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ATP-Sensitive Potassium Channels: a Review of Their Cardioprotective Pharmacology

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ATP-Sensitive Potassium Channels: a Review of Their Cardioprotective Pharmacology J Mol Cell Cardiol 32, 677±695 (2000) doi:10.1006/jmcc.2000.1111, available online at http://www.idealibrary.com on ATP-Sensitive Potassium Channels: A Review of their Cardioprotective Pharmacology Gary J. Grover1 and Keith D. Garlid2 1 Cardiovascular and Metabolic Diseases Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, N.J. 08543-4000, USA; 2 Department of Biochemistry, and Molecular Biology, Oregon Graduate Institute of Science and Technology, 200000 NW Walker Road, Beaverton, Oregon 97006-8291 (Received 8 September 1999, accepted in revised form 27 January 2000) G. J. G K. A. G. ATP-Sensitive Potassium Channels: A Review of their Cardioprotective Phar- macology. Journal of Molecular and Cellular Cardiology (2000) 32, 677±696. ATP-sensitive potassium channels (KATP) have been thought to be a mediator of cardioprotection for the last ten years. Signi®cant progress has been made in learning the pharmacology of this channel as well as its molecular regulation with regard to cardioprotection. KATP openers as a class protect ischemic/reperfused myocardium and appear to do so by conservation of energy. The reduced rate of ATP hydrolysis during ischemia exerted by these openers is not due to a cardioplegic effect and is independent of action potential shortening. Compounds have been synthesized which retain the cardioprotective effects of ®rst generation KATP openers, but are devoid of vasodilator and cardiac sarcolemmal potassium outward currents. These results suggest receptor or channel subtypes. Recent pharmacologic and molecular biology studies suggest the activation of mitochondrial KATP as the relevant cardioprotective site. Implications of these results for future drug discovery and preconditioning are discussed. 2000 Academic Press K W: ATP-sensitive potassium channels; Mitochondria; Heart; Myocardial Ischemia, Preconditioning. Introduction created enthusiasm for further studying the thera- peutic potential of KATP for the treatment of acute Recently several lines of investigation concerning myocardial ischemia. ATP-sensitive potassium channels (KATP) have con- Recent studies have further fueled interest in verged, suggesting that KATP may be an important KATP by suggesting differential importance of KATP therapeutic target for the treatment of acute myo- subtypes. These studies show that cardioprotection cardial ischemia. Pharmacologic studies starting may not be mediated by sarcolemmal KATP currents, in 1989 showed KATP openers to exert profound suggesting an intracellular site of action (mito- cardioprotective effects in numerous mammalian chondria). Therefore, it is possible to develop agents species. The results of this work were made even which can selectively open the KATP subtype of more relevant by later ®ndings showing pre- interest. conditioning to be mediated (at least in part) by With the heightened interest created by the stud- KATP activation. Therefore, pharmacologic KATP ac- ies described above, it would be useful to review tivation would be expected to mimic an endogenous what is presently known about KATP , particularly cardioprotective mechanism that also seems to be the recent insights into the molecular biology and operative in man. These converging results have regulation of these channels and how these ®ndings Please address all correspondence to: Gary J. Grover, Ph.D., Metabolic Diseases Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, PO Box 4000, Princeton, NJ 08543-4000, USA. Phone: +609 252-5139; Fax: +609 252-6609. 0022±2828/00/040677+19 $35.00/0 2000 Academic Press 678 G. J. Grover and K. D. Garlid can help us understand their cardioprotective phar- hyperpolarize or depolarize pancreatic b-cells re- macology. We will place some emphasis on the spectively.11,12 These channels are important for newly hypothesized role of mitochondrial channels setting membrane potential in pancreatic b-cells in cardioprotection. In this review, our heightened and the closure of a few channels (as seen by an knowledge of the nature of the molecular regulation increase in extracellular glucose) will depolarize of KATP will be integrated with pharmacologic and these cells and therefore stimulate insulin se- 13,14 physiologic studies so that the reader can better cretion. Sulfonylurea KATP blockers such as gli- understand the complex matrix of studies leading benclamide (glyburide) have utility for treating type to our preset understanding of the role of KATP II diabetes and increase insulin secretion by de- b and pharmacologic modulators of this channel in polarizing -cell membranes. Opening of KATP in myocardial ischemia. smooth muscle cells would