Effects of a PPARgamma agonist, GI262570, on renal filtration fraction and nitric oxide level in conscious rats.
PPARgamma agonists ameliorate insulin resistance and lower blood pressure. Volume expansion/edema has been observed in susceptible patients treated with these agents. Alterations of renal hemodynamics affect renal tubular reabsorption, and thus may contribute to volume expansion. This study seeks to determine whether volume expansion caused by a PPARgamma agonist, GI262570, is related to changes in glomerular filtration rate, effective renal plasma flow, or renal filtration fraction. Chronically catheter-implanted conscious rats were studied to determine the effects on glomerular filtration rate, effective renal plasma flow, and renal filtration fraction after 1, 4, and 10 days of GI262570 treatment (8 mg/kg, p.o., B.I.D.). Elevated adipose mRNA of PPARgamma target genes confirmed PPARgamma activation in GI262570-treated rats. GI262570 treatment for 10 days decreased hematocrit, hemoglobin, and serum albumin (all P < 0.05), indicating volume expansion, but did not alter glomerular filtration rate, effective renal plasma flow, or renal filtration fraction. However, nitrate + nitrite was significantly higher in plasma and hind limb muscle of GI262570-treated rats (both P < 0.05). This study demonstrated that treatment with PPARgamma agonist GI262570 resulted in volume expansion and increased nitric oxide, but did not affect glomerular filtration rate, effective renal plasma flow, or renal filtration fraction, indicating PPARgamma agonist-induced volume expansion is not related to changes in renal filtration fraction, and increased nitric oxide may contribute to the PPARgamma agonist-induced blood-pressure lowering.
Yang
Baichun
B
GlaxoSmithKline Research & Development, Research Triangle Park, NC 27709, USA. baichun.w.yang@gsk.com
Clifton
Lisa G
LG
McNulty
Judi A
JA
Chen
Lihong
L
Brown
Kathleen K
KK
Baer
Philip G
PG
D000818:Animals; D005919:Glomerular Filtration Rate / Q000187:drug effects*; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D008297:Male; D009566:Nitrates / Q000097:blood; D009569:Nitric Oxide / Q000097:blood / Q000378:metabolism*; D009573:Nitrites / Q000097:blood; D010080:Oxazoles; D051381:Rats; D017207:Rats, Sprague-Dawley; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000235:genetics; D017596:Renal Plasma Flow, Effective / Q000187:drug effects*; D014157:Transcription Factors / Q000819:agonists* / Q000235:genetics; D014443:Tyrosine / Q000031:analogs & derivatives
D007004:Hypoglycemic Agents; D009566:Nitrates; D009573:Nitrites; D010080:Oxazoles; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D009569:Nitric Oxide; C422415:farglitazar; D014443:Tyrosine