title: Effect of olmesartan on oxidative stress in hypertensive patients: mechanistic support to clinical trials derived evidence.
abstract: The role of oxidative stress in the pathophysiology of hypertension and target organ damage is widely recognized. Using a molecular biology approach, we report, in essential hypertensive patients, the effect of the angiotensin II type 1 receptor blocker olmesartan on the mononuclear cell (PBMC) protein expression of major elements in the oxidative stress and vascular remodeling-related pathways, p22(phox) and HO-1, along with the phosphorylation state of ERK1/2 and plasma oxidized low-density lipoproteins (oxLDL). Twenty untreated essential hypertensive patients (range blood pressure: 142?156/94?98 mmHg) were treated with olmesartan medoxomil (20 mg/day for 6 months) and blood samples collected at baseline, 3 and 6 months for PBMC p22(phox) and HO-1 protein expression, phosphorylation state of ERK1/2 (western blot) and oxLDL level (ELISA) evaluations. Olmesartan normalized blood pressure since the third month (149 ? 4.7/94.88 ? 1.9 mmHg vs 137.89 ? 2.08/88.44 ? 2.0 at 3 months and vs 135.44 ? 2.18/85.78 ? 1.2 at 6 months, analysis of variance: p < 0.001). p22(phox) protein level declined at 3 months (7.10 ? 2.61 vs 9.32 ? 2.43 densitometric units (d.u.; p < 0.001), further declining at 6 months (4.55 ? 1.26 d.u., p < 0.001). HO-1 levels increased at 3 months (10.87 ? 1.92 vs 7.70 ? 0.71 d.u., p = 0.001) and remained elevated (11.11 ? 1.89 d.u., p = 0.001), without further increase at 6 months. Phosphorylated ERK1/2 declined at 3 months (3.94 ? 1.44 vs 5.62 ? 1.11 d.u., p = 0.001), further declining at 6 months (1.94 ? 0.87, p < 0.001). oxLDL significantly declined at 3 and 6 months. These results demonstrate that olmesartan inhibits oxidative stress. Given the involvement of oxidative stress and its signaling in atherogenesis, and the available evidence of olmesartan's vasoprotective, anti-inflammatory and antiatherosclerotic effects derived from clinical trials in humans, the results of our study provide a mechanistic rationale for the omelsartan's antioxidant and anti-inflammatory potential translation, in the long term, toward the antiatherosclerotic and antiremodeling effects reported on the clinical ground.
authors.affiliation: Department of Clinical and Experimental Medicine, University of Padova, Italy. renzcalo@unipd.it
authors.forename: Lorenzo A
authors.initials: LA
authors.lastname: Cal
authors.forename: Lucia Dal
authors.initials: LD
authors.lastname: Maso
authors.forename: Paola
authors.initials: P
authors.lastname: Caielli
authors.forename: Elisa
authors.initials: E
authors.lastname: Pagnin
authors.forename: Maria
authors.initials: M
authors.lastname: Fusaro
authors.forename: Paul A
authors.initials: PA
authors.lastname: Davis
authors.forename: Achille C
authors.initials: AC
authors.lastname: Pessina
mesh_terms: D000328:Adult; D000959:Antihypertensive Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D000975:Antioxidants / Q000008:administration & dosage* / Q000627:therapeutic use; D001794:Blood Pressure; D015153:Blotting, Western; D002986:Clinical Trials as Topic; D004334:Drug Administration Schedule; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D051547:Heme Oxygenase-1 / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D006973:Hypertension / Q000188:drug therapy / Q000378:metabolism / Q000503:physiopathology; D007093:Imidazoles / Q000008:administration & dosage* / Q000627:therapeutic use; D007558:Italy; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D008077:Lipoproteins, LDL / Q000097:blood; D008297:Male; D008875:Middle Aged; D019950:Mitogen-Activated Protein Kinase 1 / Q000032:analysis / Q000096:biosynthesis; D048052:Mitogen-Activated Protein Kinase 3 / Q000032:analysis / Q000096:biosynthesis; D019255:NADPH Oxidases / Q000032:analysis / Q000096:biosynthesis; D000068557:Olmesartan Medoxomil; D018384:Oxidative Stress / Q000187:drug effects*; D010766:Phosphorylation; D013777:Tetrazoles / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D000959:Antihypertensive Agents; D000975:Antioxidants; D007093:Imidazoles; D008077:Lipoproteins, LDL; D013777:Tetrazoles; C099252:oxidized low density lipoprotein; D000068557:Olmesartan Medoxomil; C496541:HMOX1 protein, human; D051547:Heme Oxygenase-1; D019255:NADPH Oxidases; C086986:CYBA protein, human; C535150:MAPK1 protein, human; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3