title: Exercise training and losartan improve endothelial function in heart failure rats by different mechanisms.
abstract: OBJECTIVE
  To investigate the mechanisms of losartan- and exercise training-induced improvements on endothelial dysfunction in heart failure.
  
  
  METHODS
  Sprague-Dawley rats subjected to left coronary artery ligation inducing myocardial infarction and heart failure were randomized to losartan treatment, high-intensity exercise training, or both.
  
  
  RESULTS
  Losartan, but not exercise training, reduced the heart failure-associated elevation in left ventricular end-diastolic pressure (26 ± 2 mmHg vs. 19 ± 1 mmHg after losartan). In contrast, both exercise training and losartan improved exercise capacity, by 40% and 20%, respectively; no additional effects were observed when exercise training and losartan were combined. Aortic segments were mounted on a force transducer to determine vasorelaxation. Heart failure impaired endothelium-dependent vasorelaxation, observed as a 1.9-fold reduced response to acetylcholine (EC₅₀). Exercise and losartan improved acetylcholine-mediated vasorelaxation to the same extent, but by different mechanisms. Exercise training upregulated the nitric oxide pathway, whereas losartan upregulated a non-nitric oxide or -prostacyclin pathway; possibly involving the endothelium-dependent hyperpolarizing factor.
  
  
  CONCLUSIONS
  Both losartan and exercise training reversed endothelial dysfunction in heart failure; exercise training via nitric oxide-dependent vasorelaxation, and losartan via an unknown mechanism that may involve endothelium-dependent hyperpolarizing factor. Thus, the combined treatment activated an additional nitric oxide- independent mechanism that contributed to reduce endothelial dysfunction.
authors.affiliation: Institute of Cardiovascular and Medical Sciences, University of Glasgow, Glasgow, UK. Ole.Kemi@glasgow.ac.uk
authors.forename: Ole Johan
authors.initials: OJ
authors.lastname: Kemi
authors.forename: Per Magnus
authors.initials: PM
authors.lastname: Haram
authors.forename: Morten Andre
authors.initials: MA
authors.lastname: Høydal
authors.forename: Ulrik
authors.initials: U
authors.lastname: Wisløff
authors.forename: Øyvind
authors.initials: Ø
authors.lastname: Ellingsen
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology*; D000818:Animals; D001685:Biological Factors / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D005081:Exercise Therapy; D017079:Exercise Tolerance / Q000187:drug effects; D005260:Female; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology / Q000628:therapy*; D019808:Losartan / Q000494:pharmacology*; D009569:Nitric Oxide / Q000378:metabolism; D044062:Prostaglandins I / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology; D016277:Ventricular Function, Left / Q000187:drug effects; D017725:Ventricular Pressure / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D001685:Biological Factors; D044062:Prostaglandins I; D014665:Vasodilator Agents; C067410:endothelium-dependent hyperpolarization factor; D009569:Nitric Oxide; D019808:Losartan