title: Coronary microvascular dysfunction in a porcine model of early atherosclerosis and diabetes.
abstract: Detailed evaluation of coronary function early in diabetes mellitus (DM)-associated coronary artery disease (CAD) development is difficult in patients. Therefore, we investigated coronary conduit and small artery function in a preatherosclerotic DM porcine model with type 2 characteristics. Streptozotocin-induced DM pigs on a saturated fat/cholesterol (SFC) diet (SFC + DM) were compared with control pigs on SFC and standard (control) diets. SFC + DM pigs showed DM-associated metabolic alterations and early atherosclerosis development in the aorta. Endothelium-dependent vasodilation to bradykinin (BK), with or without blockade of nitric oxide (NO) synthase, endothelium-independent vasodilation to an exogenous NO-donor (S-nitroso-N-acetylpenicillamine), and vasoconstriction to endothelin (ET)-1 with blockade of receptor subtypes, were assessed in vitro. Small coronary arteries, but not conduit vessels, showed functional alterations including impaired BK-induced vasodilatation due to loss of NO (P < 0.01 vs. SFC and control) and reduced vasoconstriction to ET-1 (P < 0.01 vs. SFC and control), due to a decreased ET(A) receptor dominance. Other vasomotor responses were unaltered. In conclusion, this model demonstrates specific coronary microvascular alterations with regard to NO and ET-1 systems in the process of early atherosclerosis in DM. In particular, the altered ET-1 system correlated with hyperglycemia in atherogenic conditions, emphasizing the importance of this system in DM-associated CAD development.
authors: Department of Cardiology, Division of Pharmacology, Vascular and Metabolic Diseases, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Mieke
authors: M
authors: van den Heuvel
authors: Oana
authors: O
authors: Sorop
authors: Sietse-Jan
authors: SJ
authors: Koopmans
authors: Ruud
authors: R
authors: Dekker
authors: René
authors: R
authors: de Vries
authors: Heleen M M
authors: HM
authors: van Beusekom
authors: Etto C
authors: EC
authors: Eringa
authors: Dirk J
authors: DJ
authors: Duncker
authors: A H Jan
authors: AH
authors: Danser
authors: Willem J
authors: WJ
authors: van der Giessen
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D001920:Bradykinin / Q000494:pharmacology; D003324:Coronary Artery Disease / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D003331:Coronary Vessels / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000378:metabolism / Q000503:physiopathology; D003925:Diabetic Angiopathies / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D019332:Endothelin-1 / Q000494:pharmacology; D004730:Endothelium, Vascular / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D008297:Male; D009569:Nitric Oxide / Q000378:metabolism; D020030:Nitric Oxide Donors / Q000494:pharmacology; D017466:Receptors, Endothelin / Q000187:drug effects / Q000378:metabolism; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D013552:Swine; D013997:Time Factors; D014661:Vasoconstriction / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
chemical_list: D001786:Blood Glucose; D019332:Endothelin-1; D020030:Nitric Oxide Donors; D017466:Receptors, Endothelin; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D001920:Bradykinin