ATP-sensitive Potassium Channel Opener Research Articles

P.2.d.001 Dexamethasone-induced anhedonia: antidepressant reversion, hippocampal BDNF level, and role of glucocorticoids receptors

Cerebrovascular and cardiovascular diseases are stated as important risk factors of vascular dementia (VaD) and other cognitive disorders. In the central nervous system, melatonin (MT1/MT2) as well as serotonin subtype 2C (5-HT2C) receptors is pharmacologically associated with various neurological disorders. Brain mitochondrial potassium channels have been reported for their role in neuroprotection. This study has been structured to investigate the role of agomelatine, a melatonergic MT1/MT2 agonist and nicorandil, a selective ATP sensitive potassium (KATP) channel opener in renal artery ligation (two-kidney-one-clip: 2K1C) hypertension induced endothelial dysfunction, brain damage and VaD. 2K1C-renovascular hypertension has increased mean arterial blood pressure (MABP), impaired memory (elevated plus maze and Morris water maze), endothelial function, reduced serum nitrite/nitrate and increased brain damage (TTC staining of brain sections). Furthermore, 2K1C animals have shown high levels of oxidative stress in serum (increased thiobarbituric acid reactive species—TBARS with decreased levels of glutathione—GSH, superoxide dismutase—SOD and catalase—CAT), in the aorta (increased aortic superoxide anion) and in the brain (increased TBARS with decreased GSH, SOD and CAT). 2K1C has also induced a significant increase in brain inflammation (myeloperoxidase—MPO levels), acetylcholinesterase activity (AChE) and calcium levels. Impairment in mitochondrial complexes like NADH dehydrogenase (complex-I), succinate dehydrogenase (complex-II) and cytochrome oxidase (complex-IV) was also noted in 2K1C animals. Administration of agomelatine, nicorandil and donepezil significantly attenuated 2K1C-hypertension induced impairments in memory, endothelial function, nitrosative stress, mitochondrial dysfunction, inflammation and brain damage. Therefore, modulators of MT1/MT2 receptors and KATP channels may be considered as potential agents for the management of renovascular hypertension induced VaD.

Effective Pharmacotherapy Against Oxidative Injury: Alternative Utility of an ATP-Sensitive Potassium Channel Opener

Cardiomyocyte viability following ischemia-reperfusion critically depends on mitochondrial function. In this regard, potassium channel openers (KCOs) targeting mitochondria have emerged as powerful cardioprotective agents when applied at the onset of ischemia. However, it is controversial whether openers are still protective when applied at the onset of reoxygenation. Here, H9c2 cardiomyocytes and mitochondria isolated from the rat heart ventricle were subjected to ischemia-reoxygenation or oxidative stress in the absence or presence of 100 microM diazoxide, a potassium channel opener. Ischemia-reoxygenation or oxidative stress significantly reduced cell viability, induced structural damage in association with increased mitochondrial protein release, and impaired oxidative phosphorylation. However, treatment with diazoxide before anoxia or at the onset of reoxygenation, as well as during oxidative stress, prevented cell death and mitochondrial dysfunction and preserved cellular and mitochondrial structural integrity. These protective effects were blocked by 5-hydroxydecanoate. Thus, treatment with potassium channel openers even at the time of reoxygenation may provide a significant protection of the myocardium. The protective mechanism is at least in part endogenous to the mitochondria because protection was also observed in isolated mitochondria.

( R)-ACX, a pancreatic β-cell selective sulfonylurea, does not aggravate myocardial ischemia-reperfusion damage

The organ selectivity and the effect on myocardial ischemia-reperfusion injury of ( R)-acetoxyhexamide (( R)-ACX), a novel sulfonylurea, were examined. ( R)-ACX, as well as glibenclamide, concentration-dependently stimulated insulin release from INS-1 cell, a cell line derived from pancreatic β-cells. The potency of ( R)-ACX was about 1/10 of that of glibenclamide. In isolated guinea pig ventricular myocardial tissue, glibenclamide concentration-dependently inhibited the action potential shortening by NIP-121, an ATP-sensitive potassium channel opener, but ( R)-ACX showed only slight inhibition. In isolated rat aortic rings contracted with norepinephrine, glibenclamide concentration-dependently inhibited the relaxation by NIP-121, while ( R)-ACX showed only slight inhibition. In coronary-perfused guinea pig ventricular preparations, glibenclamide reduced the recovery of contractile force after ischemia-reperfusion, while ( R)-ACX did not. In conclusion, ( R)-ACX is a β-cell selective sulfonylurea which, unlike glibenclamide, does not aggravate cardiac ischemia-reperfusion damage.

