title: Impaired endothelial calcium signaling is responsible for the defective dilation of mesenteric resistance arteries from db/db mice to acetylcholine.
abstract: We aimed at assessing the role of endothelial cell calcium for the endothelial dysfunction of mesenteric resistance arteries of db/db mice (a model of type 2 diabetes) and determine whether treatment with sulfaphenazole, improves endothelial calcium signaling and function. Pressure myography was used to study acetylcholine (ACh) -induced vasodilation. Intracellular calcium ([Ca(2+)]i) transients was measured by confocal laser scanning microscopy and smooth muscle membrane potential with sharp microelectrodes. The impaired dilation to ACh observed in mesenteric resistance arteries from db/db mice was improved by treatment of the mice with sulfaphenazole for 8 weeks. The impaired dilation to ACh was associated with decreased endothelial [Ca(2+)]i and smooth muscle hyperpolarization. Sulfaphenazole applied in vitro improved endothelial mediated dilation of arteries from db/db mice both in the absence and the presence of inhibitors of nitric oxide and cyclooxygenase. Sulfaphenazole also increased the percentage of endothelial cells with ACh induced increases of [Ca(2+)]i. The study shows that impaired endothelial [Ca(2+)]i control can explain the reduced endothelial function in arteries from diabetic mice and that sulfaphenazole treatment improves endothelial [Ca(2+)]i responses to ACh and consequently endothelium-dependent vasodilation. These observations provide mechanistic insight into endothelial dysfunction in diabetes.
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus C, Denmark; Department of Physiology, Aarhus University, Aarhus C, Denmark.
authors.forename: Hua
authors.initials: H
authors.lastname: Chen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus C, Denmark; Department of Physiology, Aarhus University, Aarhus C, Denmark.
authors.forename: Henrik
authors.initials: H
authors.lastname: Kold-Petersen
authors.affiliation: Department of Anesthesiology, Pharmacology and Therapeutics, University of British Columbia, Vancouver, Canada.
authors.forename: Ismael
authors.initials: I
authors.lastname: Laher
authors.affiliation: Department of Pulmonary and Cardiovascular Pharmacology, Aarhus University, Aarhus C, Denmark.
authors.forename: Ulf
authors.initials: U
authors.lastname: Simonsen
authors.affiliation: Department of Biomedicine, Aarhus University, Aarhus C, Denmark; Department of Physiology, Aarhus University, Aarhus C, Denmark. Electronic address: ca@au.dk.
authors.forename: Christian
authors.initials: C
authors.lastname: Aalkjaer
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology*; D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects*; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D000072467:Cytochrome P450 Family 2; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism*; D042783:Endothelial Cells / Q000187:drug effects* / Q000378:metabolism; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects; D008638:Mesenteric Arteries / Q000187:drug effects*; D051379:Mice; D008817:Mice, Mutant Strains; D009569:Nitric Oxide / Q000037:antagonists & inhibitors; D011451:Prostaglandin-Endoperoxide Synthases; D013426:Sulfaphenazole / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D016861:Cyclooxygenase Inhibitors; D013426:Sulfaphenazole; D009569:Nitric Oxide; D003577:Cytochrome P-450 Enzyme System; C086292:Cyp2c29 protein, mouse; D000072467:Cytochrome P450 Family 2; D011451:Prostaglandin-Endoperoxide Synthases; D000109:Acetylcholine
keywords: Diabetes; Endothelial dysfunction; Mesenteric small arteries; db/db Mice