Targeting Hypertension With a New Adenosine Triphosphate–sensitive Potassium Channel Opener Iptakalim

Abstract

Hypertension is the most common cardiovascular disease. The discovery of the antihypertensive action of adenosine triphosphate-sensitive potassium (K(ATP)) channel openers was a significant advance in the treatment of hypertension. Iptakalim is a novel K(ATP) channel opener with a unique chemical structure that differs from other K(ATP) openers. Among the 3 different subtypes of K(ATP) channels heterologously expressed in human embryonic kidney cells and Xenopus oocytes, iptakalim exhibits significant selectivity for SUR2B/Kir6.1 channels, mild effects on SUR2A/Kir6.2 channels, and fails to open SUR1/Kir6.2 channels. Iptakalim is a more potent activator of the SUR2B/Kir6.1 subtype of K(ATP) channels than diazoxide and pinacidil, the 2 most commonly studied K(ATP) channel openers. Iptakalim selectively produces arteriolar vasodilation with essentially no effect on the capacitance vessels. It can preferentially relax arterioles and small arteries, without affecting large arteries. Furthermore, iptakalim strongly lowers the blood pressure of hypertensive rodents and humans but has little effect on normotensive rodents and humans. Selective antihypertensive action is not observed with pinacidil or diazoxide and may be due to the high selectivity of iptakalim for the SUR2B/Kir6.1 subtype of K(ATP) channels, as well as its selective relaxation of resistance vessels. In pulmonary arterial smooth muscle cells, iptakalim inhibits the increase of cytoplasmic free Ca2+ concentration, as well as cell proliferation induced by endothelin-1. Furthermore, iptakalim has exerted protective effects against hypertensive damage to target organs in rats and improves endothelial dysfunction associated with cardiovascular diseases by selective activation of the SUR2B/Kir6.1 subtype of K(ATP) channels expressed in the endothelium. Clinical trials of iptakalim in the treatment of mild-moderate hypertension have been completed in China. In additional to strong antihypertensive efficacy, iptakalim seems to have a favorable safety and tolerability profile. Iptakalim is a promising new generation antihypertensive drug.

Chemerin/ChemR23 signaling axis is involved in the endothelial protection by KATP channel opener iptakalim

“…In aortic endothelial cells, K ATP channels consist of a heteromultimeric complex of Kir6.1, Kir6.2, and SUR2B subunits [19] . Glibenclamide and iptakalim bind with different sites on the regulatory subunit, the sulfonylurea receptor [20] . However, some investigators reported that chemerin expression and secretion were enhanced in lupus erythematosus dermal endothelial cells and in interleukin-1β-stimulated adipocytes [13,21] .…”

Association of the antihypertensive response of iptakalim with KCNJ11 (Kir6.2 gene) polymorphisms in Chinese Han hypertensive patients

“…KCNJ11 E23K polymorphisms may also affect therapeutic efficacy of repaglinide [26,27] . Iptakalim exhibits mild effects on SUR2A/Kir6.2 channels [8] . It is possible that the different composition of Kir6.2 pore-forming proteins might in part account for the different SBP response to iptakalim in Chinese Han hypertensive patients.…”

“…Among the 3 different subtypes of K ATP channels heterologously expressed in human embryonic kidney cells and Xenopus oocytes, iptakalim exhibits significant selectivity for SUR2B/Kir6.1 channels, mild effects on SUR2A/ Kir6. 2 [8] .…”

“…It can produce long-lasting hypotensive effects without tolerance. At the same time it exertes a protective effect against hypertensive damage to target organs [8][9][10][11][12][13][14][15] . Iptakalim is an effective and well tolerated antihypertensive drug.…”

A new antihypertensive drug ameliorate insulin resistance

“…Abundant previous pharmacological studies have demonstrated that iptakalim is a highly selective K ATP channel opener, which can preferentially relax small arteries and effectively reduce blood pressure [10,11] . Another article published in Acta Pharmacologica Sinica suggested that iptakalim, via activating K ATP channels, enhances the endothelial chemerin/ChemR23 axis and NO production and thus improves endothelial function [12] .…”