KATP Openers Research Articles

Animal Models of Chronic Migraine: From the Bench to Therapy.

Chronic migraine is a disabling progressive disorder without effective management approaches. Animal models have been developed and used in chronic migraine research. However, there are several problems with existing models. Therefore, we aimed to summarize and analyze existing animal models to facilitate translation from basic to clinical. The most commonly used models are the inflammatory soup induction model and the nitric oxide donor induction model. In addition, KATP openers have also been used in model induction. Based on the above models, some molecular targets have been identified, such as glutamate receptors. However, each model has its shortcomings and characteristics, and there are still some common problems that need to be solved, such as spontaneous headache, evaluation criteria after model establishment, and identification methods. In this review, we summarized and highlighted the advantages and limitations of the currently commonly used animal models of chronic migraine with a special focus on drug discovery and current therapeutic strategies, and discussed the directions that can be worked on in the future.

The Effect of KATP Openers and Blockers on AKT and mTOR mRNA Levels in the Hippocampus and Cortex of Rats with Penicillin-Induced Epilepsy

The Effect of KATP Openers and Blockers on AKT and mTOR mRNA Levels in the Hippocampus and Cortex of Rats with Penicillin-Induced Epilepsy

Structural insights into the mechanism of pancreatic KATP channel regulation by nucleotides

ATP-sensitive potassium channels (KATP) are metabolic sensors that convert the intracellular ATP/ADP ratio to the excitability of cells. They are involved in many physiological processes and implicated in several human diseases. Here we present the cryo-EM structures of the pancreatic KATP channel in both the closed state and the pre-open state, resolved in the same sample. We observe the binding of nucleotides at the inhibitory sites of the Kir6.2 channel in the closed but not in the pre-open state. Structural comparisons reveal the mechanism for ATP inhibition and Mg-ADP activation, two fundamental properties of KATP channels. Moreover, the structures also uncover the activation mechanism of diazoxide-type KATP openers.

Structural identification of vasodilator binding sites on the SUR2 subunit

ATP-sensitive potassium channels (KATP), composed of Kir6 and SUR subunits, convert the metabolic status of the cell into electrical signals. Pharmacological activation of SUR2- containing KATP channels by class of small molecule drugs known as KATP openers leads to hyperpolarization of excitable cells and to vasodilation. Thus, KATP openers could be used to treat cardiovascular diseases. However, where these vasodilators bind to KATP and how they activate the channel remains elusive. Here, we present cryo-EM structures of SUR2A and SUR2B subunits in complex with Mg-nucleotides and P1075 or levcromakalim, two chemically distinct KATP openers that are specific to SUR2. Both P1075 and levcromakalim bind to a common site in the transmembrane domain (TMD) of the SUR2 subunit, which is between TMD1 and TMD2 and is embraced by TM10, TM11, TM12, TM14, and TM17. These KATP openers synergize with Mg-nucleotides to stabilize SUR2 in the NBD-dimerized occluded state to activate the channel.

A Study on the Role of K Channels in Regulation of Vascular Reactivity in Diabetic Rats

Abstract Background: Diabetes Mellitus (DM) is a major interna-tional health problem characterized by an absolute or relative deficiency in the production or action of insulin, which results in hyperglycemia. Unfortunately, long term insulin adminis-tration in patients with DM results in insulin resistance. In this work, a novel therapeutic strategy of one of the ATP sensitive K channel opener KATP openers called Nicorandil was tried as an adjuvant agent in ameliorating CVD in exper-imentally-induced type I DM in rats. Aim of Study: The present study was designed to elucidate possible role of K channels in glucose homeostasis and regulation of the vascular reactivity in diabetic rats. Material and Methods: Fifty adult male albino rats were used in this investigation, divided into following groups control: Non-diabetic (C), diabetic (D), diabetic insulin treated (D + I), diabetic nicorandil treated (D + N) and diabetic insulin and nicorandil treated (D + I + N). Blood samples were collected for estimation of Fasting Blood Glucose (FBG) and (HbA1c), and vascular reactivity was examined using different vasoactive agents. Results: Type 1 DM resulted in substantial alterations in biochemical variables, as fasting blood glucose level, HbA1c, ABP and vascular reactivity. In our study there is significant decrease in fasting blood glucose level, (HbA1c) in both diabetic insulin (D + I) treated group and diabetic insulin and nicorandil (D + I + N) treated group in compared with the diabetic group, but with insignif-icant change between the two groups. There was significant improvement in vascular reactivity in diabetic insulin (D + I) treated group, diabetic nicorandil (D + N) treated group and diabetic insulin and nicorandil (D + I + N) treated group in compared with the diabetic (D) non treated group, but with insignificant change between insulin and nicorandil (D + I + N) treated group and non-diabetic (C) group. Conclusion: Nicorandil can be used as an adjuvant therapy in diabetic rats to improve vascular reactivity.

