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

Abstract

Abstract. Iptakalim is a novel K ATP 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.

K ATP Channels and Cardiovascular Disease

“…Importantly, SUR2 −/− mice treated with the Ca channel blocker nifedipine exhibit a reduction in coronary artery vasospasm, implicating abnormally elevated [Ca 2+ ] i due to loss of hyperpolarizing K ATP current as causal in the hypercontractility 137 . Collectively, these K ATP -null mice recapitulate clinical features of the human disorder of Prinzmetal (or variant) angina, but several studies have failed to demonstrate any association of human coronary vasospasm or hypertension with LOF mutations in Kir6.1 or SUR2 149,150 , even though linkage analysis indicates that there are associated genes within the same locus as Kir6.1 and SUR2 151 .…”

Adenosine Triphosphate-Sensitive Potassium Currents in Heart Disease and Cardioprotection

“…SUR2 −/− mice treated with the Ca 2+ channel blocker nifedipine exhibit a reduction in coronary artery vasospasm, implicating abnormally elevated [Ca 2+ ] i due to loss of hyperpolarizing K ATP current as causal in the hypercontractility 66 . Collectively, these K ATP -null mice recapitulate clinical features of the human disorder of Prinzmetal (or variant) angina, but several studies have failed to demonstrate any association of human coronary vasospasm or hypertension with LOF mutations in Kir6.1 or SUR2 67,68 , even though linkage analysis indicates that there are associated genes within the same locus as Kir6.1 and SUR2 69 .…”

Association between potassium channel SNPs and essential hypertension in Xinjiang Kazak Chinese patients

“…The K ATP channel is an inward rectifier K + channel that is gated by intracellular nucleotides, ATP and adenosine 5-diphosphate ( 15 ). It is widely distributed in excitatory tissues, including skeletal cells, VSMCs and neurons, and non-excitatory tissues including renal tubular epithelial cells and oocytes ( 16 , 17 ). Furthermore, the K ATP channel in the smooth muscle cells is composed of the inward-rectifier K + ion channel protein Kir6.2 subunit, the high affinity sulfonylurea receptor (SUR) subunits SUR2B and additional components ( 15 ), and is important in the response to stress and changes in blood pressure ( 18 , 19 ).…”