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ATP-Dependent Potassium Channels As a Key Target for the Treatment of Myocardial and Vascular Dysfunction Piero Polleselloa and Alexandre Mebazaab

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ATP-Dependent Potassium Channels As a Key Target for the Treatment of Myocardial and Vascular Dysfunction Piero Polleselloa and Alexandre Mebazaab ATP-dependent potassium channels as a key target for the treatment of myocardial and vascular dysfunction Piero Polleselloa and Alexandre Mebazaab Purpose of review © 2004 Lippincott Williams & Wilkins 1070-5295 The aim of this review is to highlight the most recent and interesting articles on the physiologic properties and functions of ATP-dependent potassium channels in the cardiovascular Introduction system and on the role of the potassium channel openers for ATP-dependent potassium channels (KATP) are inward the treatment of cardiovascular dysfunction. rectifying channels inhibited by physiologic intracellular Recent findings ATP levels. These channels are present in tissue- The initial efforts in the development of potassium channel specific phenotypes in several tissues in the central ner- openers focused on the management of systemic vous system, heart and vasculature, lungs, pancreas, and hypertension. Lately, the range of possible indications for urinary bladder. KATP activity was initially detected at potassium channel openers has increased to include the level of sarcolemmal membrane (sarcK ) and also pulmonary hypertension and stable angina pectoris. The ATP recently at the mitochondrial level (mitoKATP). Potas- discovery of a connection between the mitochondrial sium channel openers (KCOs) are a class of chemically ATP-dependent potassium channels and the phenomenon of diverse agents sharing KATP as their common target. cardiac preconditioning created potential new uses for Their structure-activity relations and therapeutic poten- potassium channel openers in myocardial ischemia, inn tial were recently reviewed by Mannhold [1••], and cur- unstable angina, in preoperative and perioperative settings, rent knowledge on their regulation has been summarized and for the preservation of organs for transplant. by Campbell et al. [2•]. Experimental studies have iden- Summary tified a wide range of possible clinical uses for KCOs, The most recent data on the physiologic roles of sarcolemmal including roles as bronchodilators, vasodilators, and blad- and mitochondrial ATP-dependent potassium channels and the der relaxants [3]. The discovery of the effect of KCOs on pharmacology of potassium channel openers in the cardiac mitochondria and the hypothesis of a connection cardiovascular system are summarized and discussed. Finally, with the phenomenon of cardiac preconditioning created the effects of potassium channel opener drugs including further possibilities for the development of cardioprotec- minoxidil, nicorandil, pinacidil, bimakalin, and levosimendan, a tive applications [4••]. We provide an overview of the dual-action potassium channel opener and calcium sensitizer most recent literature in the field and discuss experi- with inodilator and cardioprotective activity, are discussed. ences in the use of KCOs for the treatment of myocardial and vascular dysfunctions. We also discuss examples of Keywords the use of drugs such as nicorandil and pinacidil as car- ATP-dependent potassium channel openers, therapeutic use, diovascular therapies. Special attention is given to levo- vasodilation, preconditioning, cardioprotection simendan, a novel inotropic drug, which, in addition to a calcium sensitizer effect via binding to troponin C, opens Curr Opin Crit Care 10:436–441. © 2004 Lippincott Williams & Wilkins. both sarcolemmal and mitochondrial KATP [5,6]. a b Orion-Pharma, Cardiovascular and Critical Care, Espoo, Finland, and Department Physiologic roles of KATP in the of Anaesthesiology and Critical Care Medicine, Hopital Lariboisière, Paris, France cardiovascular system Correspondence to Alexandre Mebazaa, Department of Anesthesiology and KATP play important roles in many cellular functions. Critical Care, Hôpital Larboisière, 2 Rue Amboise Paré, 75475 Paris Cedex 10, Such channel activity has been described in the vascu- France E-mail: [email protected] lature muscle cells and in cardiomyocytes at both the sarcolemmal and the mitochondrial levels. Current Opinion in Critical Care 2004, 10:436–441 Sarcolemmal KATP Abbreviations There is strong evidence that sarcKATP in the vascula- AMI acute myocardial infarction ture muscle cells are involved in the maintenance of the KATP ATP-dependent potassium channels sarcKATP sarcolemmal ATP-dependent potassium channels basal vascular tone in the coronary and mesenteric arter- mitoKATP mitochondrial ATP-dependent potassium channels ies and arterioles [7,8]. Furthermore, in conditions of KCO potassium channel opener PCWP pulmonary capillary wedge pressure hypoxia, sarcKATP contribute to the