Mutational analysis of the Kir6.1 gene in Chinese hypertensive patients treated with the novel ATP-sensitive potassium channel opener iptakalim

Duan,Ruifeng; Cui,Wenyu; Wang,Hai

doi:10.3892/etm.2011.259

Mutational analysis of the Kir6.1 gene in Chinese hypertensive patients treated with the novel ATP-sensitive potassium channel opener iptakalim

Authors:
- Ruifeng Duan
- Wenyu Cui
- Hai Wang
View Affiliations

Affiliations: Cardiovascular Drug Research Center, Institute of Health and Environmental Medicine, Academy of Military Medical Sciences, Beijing 100850, P.R. China
Published online on: April 28, 2011 https://doi.org/10.3892/etm.2011.259
Pages: 757-760

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Iptakalim is a novel KATP opener with antihypertensive properties. The Kir6.1 gene is one of the candidate genes that may influence the response to iptakalim in hypertensive patients. We aimed to ascertain whether a mutation in the coding region of the Kir6.1 gene is present in Chinese Han hypertensive patients. The study population included 162 Chinese Han hypertensive patients (81 men and 81 women with a mean age of 55±9 years). Mutational analysis of the coding region of Kir6.1 was performed using PCR-SSCP and direct sequencing. No missense or nonsense mutations were found in these samples, while a single base pair substitution (C to T) at nucleotide position 111 in exon 2 of the coding region was noted in four patients (one female and three male), who were all heterozygous for the mutation. This C to T substitution did not result in an amino acid substitution (Ile37Ile, silent mutation). In the remaining 158 patients, no mutation was detected. The blood pressure of these four patients carrying the I37I polymorphism was well controlled by iptakalim. No mutation that alters the primary structure of Kir6.1 was detected in Chinese Han hypertensive patients. The results indicate that abnormality in the primary structure of Kir6.1 is not involved in the genetic pathogenesis of essential hypertension in Chinese Han hypertensive patients and has no effect on the BP response to iptakalim treatment.

