title: Apamin-Sensitive Small Conductance Calcium-Activated Potassium Channels were Negatively Regulated by Captopril in Volume-Overload Heart Failure Rats.
abstract: In heart failure (HF), the malignant arrhythmias occur frequently; a study demonstrated that upregulation of I KAS resulted in recurrent spontaneous ventricular fibrillation in HF. However, the regulation of SK channels was poorly understood. The activation of SK channels depended on [Ca(2+)]i and PP2A; studies suggested that angiotensin II can regulate them. So, we hypothesized that in HF, the excess of angiotensin may regulate the SK channels and result in the remodeling of SK channels. To test the hypothesis, we used volume-overload-induced HF rat model, treated with captopril, performed whole-cell patch clamp to record apamin-sensitive currents (I KAS), and I-V curve was studied. The sensitivity of I KAS to [Ca(2+)]i was also explored by setting various [Ca(2+)]i (10, 100, 500, 900, 1000, and 10,000 nM), and the steady-state Ca(2+) response of I KAS was attained and performed Hill fitting with the equation (y = 1/[1 + (EC50/x) (n) ]). Immunofluorescent staining, real-time PCR, Western blot were also carried out to furtherly investigate the underlying molecular mechanisms of the regulation. Captopril significantly decreased the mean density of I KAS when [Ca(2+)]i was 500, 900, 1000, and 10000 nM. The Hill fitting showed significantly different EC50 values and the Hill coefficients and showed captopril significantly shifted rightward the steady-state Ca(2+) response of I KAS. The results of real-time PCR and Western blot demonstrated captopril decreased the mRNA and protein expression of SK3 channels. Captopril significantly downregulated the sensitivity of SK channels to [Ca(2+)]i and the SK3 channels expression in HF, and reversed the SK channels remodeling.
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, School of Medicine, Xian Jiaotong University, 157, Fifth West Road, Xi'an, 710004, Shaanxi, China.
authors.forename: Bai
authors.initials: B
authors.lastname: Hongyuan
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, School of Medicine, Xian Jiaotong University, 157, Fifth West Road, Xi'an, 710004, Shaanxi, China.
authors.forename: Dong
authors.initials: D
authors.lastname: Xin
authors.affiliation: Department of Cardiology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, 277, West Yanta Road, Xi'an, 710061, Shaanxi, China.
authors.forename: Zhang
authors.initials: Z
authors.lastname: Jingwen
authors.affiliation: Department of Cardiology, First Affiliated Hospital, School of Medicine, Xi'an Jiaotong University, 277, West Yanta Road, Xi'an, 710061, Shaanxi, China.
authors.forename: Gao
authors.initials: G
authors.lastname: Li
authors.affiliation: Department of Cardiology, Second Affiliated Hospital, School of Medicine, Xian Jiaotong University, 157, Fifth West Road, Xi'an, 710004, Shaanxi, China. ni.guo@stu.xjtu.edu.cn.
authors.forename: Ni
authors.initials: N
authors.lastname: Yajuan
mesh_terms: D000806:Angiotensin-Converting Enzyme Inhibitors / Q000494:pharmacology*; D000818:Animals; D000959:Antihypertensive Agents / Q000494:pharmacology*; D001030:Apamin / Q000633:toxicity*; D002118:Calcium / Q000378:metabolism; D002216:Captopril / Q000494:pharmacology*; D004195:Disease Models, Animal; D004452:Echocardiography; D015870:Gene Expression; D006333:Heart Failure / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D006439:Hemodynamics; D008297:Male; D032383:Myocytes, Cardiac / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000235:genetics / Q000378:metabolism*
chemical_list: D000806:Angiotensin-Converting Enzyme Inhibitors; D000959:Antihypertensive Agents; C496901:Kcnn3 protein, rat; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; D002216:Captopril; D002118:Calcium
keywords: Captopril; Downregulation; HF; SK channels