Activation of ATP‐sensitive potassium channels facilitates the function of human endothelial colony‐forming cells via Ca2+/Akt/eNOS pathway

Accumulating data, including those from our laboratory, have shown that the opening of ATP‐sensitive potassium channels (KATP) plays a protective role in pulmonary vascular diseases (PVD). As maintainers of the endothelial framework, endothelial colony‐forming cells (ECFCs) are considered excellent candidates for vascular regeneration in cases of PVD. Although KATP openers (KCOs) have been demonstrated to have beneficial effects on endothelial cells, the impact of KATP on ECFC function remains unclear. Herein, this study investigated whether there is a distribution of KATP in ECFCs and what role KATP play in ECFC modulation. By human ECFCs isolated from adult peripheral blood, KATP were confirmed for the first time to express in ECFCs, comprised subunits of Kir (Kir6.1, Kir6.2) and SUR2b. KCOs such as the classical agent nicorandil (Nico) and the novel agent iptakalim (Ipt) notably improved the function of ECFCs, promoting cell proliferation, migration and angiogenesis, which were abolished by a non‐selective KATP blocker glibenclamide (Gli). To determine the underlying mechanisms, we investigated the impacts of KCOs on CaMKII, Akt and endothelial nitric oxide synthase pathways. Enhanced levels were detected by western blotting, which were abrogated by Gli. This suggested an involvement of Ca2+ signalling in the regulation of ECFCs by KATP. Our findings demonstrated for the first time that there is a distribution of KATP in ECFCs and KATP play a vital role in ECFC function. The present work highlighted a novel profile of KATP as a potential target for ECFC modulation, which may hold the key to the treatment of PVD.

Chronic exposure to KATP channel openers results in attenuated glucose sensing in hypothalamic GT1-7 neurons

Individuals with Type 1 diabetes (T1D) are often exposed to recurrent episodes of hypoglycaemia. This reduces hormonal and behavioural responses that normally counteract low glucose in order to maintain glucose homeostasis, with altered responsiveness of glucose sensing hypothalamic neurons implicated. Although the molecular mechanisms are unknown, pharmacological studies implicate hypothalamic ATP-sensitive potassium channel (KATP) activity, with KATP openers (KCOs) amplifying, through cell hyperpolarization, the response to hypoglycaemia. Although initial findings, using acute hypothalamic KCO delivery, in rats were promising, chronic exposure to the KCO NN414 worsened the responses to subsequent hypoglycaemic challenge. To investigate this further we used GT1-7 cells to explore how NN414 affected glucose-sensing behaviour, the metabolic response of cells to hypoglycaemia and KATP activity. GT1-7 cells exposed to 3 or 24 h NN414 exhibited an attenuated hyperpolarization to subsequent hypoglycaemic challenge or NN414, which correlated with diminished KATP activity. The reduced sensitivity to hypoglycaemia was apparent 24 h after NN414 removal, even though intrinsic KATP activity recovered. The NN414-modified glucose responsiveness was not associated with adaptations in glucose uptake, metabolism or oxidation. KATP inactivation by NN414 was prevented by the concurrent presence of tolbutamide, which maintains KATP closure. Single channel recordings indicate that NN414 alters KATP intrinsic gating inducing a stable closed or inactivated state. These data indicate that exposure of hypothalamic glucose sensing cells to chronic NN414 drives a sustained conformational change to KATP, probably by binding to SUR1, that results in loss of channel sensitivity to intrinsic metabolic factors such as MgADP and small molecule agonists.

Discovery of potential ATP-sensitive potassium channel openers with potential hypotensive activity from Chinese herbs based on molecular simulation

In this research, a combined method of ligand-based pharmacophore (LBP), structure-based pharmacophore (SBP), and molecular docking was applied for virtual screening potential ATP-sensitive potassium channel (KATP) openers from Chinese herbs. LBP models were generated by 3D-QSAR pharmacophore(hypogen) program, based on the training set composed of 48 KATP agonists. The best LBP model consisted of one hydrogen-bond acceptor, one hydrogen-bond donor, one hydrophobic feature, one aromatic ring and five excluded volumes. Besides, the correlation coefficient of training set and test set, N, and CAI value of the model were 0.876 4, 0.705 8, 3.304, and 2.616 respectively. Meanwhile, SBP models were also generated based on a 3D structure of KATP (PMID: PM0079770). The best SBP model consisted of six hydrogen-bond acceptors, eight hydrogen-bond donors, seven hydrophobic features and eighteen excluded volumes. The corresponding N and CAI value were 2.200 and 2.017. Then, the best LBP model and SBP model were applied to identify potential KATP openers from Traditional Chinese Medicine Database(TCMD), respectively. 349 hits were obtained after analyzed by drug-likeness rules. Moreover, 12 compounds with high docking scores were reserved after molecular docking evaluation. Interestingly, part of the results had been verified as hypotensive active ingredients by literatures. Therefore, this study uncovers a specific target effect contained in TCMD, and provides candidates for new KATP openers' research.

