TY - JOUR
T1 - Comparison of selective versus dual endothelin receptor antagonism on cerebrovascular dysfunction in diabetes
AU - Li, Weiguo
AU - Sachidanandam, Kamakshi
AU - Ergul, Adviye
PY - 2011/3
Y1 - 2011/3
N2 - 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.
AB - 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.
KW - Cerebrovascular function
KW - Diabetes
KW - Endothelin
KW - Endothelin receptor A
KW - Endothelin receptor B
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U2 - 10.1179/016164111X12881719352417
DO - 10.1179/016164111X12881719352417
M3 - Article
C2 - 21801593
AN - SCOPUS:79951930926
SN - 0161-6412
VL - 33
SP - 185
EP - 191
JO - Neurological Research
JF - Neurological Research
IS - 2
ER -