title: Treatment with low-dose atorvastatin, losartan, and their combination increases expression of vasoactive-related genes in rat aortas.
abstract: Recently it has been shown that statins and angiotensin receptor blockers (ARBs) at low doses express beneficial pleiotropic vascular effects. We aimed to explore whether these drugs at low doses induce the expression of vasoactive-related genes. Sixty adult Wistar rats were treated with low-dose atorvastatin (2 mg/kg), low-dose losartan (5 mg/kg), their combination or saline daily for 4, 6, or 8 weeks. Expression of the vasoactive-related genes endothelin receptor type A (EDNRA), endothelial nitric oxide synthase 3 (NOS3), inducible nitric oxide synthase 2 (NOS2), and angiotensin II receptor type 1 (AGTRL1a) was measured in isolated thoracic aortas. Expression of EDNRA gradually decreased, the lowest values being obtained after 8 weeks (low-dose atorvastatin, losartan [1.6- and 1-7-fold vs controls, respectively; both P < .05], and the combination [2.3-fold vs control, P < .001]). The highest values of NOS3 were obtained after 6 weeks (low-dose atorvastatin, losartan, and their combination, 3.1-fold, P < .01; 3.4-fold, P < .001; and 3.6-fold, P < .001 vs controls, respectively) and then declined after 8 weeks. The combination was more effective in inducing total NOS3 expression when compared to the separate drugs (1.4-fold; P < .05). Importantly, expression of NOS3 was associated with increased plasma NO levels and positively correlated with thoracic aorta relaxation. No changes in expression of NOS2 and AGTRL1a were observed. We showed that low-dose atorvastatin or losartan and especially their combination increases the expression of NOS3 and decreases the expression of EDNRA. These findings are valuable in explaining the effectiveness of the "low-dose pharmacological approach" for improvement in arterial function.
authors.affiliation: Institute of Pharmacology and Experimental Toxicology, University of Ljubljana, SI-1000 Ljubljana, Slovenia. mojca.lunder@mf.uni-lj.si
authors.forename: Mojca
authors.initials: M
authors.lastname: Lunder
authors.forename: Gorazd
authors.initials: G
authors.lastname: Drevenšek
authors.forename: Darko
authors.initials: D
authors.lastname: Černe
authors.forename: Janja
authors.initials: J
authors.lastname: Marc
authors.forename: Miodrag
authors.initials: M
authors.lastname: Janić
authors.forename: Mišo
authors.initials: M
authors.lastname: Šabovič
mesh_terms: D047228:Angiotensin II Type 1 Receptor Blockers / Q000008:administration & dosage*; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects* / Q000378:metabolism*; D000069059:Atorvastatin; D004359:Drug Therapy, Combination; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects; D006538:Heptanoic Acids / Q000008:administration & dosage*; D019808:Losartan / Q000008:administration & dosage*; D008297:Male; D009924:Organ Culture Techniques; D011758:Pyrroles / Q000008:administration & dosage*; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016896:Treatment Outcome; D014664:Vasodilation / Q000187:drug effects* / Q000235:genetics*
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D006538:Heptanoic Acids; D011758:Pyrroles; D000069059:Atorvastatin; D019808:Losartan