title: Entacapone protects from angiotensin II-induced inflammation and renal injury.
abstract: OBJECTIVE
  Angiotensin II (Ang II)-induced renal damage is associated with perivascular inflammation and increased oxidative stress. We tested the hypothesis whether entacapone, a catechol-O-methyltransferase (COMT) inhibitor exerting antioxidative and anti-inflammatory properties, protects against the Ang II-induced inflammatory response and end-organ damage.
  
  
  METHODS
  Samples from double-transgenic rats harbouring human renin and human angiotensinogen genes (dTGR) and normotensive Sprague-Dawley rats (SD) were assessed by light microscopy, immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR), and high pressure liquid chromatography. The effects of entacapone treatment for 3 weeks were examined in dTGR and SD.
  
  
  RESULTS
  Entacapone completely prevented cardiovascular mortality and decreased albuminuria by 85% in dTGR. Entacapone ameliorated Ang II-induced vascular and glomerular damage, leucocyte infiltration, and intercellular adhesion molecule-1 (ICAM-1) overexpression in the kidneys. Serum 8-isoprostane concentration, as well as renal nitrotyrosine and 8-hydroxydeoxyguanosine expressions, all markers of oxidative stress, were markedly increased in dTGR and normalized by entacapone. Entacapone also decreased p22phox mRNA expression in the kidney. COMT expression was increased by 500% locally in the renal vascular wall in dTGR; however, COMT activity in the whole kidney remained unchanged. Urinary dopamine excretion, a marker of renal dopaminergic tone, was decreased by 50% in untreated dTGR. Even though entacapone decreased renal COMT activity by 40%, the renal dopaminergic tone remained unchanged in entacapone-treated dTGR.
  
  
  CONCLUSIONS
  Our findings suggest that entacapone provides protection against Ang II-induced renal damage through antioxidative and anti-inflammatory mechanisms, rather than by COMT inhibition-induced changes in renal dopaminergic tone.
authors.affiliation: Institute of Biomedicine, Pharmacology, University of Helsinki, Finland.
authors.forename: Teemu
authors.initials: T
authors.lastname: Helkamaa
authors.forename: Piet
authors.initials: P
authors.lastname: Finckenberg
authors.forename: Marjut
authors.initials: M
authors.lastname: Louhelainen
authors.forename: Saara
authors.initials: S
authors.lastname: Merasto
authors.forename: Pekka
authors.initials: P
authors.lastname: Rauhala
authors.forename: Risto
authors.initials: R
authors.lastname: Lapatto
authors.forename: Zhong Jian
authors.initials: ZJ
authors.lastname: Cheng
authors.forename: Ilkka
authors.initials: I
authors.lastname: Reenilä
authors.forename: Pekka
authors.initials: P
authors.lastname: Männistö
authors.forename: Dominik N
authors.initials: DN
authors.lastname: Müller
authors.forename: Friedrich C
authors.initials: FC
authors.lastname: Luft
authors.forename: Eero M
authors.initials: EM
authors.lastname: Mervaala
mesh_terms: D000804:Angiotensin II / Q000009:adverse effects*; D000818:Animals; D030801:Animals, Genetically Modified; D015415:Biomarkers / Q000097:blood / Q000652:urine; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D002394:Catechol O-Methyltransferase / Q000187:drug effects / Q000378:metabolism; D002396:Catechols / Q000494:pharmacology*; D003404:Creatinine / Q000097:blood / Q000652:urine; D015237:Dinoprost / Q000031:analogs & derivatives / Q000097:blood; D004195:Disease Models, Animal; D004298:Dopamine / Q000652:urine; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006973:Hypertension / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D007249:Inflammation / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D018799:Intercellular Adhesion Molecule-1 / Q000187:drug effects / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000293:injuries* / Q000378:metabolism; D007674:Kidney Diseases / Q000209:etiology* / Q000378:metabolism / Q000517:prevention & control*; D007962:Leukocytes / Q000187:drug effects / Q000378:metabolism; D008297:Male; D008955:Models, Cardiovascular; D009570:Nitriles; D009638:Norepinephrine / Q000652:urine; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley / Q000235:genetics
chemical_list: D015415:Biomarkers; D002396:Catechols; D004791:Enzyme Inhibitors; D009570:Nitriles; D012333:RNA, Messenger; D000804:Angiotensin II; D018799:Intercellular Adhesion Molecule-1; C075750:8-epi-prostaglandin F2alpha; C071192:entacapone; D003404:Creatinine; D015237:Dinoprost; D002394:Catechol O-Methyltransferase; D004298:Dopamine; D009638:Norepinephrine