The Cardioprotective Effects of Levosimendan: Preclinical and Clinical Evidence

Levosimendan, a drug used in the treatment of acute and decompensated heart failure, has positive inotropic and antistunning effects mediated by calcium sensitization of contractile proteins, and vasodilatory and antiischemic effects mediated via the opening of ATP-sensitive potassium channels in vascular smooth-muscle cells. Recently, it also has been shown to act on mitochondrial ATP-sensitive potassium (mitoKATP) channels, an action thought to protect the heart against ischemia-reperfusion damage. This finding has suggested a possible application for levosimendan in clinical situations in which preconditioning would be beneficial (eg, in pre- and perioperative settings in cardiac surgery). The demonstration that levosimendan can prevent or limit myocyte apoptosis via the activation of mitoKATP channels provides a potential mechanism whereby this agent might protect cardiac myocytes during episodes of acute heart failure. This finding may explain why short-term treatment with levosimendan may improve longer-term survival. The present article reviews the literature on the cardioprotective actions of levosimendan, with particular emphasis on its recently recognized effects on mitoKATP channels and the putative preconditioning effects of that action. A therapeutic approach to acute heart failure that includes a cardioprotective strategy could have a clinically meaningful benefit on disease progression beyond alleviation of symptoms.

Systemic administration of diazoxide induces delayed preconditioning against transient focal cerebral ischemia in rats

Diazoxide is the prototypical opener of mitochondrial ATP-sensitive potassium channels (mitoK ATP) and protects neurons in vivo and in vitro against chemical and anoxic stresses. While we have previously shown that diazoxide administration induces acute preconditioning against transient cerebral ischemia in rats, the potential for delayed preconditioning of diazoxide has not been examined. The purpose of this study was to determine whether diazoxide promotes delayed preconditioning following 90 min of middle cerebral artery occlusion (MCAO) in male Wistar rats. Diazoxide (10 mg/kg) or vehicle was injected intraperitoneally 24 h before MCAO. Infarct volumes were measured 72 h after reperfusion. In animals anesthetized with halothane, treatment with diazoxide exhibited a 35% reduction (48.3 ± 3.0% to 31.3 ± 4.8%) and 18% reduction (35.1 ± 2.2% to 28.9 ± 2.1%) in cortical and subcortical infarct volumes, respectively. Administration of the mitoK ATP blocker 5-hydroxydecanoate attenuated this beneficial effect. In contrast, diazoxide did not induce delayed preconditioning in isoflurane-anesthetized rats. These findings support the concept that diazoxide produces delayed preconditioning via mitoK ATP activation but that physiological status can affect induction of preconditioning.

Time-dependent alteration in cromakalim-induced relaxation of corpus cavernosum from streptozocin-induced diabetic rats

The purpose of the present study was to investigate the relaxant responses to the ATP-sensitive potassium (K ATP) channel opener cromakalim in corpus cavernosum strips from 1-, 2-, 4-, 6-, and 8-week streptozocin-induced diabetic rats. Cromakalim (1 nM–0.1 mM) produced concentration-dependent relaxation in phenylephrine (7.5 μM)-precontracted isolated rat corporal strips. Compared with age-matched control animals, a significant enhancement in cromakalim-induced relaxation of corpus cavernosum was observed in 2-week diabetic animals, whereas the relaxant responses to cromakalim were decreased in 6-and 8-week diabetic animals. However, the cromakalim-induced relaxation was not altered in either 1-week or 4-week rat corporal strips in comparison with corresponding age-matched non-diabetic groups. Preincubation with the K ATP channel blocker glibenclamide (10 μM) significantly inhibited the cromakalim-induced relaxation in both non-diabetic and diabetic rat corpus cavernosum, but neither the voltage-dependent K + channel (K V) antagonist 4-aminopyridine (1 mM) nor the calcium-activated K + channel (K Ca) antagonist charybdotoxin (0.1 μM) had significant effect on cromakalim-induced relaxation in both control and diabetic rat corporal strips. Relaxation responses to the nitric oxide donor sodium nitroprusside (1 nM–0.1 mM) in diabetic rat corpus cavernosum were similar to that of age-matched controls. These data demonstrated that the relaxant responses to cromakalim were altered in diabetic cavernosal strips in a time dependent manner, suggesting that the period of diabetes mellitus may play a key role in the K ATP channels function in rat corpus cavernosum.