regulation of vascu- 436 ATP-dependent potassium channels Pollesello and Mebazaa 437 lar tone in renal, cerebral, and pulmonary arteries [9]. Pharmacology of potassium channel These channels were rapidly recognized by researchers openers in the cardiovascular system as physiologically important entities and possible phar- The KCOs activate sarcKATP on vascular smooth muscle macologic targets for manipulating the function of vas- cells and cardiac myocytes, leading to potassium ion ef- cular smooth muscle [10,11]. In fact, all the drugs in flux and membrane hyperpolarization, which in turn re- clinical use that are described primarily as KCOs (nico- duce calcium influx and shorten the duration of the ac- randil, diazoxide, minoxidil, and pinacidil) have hyper- tion potential. This results in a negative inotropic effect tension among their therapeutic uses [3]. in cardiomyocytes and vasodilatation of blood vessels [21–23]. KATP is present also on the sarcolemmal membrane of cardiomyocytes. However, 20 years after the discovery of Vasodilatation such channels, many questions about their physiologic or The KCOs have an unusual chemical and structural di- pathophysiologic roles in the cardiac cells remain unre- versity [1••,24,25•,26]. Nevertheless, all have a similar solved, despite the availability of detailed structural in- pharmacologic profile with regard to their vasorelaxant formation and the existence of a broad consensus that effect, as studied in vitro in aorta or coronary artery they bridge bioenergetics to cellular electrical excitabil- preparations. KCO activities in vivo have been reviewed ity [12••,13–16]. Authors generally agree that sarcKATP comprehensively, with particular emphasis on their an- provide a means of linking the electrical activity of the tihypertensive effects [24]. Members of the first genera- cardiomyocyte to its metabolic state. In particular, these tion of drugs such as cromakalim and pinacidil were in- channels modulate the duration of the cardiac action po- tended for the treatment of hypertension but failed to tential [17]. show clear advantages over angiotensin-converting en- zyme inhibitors or calcium antagonists. A brief but comprehensive commentary on recent ad- vances in the identification and function of these chan- An active drug discovery effort in the field and develop- nels in the cardiac tissue is available [18]. The gating ments in the chemistry of KCOs led to the discovery of mechanism of KATP and their function-to-form relation new cromakalin analogues and benzothiazidine deriva- was also recently reviewed [19]. tives, which were shown to be potent vasorelaxant agents. Studies of the vasodilation effect of the KCO Mitochondrial KATP minoxidil have been reviewed [25•–27]. Structural information is lacking for mitoKATP, but there is ample evidence linking channel opening to protection Levosimendan, an inodilator recently introduced for against ischemia-reperfusion injury or apoptosis in car- acute congestive heart failure, opens sarcKATP in vascu- diac myocytes. In their recent review, Garlid et al. [4••] lar smooth muscle, among other effects. The drug has discuss the role of the mitoKATP in cardiac function and been shown to be an active vasodilator in arteries, arte- cardioprotection. The authors conclude that in low- rioles, and veins by opening sarcKATP, thereby exerting energy states, the opening of the channels triggers in- an effect on systemic vascular resistance and organ mi- creased mitochondrial reactive oxygen species produc- crocirculation [28–33]. Interestingly, a comparison be- tion, thereby amplifying a cell-signaling pathway that tween levosimendan and pinacidil on their beneficial ef- leads to gene transcription and cell growth. In high- fect on diastolic coronary flow in isolated perfused heart energy states, the opening of mitoKATP prevents the ma- showed that the two drugs are inhibited by gliben- trix contraction that would otherwise occur during high clamide but in different modes. The authors hypoth- rates of electron transport. MitoKATP-mediated mito- esized that the two drugs do not share the same binding chondrial volume regulation, in turn, prevents disruption side on sarcKATP [28]. of mitochondrial structure and function and facilitates efficient energy transfers between mitochondria and Antiarrhythmic effects myofibrillar ATPases. Whether or not opening KATP (either sarcKATP or mitoKATP, selectively or otherwise) contributes to an an- Reperfusion of the heart after a period of ischemia leads tiarrhythmic effect in ischemia or during reperfusion re- to the opening of a nonspecific pore in the inner mi- mains unresolved at present. In a recent study by Fisch- tochondrial membrane, known as the mitochondrial bach et al. [34•], selective opening of sarcKATP was permeability transition pore. This transition causes associated with some potential for ventricular arrhyth- mitochondria to become uncoupled
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