Endothelin receptor antagonist; Heart - drug effects; Heart - physiopathology; Heart Ventricles - chemistry; Indans - pharmacology; Indans - therapeutic use; Insulin - blood; KDR; Male; Nitric Oxide Synthase Type III - analysis; pAKT; Pyrimidines - pharmacology; Pyrimidines - therapeutic use; Rats; Rats, Sprague-Dawley; Sulfonamides - pharmacology; Sulfonamides - therapeutic use; Vascular Endothelial Growth Factor A - analysis; Vascular Endothelial Growth Factor Receptor-2 - drug effects; VEGF signaling; VEGF signaling; KDR; pAKT; Diabetic heart; Endothelin receptor antagonist
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2014.06.008

The aim was to study the differences in the effectiveness of two types of endothelin (ET) receptor antagonists (selective ET-A or dual ET-A/B antagonists) on the hearts of streptozotocin (STZ)-induced diabetic rats (type I diabetes) at functional and biochemical/molecular levels. Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1mg/kg/day) were then administered to these rats. One week after injection, the animals were separated into those receiving SB209670, TA-0201 or vehicle by 4-week osmotic mini-pump. The VEGF level and percent fractional shortening in the diabetic heart were significantly decreased compared to the non-diabetic heart, whereas SB209670 and TA-0201 treatments greatly and comparably prevented this decrease. SB209670 treatment was more effective in reversing decreased expressions of KDR and phosphorylated AKT, downstream of VEGF angiogenic signaling, than TA-0201 treatment. The eNOS levels in hearts were significantly higher in diabetic rats than in healthy rats, and this increase was significantly reduced by TA-0210 but not by SB209670 treatment. Improvement of KDR mRNA and pAKT levels by SB209670 but not TA-0201 suggests that dual ET-A/-B blockade may be effective in improving intracellular systems of these components in the diabetic rat heart. However, the present study also showed that TA-0201 or SB209670 improved percent fractional shortening and VEGF levels of the diabetic hearts to a similar extent, suggesting that ET-A blockade and dual ET-A/-B blockade are similarly effective in improving cardiac dysfunction in the diabetic rats.