title: The "Rise-Peak-Fall" Pattern of Time Dependency of the Cardiovascular Pleiotropic Effects of Treatment With Low-dose Atorvastatin, Losartan, and a Combination Thereof in Rats.
abstract: Treatment with low, subtherapeutic doses of statins and sartans expresses beneficial pleiotropic effects on the arterial wall. The present study explored whether these effects depend on treatment duration. Wistar rats were randomly divided into 4 groups and received low-dose atorvastatin, low-dose losartan, their combination, or saline (control) daily. After 4, 6, 8, and 10 weeks of treatment, the animals were anesthetized, blood samples taken, and hearts and thoracic aortas isolated. Thoracic aorta endothelium-dependent relaxation and parameters of the isolated heart exposed to ischemic-reperfusion injury were assessed along with blood serum parameters and vasoactive genes expression. Low-dose atorvastatin, losartan, and especially their combination showed the characteristic time dependency of all studied parameters (thoracic aorta relaxation, isolated heart parameters, C-reactive protein values, genes encoding endothelial nitric oxide synthase, and CD40). The peak in efficacy was observed after 6 weeks of treatment and subsequently steadily declined. The peak versus control values were significant for all measured parameters. Only a combination of atorvastatin and losartan increased nitric oxide and decreased asymmetric dimethylarginine. A characteristic time-dependent "rise-peak-fall" pattern of the cardiovascular pleiotropic effects of statins and sartans in subtherapeutic low doses was revealed. Evidently, resistance to the explored treatment occurs after a certain period.
authors.affiliation: *Department of Vascular Diseases, University of Ljubljana Medical Centre, Ljubljana, Slovenia; †Faculty of Medicine, Institute of Pharmacology and Experimental Toxicology, University of Ljubljana, Ljubljana, Slovenia; ‡Department of Clinical Biochemistry, Faculty of Pharmacy, University of Ljubljana, Ljubljana, Slovenia; and §Institute of Clinical Chemistry and Biochemistry, University of Ljubljana Medical Centre, Ljubljana, Slovenia.
authors.forename: Miodrag
authors.initials: M
authors.lastname: Janic
authors.forename: Mojca
authors.initials: M
authors.lastname: Lunder
authors.forename: Darko
authors.initials: D
authors.lastname: Cerne
authors.forename: Janja
authors.initials: J
authors.lastname: Marc
authors.forename: Ales
authors.initials: A
authors.lastname: Jerin
authors.forename: Milan
authors.initials: M
authors.lastname: Skitek
authors.forename: Gorazd
authors.initials: G
authors.lastname: Drevensek
authors.forename: Miso
authors.initials: M
authors.lastname: Sabovic
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000503:physiopathology; D001120:Arginine / Q000031:analogs & derivatives / Q000097:blood; D000069059:Atorvastatin / Q000008:administration & dosage*; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism; D002319:Cardiovascular System / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002352:Carrier Proteins / Q000378:metabolism; D003326:Coronary Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D004730:Endothelium, Vascular / Q000187:drug effects / Q000503:physiopathology; D005260:Female; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000008:administration & dosage*; D000067268:Isolated Heart Preparation; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology; D009206:Myocardium / Q000378:metabolism; D009569:Nitric Oxide / Q000097:blood; D052250:Nitric Oxide Synthase Type III / Q000235:genetics / Q000378:metabolism; D017208:Rats, Wistar; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D019013:CD40 Antigens; D002352:Carrier Proteins; C030929:Crp protein, rat; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D009569:Nitric Oxide; C018524:N,N-dimethylarginine; D001120:Arginine; D000069059:Atorvastatin; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019808:Losartan