Adenosine enhances cytosolic phosphorylation potential and ventricular contractility in stunned guinea pig heart: receptor-mediated and metabolic protection

Mechanisms of adenosine (ADO) protection of reperfused myocardium are not fully understood. We tested the hypothesis that ADO (0.1 mM) alleviates ventricular stunning by ADO A(1)-receptor stimulation combined with purine metabolic enhancements. Langendorff guinea pig hearts were stunned at constant left ventricular end-diastolic pressure by low-flow ischemia. Myocardial phosphate metabolites were measured by (31)P-NMR, with phosphorylation potential {[ATP]/([ADP].[P(i)]), where brackets indicate concentration} estimated from creatine kinase equilibrium. Creatine and IMP, glycolytic intermediates, were measured enzymatically and glycolytic flux and extracellular spaces were measured by radiotracers. All treatment interventions started after a 10-min normoxic stabilization period. At 30 min reperfusion, ventricular contractility (dP/dt, left ventricular pressure) was reduced 17-26%, ventricular power (rate-pressure product) by 37%, and [ATP]/([ADP].[P(i)]) by 53%. The selective A(1) agonist 2-chloro-N(6)-cyclo-pentyladenosine marginally preserved [ATP]/([ADP].[P(i)]) and ventricular contractility but not rate-pressure product. Purine salvage precursor inosine (0.1 mM) substantially raised [ATP]/([ADP].[P(i)]) but weakly affected contractility. The ATP-sensitive potassium channel blocker glibenclamide (50 microM) abolished ADO protection of [ATP]/([ADP].[P(i)]) and contractility. ADO raised myocardial IMP and glucose-6-phosphate, demonstrating increased purine salvage and pentose phosphate pathway flux potential. Coronary hyperemia alone (papaverine) was not cardioprotective. We found that ADO protected energy metabolism and contractility in stunned myocardium more effectively than both the A(1)-receptor agonist 2-chloro-N(6)-cyclo-pentyladenosine and the purine salvage precursor inosine. Because ADO failed to stimulate glycolytic flux, the enhancement of reperfusion, [ATP]/([ADP].[P(i)]), indicates protection of mitochondrial function. Reduced ventricular dysfunction at enhanced [ATP]/([ADP].[P(i)]) argues against opening of mitochondrial ATP-sensitive potassium channel. The results establish a multifactorial mechanism of ADO antistunning, which appears to combine ADO A(1)-receptor signaling with metabolic adenylate and antioxidant enhancements.

Vasorelaxant effect of levcromakalim on isolated umbilical arteries of preeclamptic women

Objective Potassium channel openers are revealed to be a new type of antihypertensive drug. We aimed to clarify the effects of levcromakalim, an ATP-sensitive potassium channel opener, on human isolated umbilical artery (UA) and to compare them with those of nifedipine and magnesium sulphate, which are currently used in the treatment of preeclampsia (PE). Study design A total of 52 umbilical arteries, isolated immediately after delivery from 27 healthy and 25 preeclamptic pregnant women, were placed into 10-ml organ baths filled with Kreb's solution at physiological pH and temperature. The concentration-dependent relaxations in response to levcromakalim, nifedipine and magnesium sulphate were compared in vessels precontracted with serotonin (1 μmol/l). Results The maximal relative relaxation responses ( E max, expressed as percentage of serotonin-induced precontraction) to magnesium sulphate, nifedipine and levcromakalim in umbilical arteries were identical in the healthy (85.06 ± 3.31, 84.80 ± 3.01 and 80.37 ± 5.32%, respectively) and preeclamptic (77.20 ± 5.30, 83.36 ± 2.37 and 79.13 ± 4.30%, respectively) groups. Conclusion Levcromakalim has a vasodilatory effect on the umbilical artery like magnesium sulphate and nifedipine, and serves as an antihypertensive potential that might be used in the treatment of preeclampsia. However, further experimental and clinical studies are needed to propose that ATP-sensitive potassium channel openers are beneficial drugs in cases of clinical preeclampsia.

