A new ATP-sensitive potassium channel opener protects the kidney from hypertensive damage in spontaneously hypertensive rats.
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 beta1 (TGF-beta1), and down-regulated overexpression of genes for ET-1, endothelin-converting enzyme 1, TGF-beta1, and the subunits of ATP-sensitive potassium channels (K(ATP)), 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-beta1, regulating the expression of K(ATP) genes and correcting MMP-9/TIMP-1 imbalance in renal tissue, which may result in reducing the accumulation of extracellular matrix molecules.
Xue
Hao
H
Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, People's Republic of China.
Zhang
Ying-Li
YL
Liu
Guo-Shu
GS
Wang
Hai
H
D018528:ATP-Binding Cassette Transporters / Q000819:agonists*; D000804:Angiotensin II / Q000097:blood; D000806:Angiotensin-Converting Enzyme Inhibitors / Q000627:therapeutic use; D000818:Animals; D000959:Antihypertensive Agents / Q000627:therapeutic use; D001552:Benzazepines / Q000627:therapeutic use; D019332:Endothelin-1 / Q000097:blood; D005109:Extracellular Matrix / Q000473:pathology; D006439:Hemodynamics; D006973:Hypertension / Q000235:genetics / Q000473:pathology*; D007150:Immunohistochemistry; D054086:KATP Channels; D007668:Kidney / Q000473:pathology*; D007674:Kidney Diseases / Q000209:etiology* / Q000473:pathology / Q000517:prevention & control*; D007677:Kidney Function Tests; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists*; D011437:Propylamines / Q000627:therapeutic use*; D051381:Rats; D011918:Rats, Inbred SHR; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016212:Transforming Growth Factor beta / Q000097:blood; D053773:Transforming Growth Factor beta1
D018528:ATP-Binding Cassette Transporters; D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; D001552:Benzazepines; D019332:Endothelin-1; D054086:KATP Channels; C502260:N-(1-methylethyl)-1,1,2-trimethylpropylamine; D024661:Potassium Channels, Inwardly Rectifying; D011437:Propylamines; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C092520:uK-ATP-1 potassium channel; D000804:Angiotensin II; C044946:benazepril