Activation of SUR2B/Kir6.1 subtype of adenosine triphosphate-sensitive potassium channel improves pressure overload-induced cardiac remodeling via protecting endothelial function.
We sought to explore new strategies targeting SUR2B/Kir6.1, a subtype of adenosine triphosphate (ATP)-sensitive potassium channels (KATP), against pressure overload-induced heart failure. The effects of natakalim, a SUR2B/Kir6.1 selective channel opener, on progression of cardiac remodeling were investigated. Pressure overload-induced heart failure was induced in Wistar rats by abdominal aortic banding. The effects of natakalim (1, 3, and 9 mg·kg⁻¹·d⁻¹ for 10 weeks) on myocardial hypertrophy and heart failure, cardiac histology, vasoactive compounds, and gene expression were assessed. Ten weeks after the onset of pressure overload, natakalim treatment potently inhibited cardiac hypertrophy and prevented heart failure. Natakalim remarkably inhibited the changes of left ventricular hemodynamic parameters and reversed the increase of heart mass index, left ventricular weight index, and lung weight index. Histological examination demonstrated that there was no significant hypertrophy or fibrosis in pressure-overloaded hearts of natakalim-treated rats. Ultrastructural examination of hearts revealed well-organized myofibrils with mitochondria grouped along the periphery of longitudinally oriented fibers in rats from the natakalim group. The content of serum nitric oxide and plasma prostacyclin was increased, whereas that of plasma endothelin-1 and cardiac tissue hydroxyproline and atrial and B-type natriuretic peptide messenger RNA was downregulated in natakalim-treated rats. Natakalim at 0.01-100 µM had no effects on isolated working hearts derived from Wistar rats; however, natakalim had endothelium-dependent vasodilatory effects on the isolated tail artery helical strips precontracted with norepinephrine. These results indicate that natakalim reduces heart failure caused by pressure overloading by activating the SUR2B/Kir6.1 KATP channel subtype and protecting against endothelial dysfunction.
Tang
Yuan
Y
Department of Cardiovascular Pharmacology, Beijing Institute of Pharmacology and Toxicology, Beijing, China.
Long
Chao-Liang
CL
Wang
Ru-Huan
RH
Cui
Wenyu
W
Wang
Hai
H
D018528:ATP-Binding Cassette Transporters / Q000819:agonists / Q000378:metabolism*; D000498:Allyl Compounds / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D006332:Cardiomegaly / Q000188:drug therapy / Q000209:etiology / Q000503:physiopathology; D002317:Cardiovascular Agents / Q000494:pharmacology* / Q000627:therapeutic use; D004305:Dose-Response Relationship, Drug; D042783:Endothelial Cells / Q000378:metabolism; D019332:Endothelin-1 / Q000097:blood; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D011464:Epoprostenol / Q000097:blood; D006333:Heart Failure / Q000209:etiology / Q000503:physiopathology / Q000517:prevention & control*; D006973:Hypertension / Q000150:complications* / Q000503:physiopathology; D066298:In Vitro Techniques; D054086:KATP Channels; D008297:Male; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D009569:Nitric Oxide / Q000097:blood; D024661:Potassium Channels, Inwardly Rectifying / Q000819:agonists / Q000378:metabolism*; D011437:Propylamines / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar; D011955:Receptors, Drug / Q000819:agonists / Q000378:metabolism*; D064233:Sulfonylurea Receptors; D013623:Tail / Q000098:blood supply; D014665:Vasodilator Agents / Q000494:pharmacology / Q000627:therapeutic use; D020257:Ventricular Remodeling / Q000187:drug effects*
D018528:ATP-Binding Cassette Transporters; D000498:Allyl Compounds; D002317:Cardiovascular Agents; D019332:Endothelin-1; D054086:KATP Channels; D024661:Potassium Channels, Inwardly Rectifying; D011437:Propylamines; D011955:Receptors, Drug; D064233:Sulfonylurea Receptors; D014665:Vasodilator Agents; C556401:natakalim; C092520:uK-ATP-1 potassium channel; D009569:Nitric Oxide; D011464:Epoprostenol