title: Metformin and sulodexide restore cardiac microvascular perfusion capacity in diet-induced obese rats.
abstract: Disturbances in coronary microcirculatory function, such as the endothelial glycocalyx, are early hallmarks in the development of obesity and insulin resistance. Accordingly, in the present study myocardial microcirculatory perfusion during rest and stress was assessed following metformin or sulodexide therapy in a rat model of diet-induced obesity. Additionally, the effect of degradation of the glycocalyx on myocardial perfusion was assessed in chow-fed rats.
  
  
  
  Rats were fed a high fat diet (HFD) for 8 weeks and were divided into a group without therapy, and groups that received the anti-diabetic drug metformin or the glycocalyx-stabilizing drug sulodexide in their drinking water during the last 4 weeks of the feeding period. Myocardial microvascular perfusion was determined using first-pass perfusion MRI before and after adenosine infusion. The effect of HFD on microcirculatory properties was also assessed by sidestream darkfield (SDF) imaging of the gastrocnemius muscle. In an acute experimental setting, hyaluronidase was administered to chow-fed control rats to determine the effect of enzymatical degradation of the glycocalyx on myocardial perfusion.
  
  
  
  HFD-rats developed central obesity and insulin sensitivity was reduced as evidenced by the marked reduction in insulin-induced phosphorylation of Akt in both cardiac and gastrocnemius muscle. We confirmed our earlier findings that the robust increase in myocardial perfusion in chow-fed rats after an adenosine challenge (+56%, p = 0.002) is blunted in HFD rats (+8%, p = 0.68). In contrast, 4-weeks treatment with metformin or sulodexide partly restored the increase in myocardial perfusion during adenosine infusion in HFD rats (+81%, p = 0.002 and +37%, p = 0.02, respectively). Treating chow-fed rats acutely with hyaluronidase, to enzymatically degrade the glyocalyx, completely blunted the increase in myocardial perfusion during stress.
  
  
  
  In early stages of HFD-induced insulin resistance myocardial perfusion becomes compromised, a process that can be countered by treatment with both metformin and sulodexide. The adverse effect of acute glycocalyx degradation and protective effect of long-term sulodexide administration on myocardial perfusion provides indirect evidence, suggesting a role for the glycocalyx in preserving coronary microvascular function in pre-diabetic animals.
authors.affiliation: Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Judith
authors.identifier: 0000-0001-9180-348X
authors.initials: J
authors.lastname: van Haare
authors.affiliation: Department of Radiology and Nuclear Medicine, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: M Eline
authors.initials: ME
authors.lastname: Kooi
authors.affiliation: Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Jurgen W G E
authors.initials: JW
authors.lastname: van Teeffelen
authors.affiliation: Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Hans
authors.initials: H
authors.lastname: Vink
authors.affiliation: Department of Radiology and Nuclear Medicine, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Jos
authors.initials: J
authors.lastname: Slenter
authors.affiliation: Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Cobelens
authors.affiliation: Biomedical Engineering and Physics, Academic Medical Center, P.O. Box 22700, 1100 DE, Amsterdam, The Netherlands.
authors.forename: Gustav J
authors.initials: GJ
authors.lastname: Strijkers
authors.affiliation: Pie Medical Imaging, P.O. Box 1132, 6201 BC, Maastricht, The Netherlands.
authors.forename: Dennis
authors.initials: D
authors.lastname: Koehn
authors.affiliation: Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Post
authors.affiliation: Department of Physiology, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. marc.vanbilsen@maastrichtuniversity.nl.|Department of Cardiology, CARIM School for Cardiovascular Diseases, Maastricht University, P.O. Box 616, 6200 MD, Maastricht, The Netherlands. marc.vanbilsen@maastrichtuniversity.nl.
authors.forename: Marc
authors.initials: M
authors.lastname: van Bilsen
mesh_terms: D000818:Animals; D003331:Coronary Vessels / Q000187:drug effects* / Q000503:physiopathology; D059305:Diet, High-Fat / Q000009:adverse effects*; D006025:Glycosaminoglycans / Q000494:pharmacology / Q000627:therapeutic use*; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use; D008297:Male; D008687:Metformin / Q000494:pharmacology / Q000627:therapeutic use*; D008833:Microcirculation / Q000187:drug effects* / Q000502:physiology; D018482:Muscle, Skeletal / Q000098:blood supply / Q000187:drug effects; D009206:Myocardium; D009765:Obesity / Q000188:drug therapy* / Q000503:physiopathology; D011673:Pulsatile Flow / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017208:Rats, Wistar
chemical_list: D006025:Glycosaminoglycans; D007004:Hypoglycemic Agents; C007858:glucuronyl glucosamine glycan sulfate; D008687:Metformin
keywords: Cardiac function; Endothelial dysfunction; Glycocalyx; Metformin; Myocardial perfusion; Obesity; Sulodexide