title: A low-dose atorvastatin and losartan combination directly improves aortic ring relaxation and diminishes ischaemic-reperfusion injury in isolated rat hearts.
abstract: BACKGROUND
  The cardiovascular pleiotropic effects of statins and angiotensin receptor blockers (ARBs) could be of interest for innovative preventive approaches. We aimed to investigate whether low-dose atorvastatin and losartan, separately not possessing protective cardiovascular pleiotropic effects, express them when combined.
  
  
  METHODS
  Forty-five adult male Wistar rats were anaesthetized and their thoracic aortas and hearts were isolated. Relaxation of aortic rings, coronary flow rate and the extent of myocardial ischaemic-reperfusion injury were measured. Different concentrations (0.01, 0.1, 1.0 µM) of atorvastatin and losartan added to a perfusion medium were first tested. The separate drugs, which were ineffective, were then combined at the same concentrations and the concentration was tested in the same model.
  
  
  RESULTS
  Low concentrations of atorvastatin or losartan (0.1 and 1 µM, respectively) produced no effects in isolated aorta. However, surprisingly, when these drug concentrations were combined, a significantly improved endothelium-dependent relaxation of the thoracic aorta was observed. Similarly, when combining individually ineffective concentrations of atorvastatin or losartan (0.01 and 0.1 µM, respectively), significantly increased coronary flow and a decreased extent of myocardial injury were observed. By using a nitric oxide-synthase inhibitor, we demonstrated that the vasodilatory effects obtained were nitric oxide-dependent. The degree of effectiveness by the combination was comparable to that obtained by 10-fold (atorvastatin) or 100-fold (losartan) higher concentrations of the separate drugs.
  
  
  CONCLUSIONS
  Our results revealed that remarkable additive/synergistic effects exist between low-doses of a statin (atorvastatin) and an ARB (losartan), resulting in important cardiovascular protection. This new concept could be valuable in cardiovascular prevention.
authors.affiliation: Institute of Pharmacology and Experimental Toxicology, Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia. mojca.lunder@mf.uni-lj.si
authors.forename: Mojca
authors.initials: M
authors.lastname: Lunder
authors.forename: Miodrag
authors.initials: M
authors.lastname: Janić
authors.forename: Lovro
authors.initials: L
authors.lastname: Žiberna
authors.forename: Gorazd
authors.initials: G
authors.lastname: Drevenšek
authors.forename: Mišo
authors.initials: M
authors.lastname: Šabovič
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001011:Aorta / Q000187:drug effects*; D000069059:Atorvastatin; D003331:Coronary Vessels / Q000502:physiology; D004305:Dose-Response Relationship, Drug; D004359:Drug Therapy, Combination; D006538:Heptanoic Acids / Q000494:pharmacology* / Q000627:therapeutic use; D019808:Losartan / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009126:Muscle Relaxation / Q000187:drug effects; D011758:Pyrroles / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D012039:Regional Blood Flow / Q000187:drug effects; D015427:Reperfusion Injury / Q000188:drug therapy / Q000517:prevention & control*; D016896:Treatment Outcome
chemical_list: D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D019808:Losartan