Cardiovascular expression of inflammatory signaling molecules, the kinin B1 receptor and COX2, in the rabbit: effects of LPS, anti-inflammatory and anti-hypertensive drugs.
We first aimed to test the effect of anti-inflammatory drugs, etanercept and dexamethasone sodium phosphate (DSP), on the expression of inducible inflammatory signaling molecules (the bradykinin [BK] B(1) receptor [B(1)R], cyclooxygenase [COX]-2) in lipopolysaccharide (LPS)-treated rabbits. Preliminary experiments mostly based on a novel cellular model, rabbit dermis fibroblasts, showed that etanercept inhibited TNF-alpha-induced B(1)R expression ([(3)H]Lys-des-Arg(9)-BK binding), but that DSP also inhibited cytokine-induced B(1)R upregulation with less selectivity. LPS (100 microg/kg i.v.) induced the expression of the B(1)R (aortic contractility ex vivo, mRNA in hearts) and COX2 (immunoblots, heart extracts). However, the function of the BK B(2) receptor was unchanged (jugular vein contractility ex vivo). DSP pre-treatment profoundly reduced the induction of the B(1)R and COX2 whereas etanercept significantly inhibited only COX2 expression. The second aim was to verify whether chronic angiotensin converting enzyme (ACE) blockade in rabbits would induce B(1)R expression, as reported in other species. 14-Day enalapril oral dosing, but not treatment with the angiotensin receptor antagonist losartan, significantly increased aortic contractions mediated by B(1)Rs, however much less than LPS. Enalapril treatment did not increase COX2 expression but increased the ex vivo relaxation of the mesenteric artery mediated by endogenous prostaglandins. Chronic ACE inhibition recruits inflammatory signaling systems.
Bawolak
Marie-Thérèse
MT
Centre de recherche en Rhumatologie et Immunologie, Centre Hospitalier Universitaire de Québec, Québec Qc, Canada G1V 4G2.
Touzin
Karine
K
Moreau
Marie Eve
ME
Désormeaux
Anik
A
Adam
Albert
A
Marceau
François
F
D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001011:Aorta / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D065169:Bradykinin B1 Receptor Antagonists; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000187:drug effects / Q000378:metabolism*; D003907:Dexamethasone / Q000031:analogs & derivatives* / Q000494:pharmacology; D000068800:Etanercept; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007074:Immunoglobulin G / Q000494:pharmacology*; D008070:Lipopolysaccharides / Q000494:pharmacology*; D008297:Male; D012333:RNA, Messenger / Q000096:biosynthesis; D011817:Rabbits; D043783:Receptor, Bradykinin B1 / Q000235:genetics / Q000378:metabolism*; D018124:Receptors, Tumor Necrosis Factor; D015398:Signal Transduction / Q000187:drug effects
D000893:Anti-Inflammatory Agents; D000959:Antihypertensive Agents; D065169:Bradykinin B1 Receptor Antagonists; D007074:Immunoglobulin G; D008070:Lipopolysaccharides; D012333:RNA, Messenger; D043783:Receptor, Bradykinin B1; D018124:Receptors, Tumor Necrosis Factor; C004180:dexamethasone 21-phosphate; D003907:Dexamethasone; D051546:Cyclooxygenase 2; D000068800:Etanercept