ATP-sensitive potassium channel activation induces angiogenesis in vitro and in vivo.

Intense research is conducted to identify new molecular mechanisms of angiogenesis. Previous studies have shown that the angiogenic effects of hydrogen sulfide (H2S) depend on the activation of ATP-sensitive potassium channels (KATP) and that C-type natriuretic peptide (CNP), which can act through KATP, promotes endothelial cell growth. We therefore investigated whether direct KATP activation induces angiogenic responses and whether it is required for the endothelial responses to CNP or vascular endothelial growth factor (VEGF). Chick chorioallantoic membrane (CAM) angiogenesis was similarly enhanced by the direct KATP channel activator 2-nicotinamidoethyl acetate (SG-209) and by CNP or VEGF. The KATP inhibitors glibenclamide and 5-hydroxydecanoate (5-HD) reduced basal and abolished CNP-induced CAM angiogenesis. In vitro, the direct KATP openers nicorandil and SG-209 and the polypeptides VEGF and CNP increased proliferation and migration in bEnd.3 mouse endothelial cells. In addition, VEGF and CNP induced cord-like formation on Matrigel by human umbilical vein endothelial cells (HUVECs). All these in vitro endothelial responses were effectively abrogated by glibenclamide or 5-HD. In HUVECs, a small-interfering RNA-mediated decrease in the expression of the inwardly rectifying potassium channel (Kir) 6.1 subunit impaired cell migration and network morphogenesis in response to either SG-209 or CNP. We conclude that 1) direct pharmacologic activation of KATP induces angiogenic effects in vitro and in vivo, 2) angiogenic responses to CNP and VEGF depend on KATP activation and require the expression of the Kir6.1 KATP subunit, and 3) KATP activation may underpin angiogenesis to a variety of vasoactive stimuli, including H2S, VEGF, and CNP.

CYP-epoxygenases contribute to A2A receptor-mediated aortic relaxation via sarcolemmal KATP channels

Previously, we have shown that A(2A) adenosine receptor (A(2A)AR) mediates aortic relaxation via cytochrome P-450 (CYP)-epoxygenases. However, the signaling mechanism is not understood properly. We hypothesized that ATP-sensitive K(+) (K(ATP)) channels play an important role in A(2A)AR-mediated relaxation. Organ bath and Western blot experiments were done using isolated aorta from A(2A)KO and corresponding wild-type (WT) mice. Aortic rings from WT and A(2A) knockout (KO) mice were precontracted with submaximal dose of phenylephrine (PE, 10(-6) M), and concentration-response curves for pinacidil, cromakalim (nonselective K(ATP) openers), and diazoxide (mitochondrial K(ATP) opener) were obtained. Diazoxide did not have any relaxation effect on PE-precontracted tissues, whereas relaxation to pinacidil (48.09 ± 5.23% in WT vs. 25.41 ± 2.73% in A(2A)KO; P < 0.05) and cromakalim (51.19 ± 2.05% in WT vs. 38.50 ± 2.26% in A(2A)KO; P < 0.05) was higher in WT than A(2A)KO aorta. This suggested the involvement of sarcolemmal rather than mitochondrial K(ATP) channels. Endothelium removal, treatment with SCH 58651 (A(2A)AR antagonist; 10(-6) M), N(G)-nitro-l-arginine methyl ester (l-NAME, nitric oxide synthase inhibitor) and methylsulfonyl-propargyloxyphenylhexanamide (MS-PPOH, CYP-epoxygenases inhibitor; 10(-5) M) significantly reduced pinacidil-induced relaxation in WT compared with controls, whereas these treatments did not have any effect in A(2A)KO aorta. Glibenclamide (K(ATP) channel inhibitor, 10(-5) M) blocked 2-p-(2-carboxyethyl)phenethylamino-5'N-ethylcarboxamido adenosine hydrochloride (CGS 21680, A(2A)AR agonist)-induced relaxation in WT and changed 5'-N-ethylcarboxamide (NECA) (nonselective adenosine analog)-induced response to higher contraction in WT and A(2A)KO. 5-Hydroxydecanoate (5-HD, mitochondrial K(ATP) channel inhibitor, 10(-4) M) had no effect on CGS 21680-mediated response in WT aorta. Our data suggest that A(2A)AR-mediated vasorelaxation occurs through opening of sarcolemmal K(ATP) channels via CYP-epoxygenases and possibly, nitric oxide, contributing to pinacidil-induced responses.

