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      Altered K ATP Channel Subunits Expression and Vascular Reactivity in Spontaneously Hypertensive Rats With Age

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          Abstract:

          ATP-sensitive potassium (K ATP) channels link membrane excitability to metabolic state to regulate a series of biological activities including the vascular tone. However, their ability to influence hypertension is controversial. Here we aim to investigate possible alteration of K ATP channel in vascular smooth muscles (VSMs) during hypertension development process. In this study, we used 16-week-old spontaneously hypertensive rats (SHRs), 49-week-old SHRs, and their age-matched Wistar-Kyoto rats to study the expression of VSM K ATP subunits at the mRNA and protein level and the function of VSM K ATP by observing the relaxation reactivity of isolated aorta rings to K ATP modulators. We found that the expression of VSM K ATP subunits Kir6.1 and sulfonylurea receptor (SUR2B) decreased during hypertension. Moreover, the expression of SUR2B and Kir6.1 in 49-week-old SHRs decreased much more than that in 16-week-old SHRs. Furthermore, the aorta rings of 49-week-old SHRs showed lower reactivity to diazoxide than 16-week-old SHRs. This study suggests that K ATP channels in VSM subunits Kir6.1 and SUR2B contribute to modify the functionality of this channel in hypertension with age.

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          A family of sulfonylurea receptors determines the pharmacological properties of ATP-sensitive K+ channels.

          We have cloned an isoform of the sulfonylurea receptor (SUR), designated SUR2. Coexpression of SUR2 and the inward rectifier K+ channel subunit Kir6.2 in COS1 cells reconstitutes the properties of K(ATP) channels described in cardiac and skeletal muscle. The SUR2/Kir6.2 channel is less sensitive than the SUR/Kir6.2 channel (the pancreatic beta cell KATP channel) to both ATP and the sulfonylurea glibenclamide and is activated by the cardiac K(ATP) channel openers, cromakalim and pinacidil, but not by diazoxide. In addition, SUR2 binds glibenclamide with lower affinity. The present study shows that the ATP sensitivity and pharmacological properties of K(ATP) channels are determined by a family of structurally related but functionally distinct sulfonylurea receptors.
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            Muscle KATP channels: recent insights to energy sensing and myoprotection.

            ATP-sensitive potassium (K(ATP)) channels are present in the surface and internal membranes of cardiac, skeletal, and smooth muscle cells and provide a unique feedback between muscle cell metabolism and electrical activity. In so doing, they can play an important role in the control of contractility, particularly when cellular energetics are compromised, protecting the tissue against calcium overload and fiber damage, but the cost of this protection may be enhanced arrhythmic activity. Generated as complexes of Kir6.1 or Kir6.2 pore-forming subunits with regulatory sulfonylurea receptor subunits, SUR1 or SUR2, the differential assembly of K(ATP) channels in different tissues gives rise to tissue-specific physiological and pharmacological regulation, and hence to the tissue-specific pharmacological control of contractility. The last 10 years have provided insights into the regulation and role of muscle K(ATP) channels, in large part driven by studies of mice in which the protein determinants of channel activity have been deleted or modified. As yet, few human diseases have been correlated with altered muscle K(ATP) activity, but genetically modified animals give important insights to likely pathological roles of aberrant channel activity in different muscle types.
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              KATP Channels in the Cardiovascular System.

              KATP channels are integral to the functions of many cells and tissues. The use of electrophysiological methods has allowed for a detailed characterization of KATP channels in terms of their biophysical properties, nucleotide sensitivities, and modification by pharmacological compounds. However, even though they were first described almost 25 years ago (Noma 1983, Trube and Hescheler 1984), the physiological and pathophysiological roles of these channels, and their regulation by complex biological systems, are only now emerging for many tissues. Even in tissues where their roles have been best defined, there are still many unanswered questions. This review aims to summarize the properties, molecular composition, and pharmacology of KATP channels in various cardiovascular components (atria, specialized conduction system, ventricles, smooth muscle, endothelium, and mitochondria). We will summarize the lessons learned from available genetic mouse models and address the known roles of KATP channels in cardiovascular pathologies and how genetic variation in KATP channel genes contribute to human disease.
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                Author and article information

                Journal
                J Cardiovasc Pharmacol
                J. Cardiovasc. Pharmacol
                jcvp
                Journal of Cardiovascular Pharmacology
                Journal of Cardiovascular Pharmacology
                0160-2446
                1533-4023
                August 2016
                01 April 2016
                : 68
                : 2
                : 143-149
                Affiliations
                [* ]Department of Cardiology, Chinese PLA General Hospital, Beijing, China; and
                []Research and Technology Service Center, 302 Hospital of PLA, Beijing, China.
                Author notes
                Reprints: Qinglei Zhu, PhD, Department of Cardiology, Chinese PLA General Hospital, 28 Fuxing Rd, Beijing 100853, China (e-mail: qlzhu@ 123456yahoo.com ).
                Article
                JCVP-15-790 00006
                10.1097/FJC.0000000000000394
                4979625
                27035370
                485cc573-09d3-4b2c-905a-4dd0c6d889bd
                Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved.

                This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND), which permits downloading and sharing the work provided it is properly cited. The work cannot be changed in any way or used commercially.

                History
                : 11 December 2015
                : 12 March 2016
                Categories
                Original Article
                Custom metadata
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                katp channel,hypertension,mitokatp,diazoxide,in vitro
                katp channel, hypertension, mitokatp, diazoxide, in vitro

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