Protecting endothelial function: A novel therapeutic target of ATP-sensitive potassium channel openers

See article by Wang et al. [7] (pages 497–503) in this issue . Endothelial dysfunction is commonly observed in patients with hypertension, type II diabetes mellitus, and hypercholesteremia and is considered to be an early event in the changes accompanying atherosclerosis [1,2]. Disruption of normal endothelial function leads to loss of vasomotor control, reduced production of nitric oxide (NO), formation of a procoagulant surface, and promotion of inflammation [1,2]. These events may lead to destabilization of atherosclerotic plaques and could cause acute coronary syndrome. Indeed, recent clinical studies have demonstrated that endothelial dysfunction is a predictor for the development of cardiovascular events [3,4]. Endothelial cells express a diverse array of ion channels which play important roles in modulating cell function [5]. Since Noma first identified ATP-sensitive potassium (KATP) channels in cardiac myocytes, the physiological roles of KATP channels have been extensively studied in cardiac muscle and other tissues [5,6]. Endothelial KATP channels contribute to maintaining the resting membrane potential. In addition, they also regulate intracellular Ca2+ levels that affect the production and release of endothelial autacoids, … *Corresponding author. Tel.: +81 6 6879 3635; fax: +81 6 6879 3634. Email address: mhori{at}medone.med.osaka-u.ac.jp

A new ATP-sensitive potassium channel opener protects endothelial function in cultured aortic endothelial cells

Endothelial dysfunction is an early risk factor for cardiovascular disease and hypertension. Mechanisms that participate in endothelial dysfunction include reduced nitric oxide (NO) generation and increased endothelin-1 (ET-1) generation. Endothelial ATP-sensitive potassium (K(ATP)) channels are responsible for maintaining the resting potential of endothelial cells and modulating the release of vasoactive compounds. We hypothesized that activation of endothelial K(ATP) channels might result in the protection against endothelial dysfunction. Using cultured bovine or rat aortic endothelial cells, we examined the effects of a new K(ATP) channels opener, iptakalim, on the secretion of vasoactive substances. We also investigated its effects on the expression of adhesion molecules in metabolically disturbed cultured endothelial cells. In cultured aortic endothelial cells, iptakalim caused a concentration-dependent inhibition of ET-1 release and synthesis that correlated with reduced levels of mRNA for ET-1 and endothelin-converting enzyme. These effects of iptakalim were significantly inhibited by pretreatment with glibenclamide (a K(ATP) channel blocker) for 1 h. Similarly, iptakalim enhanced the release of NO in a concentration-dependent manner and increased basal levels of free intracellular calcium. Iptakalim at the concentrations of 100 and 1000 microM increased the activities of NO synthase (NOS) significantly. After the activity of NOS was blocked by L-N(omega)-nitro-arginine methyl ester (L-NAME), the inhibition of iptakalim on ET-1 release was abolished. In endothelial cell models of metabolic disturbance induced by low-density lipoprotein, homocysteine, or hyperglycemia, treatment with iptakalim could inhibit the overexpression of monocyte chemoattractant protein-1 (MCP-1), Intercellular adhesive molecule-1 (ICAM-1), and vascular cell adhesive molecule-1 (VCAM-1) mRNA. Iptakalim is a promising drug that could protect against endothelial dysfunction through activating K(ATP) channels in endothelial cells.

Iptakalim protects PC12 cell against H 2O 2-induced oxidative injury via opening mitochondrial ATP-sensitive potassium channel

The final common pathway in the demise of dopaminergic neurons in Parkinson’s disease may involve oxidative stress and excitotoxicity. In this study, we examined the neuroprotective effects of a novel ATP-sensitive potassium channel (K ATP) opener, iptakalim (IPT), against H 2O 2-induced cytotoxicity in rat dopaminergic PC12 cells. Pretreatment with IPT could attenuate increased extracellular glutamate levels and inhibit calcium influxing induced by H 2O 2. Moreover, IPT regulated the expressions of bcl-2 and bax which were responsible for inhibiting apoptosis in PC12 cells. These protective effects of IPT were abolished by selective mitoK ATP channel blocker 5-hydroxydecanoate. Therefore, IPT can protect PC12 cells against H 2O 2-induced oxidative injury via activating mitoK ATP channel.

Influence of ATP-sensitive potassium channels on lithium state-dependent memory of passive avoidance in mice

The effects of ATP-sensitive potassium channels on lithium induced state-dependent memory of passive avoidance task were examined in mice. The pre-training (5 mg/kg) and pre-test (5 mg/kg) injection of lithium impaired memory retrieval on the test day. Impairment of pre-training lithium was restored by pre-test administration of lithium (5 mg/kg), diazoxide, an ATP-sensitive potassium channel opener, (15, 30 and 60 mg/kg) or glibenclamide, an ATP-sensitive potassium channel blocker, (6 and 18 mg/kg). Pre-test administration of inactive doses of lithium (2.5 and 10 mg/kg) plus lower and inactive dose of glibenclamide (2 mg/kg) or diazoxide (1.5 mg/kg) also reversed the amnesia induced by pre-training lithium (5 mg/kg). In conclusion, the ATP-sensitive potassium channel opener or blocker not only mimicked the effect of lithium in state-dependent learning in the absence of lithium on the test day, but also potentiated the effect of low dose of lithium in restoration of memory. Therefore, ATP-sensitive potassium channels may have a modulatory influence on lithium response.