Targeting Hypertension With a New Adenosine Triphosphate–sensitive Potassium Channel Opener Iptakalim

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.

Effects of KATP openers on the QT prolongation induced by HERG-blocking drugs in guinea-pigs

Abstract Objectives This work evaluated the potential usefulness of pharmacological activation of cardiac ATP-sensitive potassium channels (KATP) in the prevention of drug-induced QT prolongation in anaesthetised guinea-pigs. Prolongation of cardiac repolarisation and QT interval is an adverse effect of many drugs blocking HERG potassium channels. This alteration can be dangerously arrhythmogenic and has been associated with the development of a particular form of ventricular tachyarrhythmia known as torsade de pointes. Methods The well-known KATP openers aprikalim, cromakalim and pinacidil were used. Moreover, three benzothiazine derivatives, which have been reported as potent activators of KATP channels, were also used. Key findings Pharmacological activation of KATP channels caused a reduction of the QT prolongation, induced by astemizole, cisapride, quinidine and thioridazine. In contrast, the QT prolongation induced by haloperidol, sotalol and terfenadine, which are known to block HERG channels but also KATP channels, was not influenced by KATP activation. Glibenclamide and tolbutamide (non-selective blockers of KATP channels expressed both in sarcolemmal and in mitochondrial membranes) antagonised the effects of KATP openers, whereas 5-hydroxydecanoic acid (selective blocker of the mitochondrial KATP channels) failed to antagonise the effects of KATP openers, indicating that only the sarcolemmal KATP is involved in the cardioprotective activity. Conclusions The data suggest that pharmacological KATP activation might represent an option for treatment of patients exposed to QT-prolonging drugs.

Potassium channels as drug targets for therapeutic intervention in respiratory diseases

Background: Potassium channels represent a rich source of potential targets for therapeutic intervention. Clinically used potassium channel modulators comprise the sulfonylurea hypoglycemic agents (e.g., nateglinide, glipizide, mitiglinide), antiarrhythmic agents (dexsotalol, nifekalant, dofetilide, ibutilide), antianginal agents (nicorandil) and inotropic agents (levosimendan). Experimental evidence and preclinical models suggest the involvement of a number of potassium channels in respiratory diseases such as asthma and chronic obstructive pulmonary disease, supporting the prospects of potassium channel modulators as promising candidates in their therapeutic treatment. Objective: To present a survey on the most recent and relevant patents and patent applications of potassium channel modulators that have been claimed to be valuable for the treatment of chronic respiratory diseases: ATP-dependent K+ (KATP) channel openers, big-conductance K+ (BK) channel openers and intermediate-conductance K+ (IK) channel blockers. Methods: The review focuses on the most recent (January 2004 – June 2008) and relevant patents and patent applications in which respiratory diseases are included in the claims. Results/conclusion: KATP openers, the pioneer potassium channel modulators investigated for the treatment of respiratory diseases, are nowadays object of lesser attention by the pharmaceutical industry, probably due to lack of clinical success experienced by big Pharma in the face of the large medicinal chemistry efforts directed to identify airway-selective drugs. Emerging attention can instead be perceived in the patent literature for BKCa channel openers and their potential use for the same therapeutic indications. Preclinical data support this interest, although clinical proof of concept has not yet been obtained due to the lack of potent and selective BKCa drug candidates. This scenario may, however, change in the near future, given the claims of recently-synthesized BKCa openers superior to the benchmark NS1619. Until now, the only potassium channel modulating agent under clinical development in an airway indication is the IKCa1 channel blocker senicapoc (ICA-17043) from Icagen. This compound, which was investigated in Phase III trial for sickle cell anemia, is at present in Phase I for asthma.

