Late dual endothelin receptor blockade with bosentan restores impaired cerebrovascular function in diabetes

Mohammed Abdelsaid, Handong Ma, Maha Coucha, Adviye Ergul

Research output: Contribution to journalArticle

15 Citations (Scopus)

Abstract

AIMS: Up-regulation of the endothelin (ET) system in type-2 diabetes increases contraction and decreases relaxation in basilar artery. We showed that 1) ET-receptor antagonism prevents diabetes-mediated cerebrovascular dysfunction; and 2) glycemic control prevents activation of the ET-system in diabetes. Here, our goal is to determine whether and to what extent glycemic control or ET-receptor antagonism reverses established cerebrovascular dysfunction in diabetes.

MAIN METHODS: Non-obese type-2 diabetic Goto-Kakizaki rats were administered either vehicle, metformin (300 mg/kg/day) or dual ET-receptor antagonist bosentan (100mg/kg) for 4-weeks starting at 18-weeks after established cerebrovascular dysfunction (n=5-6/group). Control group included vehicle-treated aged-matched Wistar rats. Blood glucose and pressure were monitored weekly. At termination, basilar arteries were collected and cumulative dose-response curves to ET-1 (0.1-500 nM), 5-HT (1-1000 nM) and acetylcholine (Ach, 0.1 nM-5 μM) were studied by wire myograph. Middle cerebral artery (MCA) myogenic reactivity and tone were measured using pressurized arteriograph.

KEY FINDINGS: There was no difference in ET-1 and 5-HT-mediated constrictions. Endothelium-dependent relaxation was impaired in diabetes. Bosentan improved sensitivity to Ach as well as the maximum relaxation. Myogenic-tone is decreased over the course of the disease. Both treatments improved the ability of MCAs to develop tone at 80 mm Hg and only bosentan improved the tone at higher pressures.

SIGNIFICANCE: These results suggest that contractile response is not affected by glycemic control or ET-receptor antagonism. Meanwhile, dual ET-receptor blockade is effective in partially improving endothelium-dependent relaxation and myogenic response in a blood pressure-independent manner even after established cerebrovascular dysfunction and offers therapeutic potential.

Original languageEnglish (US)
Pages (from-to)263-267
Number of pages5
JournalLife sciences
Volume118
Issue number2
DOIs
StatePublished - Nov 24 2014

Fingerprint

Endothelin Receptors
Medical problems
Basilar Artery
Endothelins
Endothelin-1
Endothelium
Serotonin
Blood Pressure
Endothelin A Receptors
Metformin
Middle Cerebral Artery
Rats
Constriction
Type 2 Diabetes Mellitus
Acetylcholine
Blood Glucose
Wistar Rats
Up-Regulation
Blood pressure
Pressure

Keywords

  • Basilar artery
  • Endothelial function
  • Endothelin
  • Middle cerebral artery
  • Myogenic tone

ASJC Scopus subject areas

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

Cite this

Late dual endothelin receptor blockade with bosentan restores impaired cerebrovascular function in diabetes. / Abdelsaid, Mohammed; Ma, Handong; Coucha, Maha; Ergul, Adviye.

In: Life sciences, Vol. 118, No. 2, 24.11.2014, p. 263-267.

Research output: Contribution to journalArticle

Abdelsaid, Mohammed ; Ma, Handong ; Coucha, Maha ; Ergul, Adviye. / Late dual endothelin receptor blockade with bosentan restores impaired cerebrovascular function in diabetes. In: Life sciences. 2014 ; Vol. 118, No. 2. pp. 263-267.
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AB - AIMS: Up-regulation of the endothelin (ET) system in type-2 diabetes increases contraction and decreases relaxation in basilar artery. We showed that 1) ET-receptor antagonism prevents diabetes-mediated cerebrovascular dysfunction; and 2) glycemic control prevents activation of the ET-system in diabetes. Here, our goal is to determine whether and to what extent glycemic control or ET-receptor antagonism reverses established cerebrovascular dysfunction in diabetes.MAIN METHODS: Non-obese type-2 diabetic Goto-Kakizaki rats were administered either vehicle, metformin (300 mg/kg/day) or dual ET-receptor antagonist bosentan (100mg/kg) for 4-weeks starting at 18-weeks after established cerebrovascular dysfunction (n=5-6/group). Control group included vehicle-treated aged-matched Wistar rats. Blood glucose and pressure were monitored weekly. At termination, basilar arteries were collected and cumulative dose-response curves to ET-1 (0.1-500 nM), 5-HT (1-1000 nM) and acetylcholine (Ach, 0.1 nM-5 μM) were studied by wire myograph. Middle cerebral artery (MCA) myogenic reactivity and tone were measured using pressurized arteriograph.KEY FINDINGS: There was no difference in ET-1 and 5-HT-mediated constrictions. Endothelium-dependent relaxation was impaired in diabetes. Bosentan improved sensitivity to Ach as well as the maximum relaxation. Myogenic-tone is decreased over the course of the disease. Both treatments improved the ability of MCAs to develop tone at 80 mm Hg and only bosentan improved the tone at higher pressures.SIGNIFICANCE: These results suggest that contractile response is not affected by glycemic control or ET-receptor antagonism. Meanwhile, dual ET-receptor blockade is effective in partially improving endothelium-dependent relaxation and myogenic response in a blood pressure-independent manner even after established cerebrovascular dysfunction and offers therapeutic potential.

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KW - Middle cerebral artery

KW - Myogenic tone

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