title: Effect of Cyclooxygenase(COX)-1 and COX-2 inhibition on furosemide-induced renal responses and isoform immunolocalization in the healthy cat kidney.
abstract: BACKGROUND
  The role of cyclooxygenase(COX)-1 and COX-2 in the saluretic and renin-angiotensin responses to loop diuretics in the cat is unknown. We propose in vivo characterisation of isoform roles in a furosemide model by administering non-steroidal anti-inflammatory drugs (NSAIDs) with differing selectivity profiles: robenacoxib (COX-2 selective) and ketoprofen (COX-1 selective).
  
  
  RESULTS
  In this four period crossover study, we compared the effect of four treatments: placebo, robenacoxib once or twice daily and ketoprofen once daily concomitantly with furosemide in seven healthy cats. For each period, urine and blood samples were collected at baseline and within 48 h of treatment starting. Plasma renin activity (PRA), plasma and urinary aldosterone concentrations, glomerular filtration rate (GFR) and 24 h urinary volumes, electrolytes and eicosanoids (PGE2, 6-keto-PGF1α, TxB2), renal injury biomarker excretions [N-acetyl-beta-D-glucosaminidase (NAG) and Gamma-Glutamyltransferase] were measured. Urine volume (24 h) and urinary sodium, chloride and calcium excretions increased from baseline with all treatments. Plasma creatinine increased with all treatments except placebo, whereas GFR was significantly decreased from baseline only with ketoprofen. PRA increased significantly with placebo and once daily robenacoxib and the increase was significantly higher with placebo compared to ketoprofen (10.5 ± 4.4 vs 4.9 ± 5.0 ng ml(-1) h(-1)). Urinary aldosterone excretion increased with all treatments but this increase was inhibited by 75 % with ketoprofen and 65 % with once daily robenacoxib compared to placebo. Urinary PGE2 excretion decreased with all treatments and excretion was significantly lower with ketoprofen compared to placebo. Urinary TxB2 excretion was significantly increased from baseline only with placebo. NAG increased from baseline with all treatments. Immunohistochemistry on post-mortem renal specimens, obtained from a different group of cats that died naturally of non-renal causes, suggested constitutive COX-1 and COX-2 co-localization in many renal structures including the macula densa (MD).
  
  
  CONCLUSIONS
  These data suggest that both COX-1 and COX-2 could generate the signal from the MD to the renin secreting cells in cats exposed to furosemide. Co-localization of COX isoenzymes in MD cells supports the functional data reported here.
authors.affiliation: Department of Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London, NW1 0TU, UK. lpelligand@rvc.ac.uk.|Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, Hertfordshire, UK. lpelligand@rvc.ac.uk.
authors.forename: L
authors.initials: L
authors.lastname: Pelligand
authors.affiliation: Faculty of Veterinary Science, Mahidol University, Nakhon Pathom, Thailand. phungcud35@hotmail.com.
authors.forename: N
authors.initials: N
authors.lastname: Suemanotham
authors.affiliation: Novartis Animal Health Inc., Clinical Development, Basel, Switzerland. jonathan.king@novartis.com.
authors.forename: J N
authors.initials: JN
authors.lastname: King
authors.affiliation: Novartis Animal Health Inc., Clinical Development, Basel, Switzerland. wolfgang.seewald@novartis.com.
authors.forename: W
authors.initials: W
authors.lastname: Seewald
authors.affiliation: Department of Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, Hertfordshire, UK. hsyme@rvc.ac.uk.
authors.forename: H
authors.initials: H
authors.lastname: Syme
authors.affiliation: Department of Pathology and Pathogen Biology, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, AL9 7TA, Hertfordshire, UK. ksmith@rvc.ac.uk.
authors.forename: K
authors.initials: K
authors.lastname: Smith
authors.affiliation: Department of Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London, NW1 0TU, UK. plees@rvc.ac.uk.
authors.forename: P
authors.initials: P
authors.lastname: Lees
authors.affiliation: Department of Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London, NW1 0TU, UK. jelliott@rvc.ac.uk.
authors.forename: J
authors.initials: J
authors.lastname: Elliott
mesh_terms: D000818:Animals; D002415:Cats; D018592:Cross-Over Studies; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism*; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D016861:Cyclooxygenase Inhibitors / Q000008:administration & dosage / Q000494:pharmacology; D004159:Diphenylamine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D015777:Eicosanoids / Q000652:urine; D005665:Furosemide / Q000633:toxicity*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects / Q000502:physiology; D005919:Glomerular Filtration Rate / Q000187:drug effects / Q000662:veterinary; D007660:Ketoprofen / Q000008:administration & dosage / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D010648:Phenylacetates / Q000008:administration & dosage / Q000494:pharmacology*; D020033:Protein Isoforms; D021381:Protein Transport; D012083:Renin / Q000097:blood / Q000378:metabolism
chemical_list: D016861:Cyclooxygenase Inhibitors; D015777:Eicosanoids; D010648:Phenylacetates; D020033:Protein Isoforms; D005665:Furosemide; D007660:Ketoprofen; D004159:Diphenylamine; D051545:Cyclooxygenase 1; D051546:Cyclooxygenase 2; D012083:Renin; C551524:robenacoxib