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

Yumi Miyauchi, Subrina Jesmin, Satoshi Sakai, Junko Kamiyama, Nobutake Shimojo, Arifur Rahman, Majedul Islam, Sohel Zaedi, Seiji Maeda, Hidekazu Maruyama, Taro Mizutani, Satoshi Homma, Kazutaka Aonuma, Takashi Miyauchi

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

Abstract

Aims 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. Main methods Citrate saline (vehicle) or STZ was injected into rats. The ET-A/B dual receptor antagonist (SB209670, 1 mg/kg/day) and the ET-A receptor antagonist (TA-0201, 1 mg/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. Key findings 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. Significance 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.

Original languageEnglish
Pages (from-to)6-11
Number of pages6
JournalLife Sciences
Volume111
Issue number1
DOIs
Publication statusPublished - 2014
Externally publishedYes

Keywords

  • Diabetic heart
  • Endothelin receptor antagonist
  • KDR
  • VEGF signaling
  • pAKT

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology, Toxicology and Pharmaceutics(all)

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