Effects of dietary n-3 fatty acid supplementation versus thromboxane synthetase inhibition on gentamicin-induced nephrotoxicosis in healthy male dogs.
OBJECTIVE
To evaluate the protective effects of dietary n-3 fatty acid supplementation versus treatment with a thromboxane synthetase inhibitor (TXSI) in dogs given high-dose gentamicin.


METHODS
Clinicopathologic and renal histopathologic changes induced by gentamicin (10 mg/kg of body weight, IM, q 8 h, for 8 days) were compared in dogs fed an n-3 fatty acid-supplemented diet containing a fatty acid ratio of 5.7:1 (n-6:n-3), dogs treated with CGS 12970 (a specific TXSI given at 30 mg/kg, PO, q 8 h, beginning 2 days prior to gentamicin administration), and control dogs. The TXSI-treated and control dogs were fed a diet with a fatty acid ratio of 51.5:1 (n-6:n-3). Both diets were fed beginning 42 days prior to and during the 8-day course of gentamicin administration.


METHODS
Eighteen 6-month-old male Beagles, 6 in each group.


RESULTS
After 8 days of gentamicin administration, differences existed among groups. Compared with n-3-supplemented and control dogs. TXSI-treated dogs had higher creatinine clearance. Both TXSI-treated and n-3-supplemented dogs had higher urinary prostaglandin E2 and E3 (PGE2/3) and 6-keto prostaglandin F1a (PGF1a) excretion, compared with control dogs. Urinary thromboxane B2 (TXB2) excretion was higher in n-3-supplemented and control dogs, compared with TXSI-treated dogs. Urine PGE2/3-to-TXB2 and PGF(in)-to-TXB2, ratios were increased in TXSI-treated dogs, compared with n-3-supplemented and control dogs, and these ratios were increased in n-3-supplemented dogs, compared with control dogs. In addition, TXSI-treated and n-3-supplemented dogs had lower urinary protein excretion, compared with control dogs. Proximal tubular necrosis was less severe in TXSI-treated dogs, compared with control dogs.


CONCLUSIONS
Treatment with CGS 12970 prior to and during gentamicin administration prevented increases in urinary TXB2 excretion and reduced nephrotoxicosis.


CONCLUSIONS
Increased renal production/excretion of thromboxane is important in the pathogenesis of gentamicin-induced nephrotoxicosis.
Grauer
G F
GF
Department of Clinical Sciences, College of Veterinary Medicine and Biomedical Sciences, Colorado State University, Fort Collins 80523, USA.
Greco
D S
DS
Behrend
E N
EN
Fettman
M J
MJ
Mani
I
I
Getzy
D M
DM
Reinhart
G A
GA
D000818:Animals; D001835:Body Weight / Q000502:physiology; D003404:Creatinine / Q000652:urine; D004032:Diet / Q000662:veterinary*; D004283:Dog Diseases / Q000139:chemically induced* / Q000378:metabolism; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D004435:Eating / Q000502:physiology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015525:Fatty Acids, Omega-3 / Q000008:administration & dosage / Q000494:pharmacology*; D005527:Food, Fortified; D005839:Gentamicins / Q000009:adverse effects* / Q000032:analysis / Q000097:blood; D005919:Glomerular Filtration Rate; D007672:Kidney Cortex / Q000737:chemistry / Q000187:drug effects / Q000502:physiology; D007674:Kidney Diseases / Q000139:chemically induced / Q000378:metabolism / Q000662:veterinary*; D008297:Male; D011188:Potassium / Q000493:pharmacokinetics; D011453:Prostaglandins / Q000652:urine; D011500:Protein Synthesis Inhibitors / Q000009:adverse effects* / Q000032:analysis / Q000097:blood; D011725:Pyridines / Q000494:pharmacology; D011897:Random Allocation; D012964:Sodium / Q000493:pharmacokinetics; D013929:Thromboxane B2 / Q000652:urine; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors* / Q000502:physiology
D004791:Enzyme Inhibitors; D015525:Fatty Acids, Omega-3; D005839:Gentamicins; D011453:Prostaglandins; D011500:Protein Synthesis Inhibitors; D011725:Pyridines; D013929:Thromboxane B2; C049113:3-methyl-2-(3-pyridyl)-1-indoleoctanoic acid; D012964:Sodium; D003404:Creatinine; D013930:Thromboxane-A Synthase; D011188:Potassium