Abstract
The effects of iptakalim, a new ATP-sensitive potassium channel opener, were studied in spontaneously hypertensive rats (SHR). Treatment of 12-week-old male SHR (six animals in each group) with iptakalim by gastric lavage at doses of 1, 3, or 9 mg/kg/day for 12 weeks resulted in a lowering of blood pressure. Iptakalim provided significant renoprotection to SHR rats as measured by decreased proteinuria and improved renal function. Histological evidence demonstrated that iptakalim could reverse renal vascular remodeling (of afferent arterioles, arcuate arteries, or interlobular arteries), and improve pathological changes of glomerular, renal interstitial, and glomerular filtration membranes. These effects were accompanied by the decreased circulation and intrarenal concentrations of endothelin 1 and transforming growth factor β1 (TGF-β1), and down-regulated overexpression of genes for ET-1, endothelin-converting enzyme 1, TGF-β1, and the subunits of ATP-sensitive potassium channels (KATP), Kir1.1 and Kir6.1, in the kidney during hypertension. Abnormal expression of matrix components [collagen IV, fibronectin, matrix metalloproteinase 9 (MMP-9) and MMP tissue inhibitor 1 (TIMP-1)] was also significantly reversed by iptakalim. Our results demonstrate that chronic treatment with iptakalim not only reduces blood pressure but also preserves renal structure and function in SHR. In addition to reducing blood pressure, the renoprotective of iptakalim may be involved in inhibiting the circulation and intrarenal concentrations of endothelin 1 and TGF-β1, regulating the expression of KATP genes and correcting MMP-9/TIMP-1 imbalance in renal tissue, which may result in reducing the accumulation of extracellular matrix molecules.
Footnotes
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This work was supported by grants from the 863-High Technology Research and Development Program Plan (2002 AA2Z3137) and The National 1035 Project (969010101) of China.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.105.089722.
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ABBREVIATIONS: ESRD, end-stage renal disease; IDDM, insulin-dependent diabetes mellitus; SHR, spontaneously hypertensive rat(s); WKY, Wistar-Kyoto; SBP, systolic blood pressure; ET-1, endothelin 1; TGF-β1, transforming growth factor β1; MMP-9, matrix metalloproteinase 9; TIMP-1, matrix metalloproteinase tissue inhibitor 1; RT-PCR, reverse transcription-polymerase chain reaction; PCR, polymerase chain reaction; SUR2, sulfonylurea receptor 2; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; ACE, angiotensin-converting enzyme; ECE, endothelin-converting enzyme; BP, blood pressure.
- Received May 17, 2005.
- Accepted July 25, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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