be expected to hy- perpolarize sarcolemmal membranes and therefore 15 cause relaxation. Most KATP openers are potent vasodilators and smooth muscle relaxants and their Properties and Molecular Biology of earliest proposed clinical uses were asthma, hyper- Plasma Membrane KATP tension, and urinary incontinence. The role of KATP in normal myocardium is presently unclear, al- 1 KATP were ®rst described by Noma in cardiac vent- though a role in ischemic conditions is well known ricular myocytes. These channels are of inter- and will be discussed in full detail in this review. mediate conductance and are inhibited by Opening cardiac KATP will, of course, enhance a physiologic concentrations of ATP. KATP were ori- repolarizing potassium current and therefore cause 16 ginally termed ATP-dependent potassium channels action potential duration (APD) shortening. KATP because ATP was the ®rst modulator studied, al- are thought to be involved with the early re- though other endogenous modulators have since polarization seen in ischemic cardiac tissue.17±19 This been found and therefore they are now referred to early repolarization is associated with the ªinjury as ªATP-sensitiveº channels. KATP are inhibited by currentº of ischemia which is the basis for ST- physiologic levels of ATP and, as ATP falls, channel segment shifts and it is thought that KATP contribute, open probability increases (although the degree of at least in part, to this electrophyiologic ab- ATP reduction needed would rarely be seen under normality.17,20 21±23 physiologic conditions; see review by Edwards and KATP is a complex of two different proteins. 2 Weston ). KATP have been found to be modulated One subunit is an inwardly-rectifying potassium by pH, fatty acids, NO, SH-redox state, various channel (Kir) subunit and it is thought that four nucleotides, G-proteins and various ligands (ad- of these combine to form the channel pore. Two enosine, acetylcholine, benzopyrans, cyano- types of Kir (Kir6.1 and Kir6.2) are thought to be 2±6 7 guanidines, etc.). Larsson et al. showed that associated with KATP at this time. The sulfonylurea pancreatic KATP are opened by long-chain acyl CoA receptor (SUR) is the protein which confers a regu- esters, and Paucek and Garlid (unpublished results) latory role as well as sensitivity of the channel to have observed similar opening of cardiac sar- pharmacologic agents and ATP.22 SUR is a member colemmal channels by acyl CoA esters. KATP appear of the ATP-binding cassette protein superfamily, to be linked to the metabolic state of the cell and also called ABC transporters and is related to CFTR have therefore also been labeled as metabolicaly channels (cystic ®brosis transmembrane regulator, 24 regulated channels. KATP are expressed in numerous also glyburide inhibitable). This ATP transporter, tissue types including skeletal muscle, brain, kidney, CFTR, releases ATP, which interacts with a pur- heart, pancreatic b-cells, and smooth muscle.1,2,8±10 inergic receptor subtype which then opens chloride KATP are thought to serve as a link between meta- channels. SUR is a related ATP permeant protein. bolism and either secretory activity (insulin, brain) SUR1 is highly expressed in pancreatic b-cells, while or electro-mechanical coupling in muscle. KATP are SUR2 is highly expressed in cardiac and skeletal also found in the inner mitochondrial membrane, muscle cells.25 It is unknown how many ways and these will be described in a later section. these different Kirs and SURs can interact, but data In the case of pancreatic b-cells, insulin secretion suggest different combinations in different tissue is controlled by glucose metabolism. KATP opening types. Currently, it is thought that Kir6.2 and SUR2 23 inhibits secretion due to hyperpolarization while form cardiac sarcolemmal KATP . In the study by reduction of channel activity will increase insulin Inagaki et al.,23 diazoxide did not activate the sar- secretion (see review by Edwards and Weston2). colemmal cardiac channel while it did open pan- Pharmacologic openers and blockers of KATP will creatic KATP , which is thought to be formed by ATP-Sensitive Potassium Channels 679 21 Kir6.2 and SUR1. This ®nding suggests the ex- gene-related peptide, adenosine (adenosine A2 re- citing possibility of tissue selectivity, which has ceptor subtype), prostacyclin and b-adrenoceptor already been strongly suggested on the basis of agonists,6,30,31 although some of these effects could pharmacologic evidence. The excellent agreement be due to indirect effects of these various agonists.32 of the pharmacology and molecular biologic data Recent data33 show that extracellular ATP can on KATP (particularly with regard to the phar- enhance KATP current via a P2 receptor, through macology of diazoxide) will be discussed later in activation of adenylyl cyclase, although this is
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