Mechanism of reactive oxygen species generation after opening of mitochondrial KATP channels

opening of the ATP-sensitive K+ (KATP) channel mediates the cardioprotective effect induced by pathophysiological stressors such as ischemic preconditioning (IPC) ([15][1], [29][2]), heat shock ([19][3]), and pharmacological agents, including adenosine ([5][4]), ACh ([26][5]), opioids ([12][6]),

Iptakalim alleviated the increase of extracellular dopamine and glutamate induced by 1-methyl-4-phenylpyridinium ion in rat striatum

The present study examined the effect of iptakalim (Ipt), a novel ATP-sensitive potassium (K ATP) channel opener (KCO), on 1-methyl-4-phenylpyridinium ion (MPP +)-induced dopamine (DA) and glutamate efflux in extracellular fluid of rat striatum, using microdialysis technique. Rats were implanted guide cannula in the striatum and artificial cerebrospinal fluid was infused through a microdialysis probe to detect the level of DA and glutamate in the striatum. MPP + significantly enhanced the extracellular levels of DA and its metabolites, DOPAC and HVA, as well as glutamate. Application of Ipt (1, 10, 100 μM) concentration-dependently suppressed DA and its metabolites efflux induced by MPP +. Concomitantly, Ipt reduced the increase of extracellular glutamate induced by MPP +. These results suggest that Ipt can regulate DA and glutamate efflux induced by MPP + in rat striatum.

Hypoxic Pulmonary Hypertension (HPH) and Iptakalim, a Novel ATP-sensitive Potassium Channel Opener Targeting Smaller Arteries in Hypertension

Hypoxic pulmonary hypertension (HPH) is a serious and potentially devastating chronic disorder of the pulmonary circulation. Attempts to use drugs in the therapy of hypoxic pulmonary hypertension indicated the importance of prevention or reduction of vasoconstriction as well as of the reversal of remodeling within the cardiovascular system. Iptakalim (2,3-dimethyl-N-(1-methylethyl)-2-butylamine), a novel ATP-sensitive potassium channel opener, has the desired effects on hypoxic pulmonary arteries. Iptakalim decreases the elevated mean pressure in pulmonary arteries, and attenuates remodeling in the right ventricle, pulmonary arteries and airways. Moreover, iptakalim has selective antihypertensive effects: it significantly lowers arterial pressure in hypertensive animals, but has little if any effect in normotensive animals. In HPH iptakalim has selective effects on smaller arteries. Long-term iptakalim therapy decreases expression of sulfonylurea receptor 2 and of mRNA of inwardly rectifying potassium channel in smaller arteries of spontaneously hypertensive rats. Iptakalim inhibits the effects of endothelin-1, reduces the intracellular calcium concentration and inhibits the cell cycle in smooth muscle cells of pulmonary arteries. There is no evidence for the development of tolerance to the long-lasting antihypertensive action of iptakalim. At therapeutic doses iptakalim has no effects on the central nervous, respiratory, digestive, or endocrine systems. It has a broad therapeutic range, so that it can be safely used in the therapy of HPH.

Protective effects of iptakalim, a novel ATP-sensitive potassium channel opener, on global cerebral ischemia-evoked insult in gerbils1

To investigate the protective role of iptakalim, a novel ATP sensitive potassium channel opener, on global cerebral ischemia-evoked insult in gerbils and glutamate-induced PC12 cell injury. Global cerebral ischemia was induced by occluding the bilateral common carotid arteries in gerbils for 5 min. The open field maze and T-maze were employed to investigate the experimental therapeutic value of iptakalim on ischemic brain insult (n=8). The pyramidal cells in the hippocampal CA1 regions were counted to assess the protective effects of iptakalim. Glutamate released from the gerbil hippocampus and PC12 cells were determined by HPLC. Intracellular calcium was measured by Fluo-3 AM with A Bio-Rad Radiance 2100TM confocal system in conjunction with a Nikon TE300 microscope. Astrocyte glutamate uptake measurements were determined by liquid scintillation counting. Iptakalim (0.5-4.0 mg/kg per day, ip) could reduce the high locomotor activity evoked by ischemia and improve global cerebral ischemia-induced working memory impairments. Histological studies revealed that iptakalim could increase the survival neuron in the hippocampus CA1 zone in a dose-dependent manner. Moreover, iptakalim could reverse ischemia-evoked increases of glutamate in the hippocampus of gerbils. In an in vitro study, iptakalim protected PC12 cells against glutamate-induced excitotoxicity, reduced the [Ca(2+)](i) increases, and enhanced the glutamate uptake activity of primary cultured astrocytes. Iptakalim plays a key role in preventing global cerebral ischemia-evoked insults in gerbils and glutamate-induced PC12 cell injury by anti-excitotoxicity. Iptakalim might be a promising novel candidate for the prevention and/or treatment of stroke.

