Yang Baichun, Clifton Lisa G, McNulty Judi A, Chen Lihong, Brown Kathleen K, Baer Philip G
GlaxoSmithKline Research & Development, Research Triangle Park, NC 27709, USA.
J Cardiovasc Pharmacol. 2003 Sep;42(3):436-41. doi: 10.1097/00005344-200309000-00016.
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.
过氧化物酶体增殖物激活受体γ（PPARγ）激动剂可改善胰岛素抵抗并降低血压。在接受这些药物治疗的易感患者中已观察到容量扩张/水肿。肾血流动力学的改变会影响肾小管重吸收，因此可能导致容量扩张。本研究旨在确定由PPARγ激动剂GI262570引起的容量扩张是否与肾小球滤过率、有效肾血浆流量或肾滤过分数的变化有关。对长期植入导管的清醒大鼠进行研究，以确定在给予GI262570治疗（8mg/kg，口服，每日两次）1、4和10天后对肾小球滤过率、有效肾血浆流量和肾滤过分数的影响。GI262570治疗的大鼠中PPARγ靶基因的脂肪mRNA升高证实了PPARγ的激活。GI262570治疗10天可降低血细胞比容、血红蛋白和血清白蛋白（均P<0.05），表明存在容量扩张，但未改变肾小球滤过率、有效肾血浆流量或肾滤过分数。然而，GI262570治疗的大鼠血浆和后肢肌肉中的硝酸盐+亚硝酸盐显著更高（均P<0.05）。本研究表明，用PPARγ激动剂GI262570治疗会导致容量扩张并增加一氧化氮，但不影响肾小球滤过率、有效肾血浆流量或肾滤过分数，这表明PPARγ激动剂诱导的容量扩张与肾滤过分数的变化无关，并且一氧化氮增加可能有助于PPARγ激动剂引起的血压降低。
