Inhibition of endothelin-1 receptors improves impaired nitric oxide synthase-dependent dilation of cerebral arterioles in type-1 diabetic rats.
OBJECTIVE
Endothelin-1 has been implicated in the pathogenesis of many cardiovascular-related diseases, including diabetes. The goal of this study was to examine the influence of endothelin-1 receptors (ET(A)) in impaired responses of cerebral (pial) arterioles in type-1 diabetic rats.


METHODS
We measured responses of cerebral arterioles in non-diabetic rats to endothelial nitric oxide synthase (eNOS)-dependent (ADP), neuronal nitric oxide synthase (nNOS)-dependent (N-methyl-d-aspartic acid [NMDA]) and NOS-independent (nitroglycerin) agonists before and during application of BQ-123, an ET(A) receptor antagonist. In addition, we harvested brain tissue from non-diabetic and diabetic rats to measure the production of superoxide anion under basal conditions and during inhibition of ET(A) receptors.


RESULTS
We found that diabetes specifically impaired eNOS- and nNOS-dependent reactivity of cerebral arterioles, but did not alter NOS-independent vasodilation. In addition, while BQ-123 did not alter responses in non-diabetic rats, BQ-123 restored impaired eNOS- and nNOS-dependent vasodilation in diabetic rats. Further, superoxide production was higher in brain tissue from diabetic rats compared with non-diabetic rats under basal conditions and BQ-123 decreased basal production of superoxide in diabetic rats.


CONCLUSIONS
We suggest that activation of ET(A) receptors during type-1 diabetes mellitus plays an important role in impaired eNOS- and nNOS-dependent dilation of cerebral arterioles.
Arrick
Denise M
DM
Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.
Mayhan
William G
WG
D000244:Adenosine Diphosphate / Q000494:pharmacology; D000818:Animals; D001160:Arterioles / Q000187:drug effects / Q000503:physiopathology; D003922:Diabetes Mellitus, Type 1 / Q000503:physiopathology*; D065130:Endothelin A Receptor Antagonists; D008297:Male; D016202:N-Methylaspartate / Q000494:pharmacology; D019001:Nitric Oxide Synthase / Q000502:physiology*; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III / Q000502:physiology*; D010456:Peptides, Cyclic / Q000494:pharmacology; D010841:Pia Mater / Q000098:blood supply*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044022:Receptor, Endothelin A / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects / Q000502:physiology*
D065130:Endothelin A Receptor Antagonists; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D000244:Adenosine Diphosphate; D016202:N-Methylaspartate; D019001:Nitric Oxide Synthase; D052248:Nitric Oxide Synthase Type I; D052250:Nitric Oxide Synthase Type III; C496322:Nos1 protein, rat; C496316:Nos3 protein, rat; C072247:cyclo(Trp-Asp-Pro-Val-Leu)