B-type natriuretic peptide limits reperfusion injury via opening of ATP-sensitive potassium channels

B-type natriuretic peptide (BNP) and other natriuretic peptides given pre-ischaemia, limit infarction both in in-vivo and ex-vivo models of ischaemia–reperfusion injury. Furthermore, many studies have implicated the opening of the mitochondrial and sarcolemmal ATP-sensitive potassium (KATP) channels to be an important trigger of this protection. However, fewer studies have solely examined the role of natriuretic peptides in attenuating the extent of myocardial reperfusion injury. We hypothesise that BNP salvages the myocardium when given at reperfusion, and that this protection is dependent on the opening of KATP channels.

The antiarrhythmic effect and clinical consequences of ischemic preconditioning

Potentially hazardous short ischemic episodes increase the tolerance of myocardium to ischemia paradoxically. This condition decreases the infarct area markedly caused by a longer duration of coronary occlusion. This phenomenon is known as 'ischemic preconditioning' and its powerful cardioprotective effect has been shown in experimental and clinical studies. Ischemic preconditioning decreases cardiac mortality markedly by preventing the development of left ventricular dysfunction and ventricular and supraventricular arrhythmias after acute myocardial infarction. Ischemia-induced opening of ATP-sensitive potassium channels and synthesis of stress proteins via activation of adenosine, bradykinin and prostaglandin receptors seem to be the possible mechanisms. By understanding the underlying mechanisms of ischemic preconditioning, it may be possible to develop new pharmacologic agents that cause ischemic preconditioning with antiischemic and antiarrhythmic properties without causing myocardial ischemia.

From Cromakalim to Different Structural Classes of KATP Channel Openers

ATP-Sensitive potassium channel openers (K(ATP)COs) are a group of compounds with a broad spectrum of potential therapeutic applications, as they constitute efficient tools for dampening cell excitability. Interest in the K(ATP)COs was triggered in the early 1980s by the discovery of the benzopyran-based structure cromakalim (CRK), which is a powerful smooth muscle relaxant. CRK can be considered the archetype of K(ATP)COs and is by far the most mimicked structure. In many structure-activity studies various substitutions have been made at the different positions of the benzopyran ring permitting the optimal activity to be correlated with a specific set of structural characteristics and stereochemical features of the molecule. Thus, many potent benzopyran derivatives have been identified. The benzopyran nucleus itself has also been modified in both the aromatic ring and in the pyran moiety. The intention of this review is to bring together all the different structural classes of K(ATP)COs arising from the replacement of CRK benzopyran-based structure with various ring systems; design, structure-activity relationship, and synthesis will be given.

Iptakalim inhibits nicotine-induced enhancement of extracellular dopamine and glutamate levels in the nucleus accumbens of rats

Iptakalim (Ipt) is a novel ATP-sensitive potassium channel opener. It has been reported that Ipt inhibited cocaine-induced dopamine and glutamate release, suggesting that Ipt may regulate drug addiction. Recently, we found that Ipt blocked nicotinic acetylcholine receptor (nAChR)-mediated currents in a heterologously expressed SH-EP1 cell line and in native midbrain dopamine neurons. In the present study, we examined whether Ipt prevents nicotine-induced neurotransmitter release in the nucleus accumbens (NAc) using in vivo microdialysis methods in awake, freely moving rats. Ipt was administered through a microdialysis probe, following systemic administration of nicotine (0.5 mg/kg, s.c.). The results show that acute nicotine treatment induced an increase of both dopamine and glutamate levels in the rat NAc, and that Ipt significantly attenuated nicotine's effects in a concentration-dependent manner. Therefore, Ipt may serve as a novel compound to block nicotine-induced dopamine and glutamate release in the brain reward center, in turn decreasing nicotine reinforcement and dependence.