title: Coronary microvascular dysfunction after long-term diabetes and hypercholesterolemia.
abstract: Coronary microvascular dysfunction (CMD) has been proposed as an important component of diabetes mellitus (DM)- and hypercholesterolemia-associated coronary artery disease (CAD). Previously we observed that 2.5 mo of DM and high-fat diet (HFD) in swine blunted bradykinin (BK)-induced vasodilation and attenuated endothelin (ET)-1-mediated vasoconstriction. Here we studied the progression of CMD after 15 mo in the same animal model of CAD. Ten male swine were fed a HFD in the absence (HFD, n = 5) or presence of streptozotocin-induced DM (DM + HFD, n = 5). Responses of small (∼300-μm-diameter) coronary arteries to BK, ET-1, and the nitric oxide (NO) donor S-nitroso-N-acetylpenicillamine were examined in vitro and compared with those of healthy (Normal) swine (n = 12). Blood glucose was elevated in DM + HFD (17.6 ± 4.5 mmol/l) compared with HFD (5.1 ± 0.4 mmol/l) and Normal (5.8 ± 0.6 mmol/l) swine, while cholesterol was markedly elevated in DM + HFD (16.8 ± 1.7 mmol/l) and HFD (18.1 ± 2.6 mmol/l) compared with Normal (2.1 ± 0.2 mmol/l) swine (all P < 0.05). Small coronary arteries showed early atherosclerotic plaques in HFD and DM + HFD swine. Surprisingly, DM + HFD and HFD swine maintained BK responsiveness compared with Normal swine due to an increase in NO availability relative to endothelium-derived hyperpolarizing factors. However, ET-1 responsiveness was greater in HFD and DM + HFD than Normal swine (both P < 0.05), resulting mainly from ETBreceptor-mediated vasoconstriction. Moreover, the calculated vascular stiffness coefficient was higher in DM + HFD and HFD than Normal swine (both P < 0.05). In conclusion, 15 mo of DM + HFD, as well as HFD alone, resulted in CMD. Although the overall vasodilation to BK was unperturbed, the relative contributions of NO and endothelium-derived hyperpolarizing factor pathways were altered. Moreover, the vasoconstrictor response to ET-1 was enhanced, involving the ETBreceptors. In conjunction with our previous study, these findings highlight the time dependence of the phenotype of CMD.
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.|Netherlands Heart Institute, Utrecht, The Netherlands; and.
authors: Oana
authors: O
authors: Sorop
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.|Department of Internal Medicine, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Mieke
authors: M
authors: van den Heuvel
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Nienke S
authors: NS
authors: van Ditzhuijzen
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Vincent J
authors: VJ
authors: de Beer
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Ilkka
authors: I
authors: Heinonen
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Richard W B
authors: RW
authors: van Duin
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Zhichao
authors: Z
authors: Zhou
authors: Livestock Research, Wageningen University and Research Center, Wageningen, The Netherlands.
authors: Sietse J
authors: SJ
authors: Koopmans
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: Daphne
authors: 0000-0002-4852-831X
authors: D
authors: Merkus
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.|Netherlands Heart Institute, Utrecht, The Netherlands; and.
authors: Wim J
authors: WJ
authors: van der Giessen
authors: Department of Internal Medicine, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors: A H Jan
authors: AH
authors: Danser
authors: Division of Experimental Cardiology, Department of Cardiology, Thoraxcenter, Cardiovascular Research School COEUR, Erasmus University Medical Center, Rotterdam, The Netherlands; d.duncker@erasmusmc.nl.
authors: Dirk Jan
authors: 0000-0003-2836-2241
authors: DJ
authors: Duncker
mesh_terms: D000818:Animals; D001920:Bradykinin / Q000494:pharmacology; D003331:Coronary Vessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D059305:Diet, High-Fat; D019332:Endothelin-1 / Q000494:pharmacology; D006937:Hypercholesterolemia / Q000150:complications / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels / Q000235:genetics; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000235:genetics; D008297:Male; D055806:Microvessels / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D009569:Nitric Oxide / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000473:pathology; D060888:Real-Time Polymerase Chain Reaction; D044022:Receptor, Endothelin A / Q000235:genetics; D044023:Receptor, Endothelin B / Q000235:genetics; D026423:S-Nitroso-N-Acetylpenicillamine / Q000494:pharmacology; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics; D034421:Sus scrofa; D013552:Swine; D014661:Vasoconstriction / Q000187:drug effects* / Q000502:physiology; D014664:Vasodilation / Q000187:drug effects* / Q000502:physiology; D014665:Vasodilator Agents / Q000494:pharmacology*
chemical_list: D019332:Endothelin-1; D051660:Intermediate-Conductance Calcium-Activated Potassium Channels; D051036:Large-Conductance Calcium-Activated Potassium Channels; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D051640:Small-Conductance Calcium-Activated Potassium Channels; D014665:Vasodilator Agents; D009569:Nitric Oxide; D026423:S-Nitroso-N-Acetylpenicillamine; D001920:Bradykinin
keywords: coronary microvascular dysfunction; diabetes; endothelin-1; hypercholesterolemia; swine