A low-dose atorvastatin and losartan combination directly improves aortic ring relaxation and diminishes ischaemic-reperfusion injury in isolated rat hearts
Mojca Lunder, Miodrag Janić, Lovro Žiberna, Gorazd Drevenšek, Mišo Šabovič
Med Sci Monit 2012; 18(9): BR366-374
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.
Material/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.
Keywords: Regional Blood Flow - drug effects, Rats, Rats, Wistar, Pyrroles - therapeutic use, Muscle Relaxation - drug effects, Male, Losartan - therapeutic use, Heptanoic Acids - therapeutic use, Drug Therapy, Combination, Dose-Response Relationship, Drug, Coronary Vessels - physiology, Aorta - drug effects, Animals, Analysis of Variance, Reperfusion Injury - prevention & control, Treatment Outcome