Comparison of selective versus dual endothelin receptor antagonism on cerebrovascular dysfunction in diabetes

Weiguo Li, Kamakshi Sachidanandam, Adviye Ergul

Research output: Contribution to journalArticle

13 Citations (Scopus)

Abstract

Objectives: Cerebrovascular tone plays a key role in controlling cerebral blood flow. Our studies have demonstrated that the endothelin system is upregulated in type 2 diabetes leading to increased sensitivity to endothelin-1 and decreased relaxation in basilar artery. While chronic endothelin A receptor blockade restored relaxation, selective endothelin B receptor blockade caused paradoxical constriction in diabetes. Whether this effect was due to activation of endothelin A receptors in the presence of endothelin B receptor blockade or due to the loss of vasculoprotective effects of endothelin B receptors remained unknown. The current study hypothesizes that due to the antagonism of the vasculoprotective endothelin receptor B, dual blockade will not be as effective as selective endothelin receptor A antagonism in improving cerebrovascular dysfunction in type 2 diabetes. Methods: These studies were done in non-obese, type 2 diabetic Goto-Kakizaki rats administered either vehicle, selective endothelin receptor A antagonist Atrasentan (5 mg/kg) or dual endothelin antagonist Bosentan (100 mg/kg) for 4 weeks. At termination, basilar arteries were collected and mounted on a wire myograph and cumulative dose-response curves to endothelin-1 (1-500 nM) and acetylcholine (1 nM-5 μm) were studied. Results: Basilar artery was highly sensitive to endothelin-1-mediated constriction in diabetic animals. While neither Atrasentan nor Bosentan affected endothelium-dependent vascular relaxation in control animals, both treatments improved the maximum dilatation in diabetes and Atrasentan also improved sensitivity to acetylcholine. Conclusion: In light of our previous data which showed that endothelin B receptors are vasculoprotective and blockade of this receptor worsens relaxation, current findings suggest that when blocked simultaneously with the endothelin receptor A, the endothelin receptor B antagonism is protective by reducing the hyperreactivity and improving cerebrovascular function in diabetes.

Original languageEnglish (US)
Pages (from-to)185-191
Number of pages7
JournalNeurological Research
Volume33
Issue number2
DOIs
StatePublished - Mar 1 2011

Fingerprint

Endothelin B Receptors
Endothelin Receptors
Endothelin A Receptors
Basilar Artery
Endothelin-1
Constriction
Type 2 Diabetes Mellitus
Acetylcholine
Cerebrovascular Circulation
Endothelins
Vasodilation
Dilatation
atrasentan

Keywords

  • Cerebrovascular function
  • Diabetes
  • Endothelin
  • Endothelin receptor A
  • Endothelin receptor B

ASJC Scopus subject areas

  • Clinical Neurology
  • Neurology

Cite this

Comparison of selective versus dual endothelin receptor antagonism on cerebrovascular dysfunction in diabetes. / Li, Weiguo; Sachidanandam, Kamakshi; Ergul, Adviye.

In: Neurological Research, Vol. 33, No. 2, 01.03.2011, p. 185-191.

Research output: Contribution to journalArticle

Li, Weiguo ; Sachidanandam, Kamakshi ; Ergul, Adviye. / Comparison of selective versus dual endothelin receptor antagonism on cerebrovascular dysfunction in diabetes. In: Neurological Research. 2011 ; Vol. 33, No. 2. pp. 185-191.
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