Journal ArticleDOI
Targeting hypertension with a new adenosine triphosphate-sensitive potassium channel opener iptakalim.
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TLDR
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 KATP channels expressed in the endothelium.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.read more
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References
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Journal ArticleDOI
Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle.
TL;DR: In arterial rings the vasorelaxing actions of the drugs diazoxide, cromakalim, and pinacidil and the hyperpolarizing actions of vasoactive intestinal polypeptide and acetylcholine were blocked by inhibitors of the ATP-sensitive K+ channels, suggesting that all these agents may act through a common pathway in smooth muscle by opening ATP- sensitivity channels.
Journal ArticleDOI
KATP channels as molecular sensors of cellular metabolism.
TL;DR: In responding to cytoplasmic nucleotide levels, ATP-sensitive potassium (KATP) channel activity provides a unique link between cellular energetics and electrical excitability, which has led to detailed structural and kinetic models that define the molecular basis of channel activity.
Journal ArticleDOI
Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea‐sensitive but ATP‐insensitive K+ channel.
Mitsuhiko Yamada,Shojiro Isomoto,Shigeto Matsumoto,Chikako Kondo,Takashi Shindo,Yoshiyuki Horio,Yoshihisa Kurachi +6 more
TL;DR: The K+ channel composed of the sulphonylurea receptor 2B and an inwardly rectifying K+Channel subunit Kir6.1 is not a classical ATP‐sensitive K+channel but closely resembles the nucleotide diphosphate‐dependent K+ channels in vascular smooth muscle cells.
Journal ArticleDOI
The essential role of the Walker A motifs of SUR1 in K‐ATP channel activation by Mg‐ADP and diazoxide
TL;DR: The results indicate that the WA lysine of NBD1 (but not NBD2) is essential for activation of K‐ATP currents by diazoxide, and Mutant currents were slightly more sensitive to ATP than wild‐type currents.
Journal ArticleDOI
K(+) channels as therapeutic drug targets.
TL;DR: Progress toward identifying selective K(+) channel modulators has been severely hampered by the need to use native currents and primary cells in the drug-screening process, but an understanding of the molecular composition of many important native K(-) currents has begun to emerge.