View Figures

View References

1.	Zhang S, Mao G, Zhang Y, et al: Association between human atrial natriuretic peptide Val7Met polymorphism and baseline blood pressure, plasma trough irbesartan concentrations, and the antihypertensive efficacy of irbesartan in rural Chinese patients with essential hypertension. Clin Ther. 27:1774–1784. 2005. View Article : Google Scholar
2.	Trotta R, Donati MB and Iacoviello L: Trends in pharmacogenomics of drugs acting on hypertension. Pharmacol Res. 49:351–356. 2004. View Article : Google Scholar : PubMed/NCBI
3.	Arnett DK and Claas SA: Pharmacogenetics of antihypertensive treatment: detailing disciplinary dissonance. Pharmacogenomics. 10:1295–1307. 2009. View Article : Google Scholar : PubMed/NCBI
4.	Sherva R, Ford CE, Eckfeldt JH, Davis BR, Boerwinkle E and Arnett DK: Pharmacogenetic effect of the stromelysin (MMP3) polymorphism on stroke risk in relation to antihypertensive treatment: the genetics of hypertension associated treatment study. Stroke. 42:330–335. 2011. View Article : Google Scholar
5.	Duarte JD, Lobmeyer MT, Wang Z, et al: Lack of association between polymorphisms in STK39, a putative thiazide response gene, and blood pressure response to hydrochlorothiazide. Pharmacogenet Genomics. 20:516–519. 2010. View Article : Google Scholar : PubMed/NCBI
6.	Suonsyrjä T, Donner K, Hannila-Handelberg T, Fodstad H, Kontula K and Hiltunen TP: Common genetic variation of beta1- and beta2-adrenergic receptor and response to four classes of antihypertensive treatment. Pharmacogenet Genomics. 20:342–345. 2010.PubMed/NCBI
7.	Nichols CG: KATP channels as molecular sensors of cellular metabolism. Nature. 440:470–476. 2006. View Article : Google Scholar : PubMed/NCBI
8.	Wang H, Zhang YL and Chen YP: Targeting small arteries of hypertensive status with novel ATP-sensitive potassium channel openers. Curr Vasc Pharmacol. 3:119–124. 2005. View Article : Google Scholar : PubMed/NCBI
9.	Wang H, Long CL and Zhang YL: A new ATP-sensitive potassium channel opener reduces blood pressure and reverses cardiovascular remodeling in experimental hypertension. J Pharmacol Exp Ther. 312:1326–1333. 2005. View Article : Google Scholar
10.	Gao S, Long CL, Wang RH and Wang H: K_ATP activation prevents progression of cardiac hypertrophy to failure induced by pressure overload via protecting endothelial function. Cardiovasc Res. 83:444–456. 2009.
11.	Wang H, Tang Y, Wang L, Long CL and Zhang YL: ATP-sensitive potassium channel openers and 2,3-dimethyl-2-butylamine derivatives. Curr Med Chem. 14:133–155. 2007. View Article : Google Scholar : PubMed/NCBI
12.	Chen YP, Qiu CR and Wang H: Cardiovascular pharmacological characterization of novel 2,3-dimethyl-2-butylamine derivatives in rats. Life Sci. 75:2131–2142. 2004. View Article : Google Scholar : PubMed/NCBI
13.	Chen YP, Cui WY and Wang H: Selective actions of iptakalim on the subtypes of K_ATP channels. Chin Pharmacol Bull. 22:278–284. 2006.
14.	Long CL, Qin XC, Pan ZY, et al: Activation of ATP-sensitive potassium channels protects vascular endothelial cells from hypertension and renal injury induced by hyperuricemia. J Hypertens. 26:2326–2338. 2008. View Article : Google Scholar : PubMed/NCBI
15.	Duan RF, Cui WY, Gao HY, et al: Correlation between ACE gene I/D polymorphism and clinical efficacy of iptakalim in Chinese Han hypertensive population. Chin J Clin Pharmacol Ther. 15:961–966. 2010.
16.	Evans WE and Relling MV: Pharmacogenomics: translating functional genomics into rational therapeutics. Science. 286:487–491. 1999. View Article : Google Scholar : PubMed/NCBI
17.	Bettinaglio P, Galbusera A, Caprioli J, et al: Single strand conformation polymorphism (SSCP) as a quick and reliable method to genotype M235T polymorphism of angiotensinogen gene. Clin Biochem. 35:363–368. 2002. View Article : Google Scholar : PubMed/NCBI
18.	Lu Jun, Jiang Shan, Ye Song and Li Chaopin: Detecting drug resistant genetic mutation among pneumoconiosis patients complicated with tuberculosis in Mycobacterium tuberculosis L-forms application of PCR-SSCP technique in Huainan mining district. J Nanjing Med Univ. 3:180–184. 2007.
19.	Tomita H, Sasaki S, Osanai T, et al: Mutational analysis of Kir6.1 in Japanese patients with coronary spastic angina. Int J Mol Med. 18:589–591. 2006.
20.	Emanuele E, Falcone C, Carabela M, et al: Absence of Kir6.1/ KCNJ8 mutations in Italian patients with abnormal coronary vasomotion. Int J Mol Med. 12:509–512. 2003.PubMed/NCBI
21.	Haïssaguerre M, Chatel S, Sacher F, et al: Ventricular fibrillation with prominent early repolarization associated with a rare variant of KCNJ8/KATP channel. J Cardiovasc Electrophysiol. 20:93–98. 2009.PubMed/NCBI
22.	Kane GC, Lam CF, O’Cochlain F, et al: Gene knockout of the KCNJ8-encoded Kir6.1 K(ATP) channel imparts fatal susceptibility to endotoxemia. FASEB J. 20:2271–2280. 2006. View Article : Google Scholar : PubMed/NCBI
23.	Pan Z, Huang J, Cui W, Long C, Zhang Y and Wang H: Targeting hypertension with a new adenosine triphosphate-sensitive potassium channel opener iptakalim. J Cardiovasc Pharmacol. 56:215–228. 2010. View Article : Google Scholar : PubMed/NCBI