Endothelium and nitric oxide

Studied nature of the "blood vessels relaxing factor" derived from endothelium that was identified as nitric oxide caused intensive scientific research on nitric oxide regarding some aspects of its impact on human physiological and pathological processes. The objective of this short review is to discuss widely used (in the clinical practice) direct and indirect donors of nitric oxide and/or other agents, increasing nitric oxide concentration in human body, and their beneficial role for the prevention of atherosclerosis. Under physiological conditions, endothelium regulates the tone of blood vessels, homeostasis of which is maintained by endothelium-generated vasoconstrictors and vasodilators. The most important vasodilator and the main substance produced by the endothelium is nitric oxide. The failure of synthesis and/or the lost of nitric oxide bioavailability is the major feature of endothelial dysfunction and key factor initiating progression of atherosclerosis. The endothelial dysfunction initiates the series of events, which stimulate and aggravate the course of atherosclerosis by increasing endothelial permeability, platelet aggregation, and leukocyte adhesion, and cytokine expression. Further, the review deals with the mechanisms of action of statins, angiotensin-converting enzyme inhibitors, L-arginine, direct nitric oxide donors (nitroglycerin, isosorbide mononitrate and isosorbide dinitrate), and indirect nitric oxide donors (phosphodiesterase-V inhibitors, K(ATP) openers).

Effects of Substitution on 9-(3-Bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4- azacyclopenta[b]naphthalene-1,8-dione, a Dihydropyridine ATP-Sensitive Potassium Channel Opener

Structure-activity relationships were investigated on the tricyclic dihydropyridine (DHP) KATP openers 9-(3-bromo-4-fluorophenyl)-5,9-dihydro-3H,4H-2,6-dioxa-4-azacyclopenta[b]naphthalene-1,8-dione (6) and 10-(3-bromo-4-fluorophenyl)-9,10-dihydro-1H,8H-2,7-dioxa-9-azaanthracene-4,5-dione (65). Substitution off the core of the DHP, absolute stereochemistry, and aromatic substitution were evaluated for KATP channel activity using Ltk- cells stably transfected with the Kir6.2/SUR2B exon 17- splice variant and in an electrically stimulated pig bladder strip assay. A select group of compounds was evaluated for in vitro inhibition of spontaneous bladder contractions. Several compounds were found to have the unique characteristic of partial efficacy in both the cell-based and electrically stimulated bladder strip assays but full efficacy in inhibiting spontaneous bladder strip contractions. For compound 23b, this profile was mirrored in vivo where it was fully efficacious in inhibiting spontaneous myogenic bladder contractions but only partially able to reduce neurogenically mediated reflex bladder contractions.

A129. Bradykinin cardioprotection is mediated by receptor internalization and mitoKATP opening

Bradykinin (Bk) mimics the cardioprotective effects of ischemic preconditioning (IPC) by a complex series of cellular signaling events that include activation of protein kinase G (PKG), opening of mitochondrial ATP-sensitive K+-channels (mitoKATP), and increased production of reactive oxygen species (ROS). In this study, we investigate the hypothesis that the bradykinin B2 receptor is internalized within a signaling platform that mediates the opening of mitoKATP and cardioprotection. We describe a procedure in which hearts are perfused with Bk in a Langendorff apparatus. Following perfusion, mitochondria are isolated and subjected to purification in a Percoll density gradient. This yields a low-density fraction (henceforth termed the light-layer) and a purified mitochondrial fraction. As determined by western blot analysis, the light-layer contains caveolin-1 and -3, the bradykinin B2 receptor, and PKG as well as other proteins. We find that addition of the light-layer to untreated mitochondria opens mitoKATP similar to KATP openers such as diazoxide, as measured by changes in matrix volume. MitoKATP opening by the light-layer does not require the addition of cyclic-GMP but is sensitive to the mitoKATP blocker 5-hydroxydecanoate, the PKCε peptide antagonist εV1–2, the serine/threonine phosphatase PP2A and the PKG-specific blocker KT5823, indicating that PKG was activated by Bk treatment. Inhibition of the open state was not observed upon addition of the Src kinase inhibitor PP2, the tyrosine phosphatase PTP2B, MEK inhibitor I or the ERK inhibitor 3-(2-Aminoethyl)-5-((4-ethoxyphenyl)methylene)-2,4-thiazolidinedione, HCl. From this data, we conclude that the light-layer from Bk perfused hearts contains a cardioprotective signaling platform that migrates to mitochondria and opens mitoKATP, resulting in a protected state.

Mitochondrial ATP-sensitive potassium channels and mitochondrial protein kinase C: sometimes it's good to have a close neighbor

the fine study by Jiang et al. ([8][1]) in this issue of the American Journal of Physiology Heart and Circulatory Physiology is an important milestone in the ongoing studies on the role of the mitochondrial ATP-sensitive K+ (mitoKATP) channels in myocardial ischemia. It is not particularly

ATP-Sensitive Potassium Channels

ATP-sensitive potassium (K(ATP)) channels link membrane excitability to metabolism. They are regulated by intracellular nucleotides and by other factors including membrane phospholipids, protein kinases and phosphatases. K(ATP) channels comprise octamers of four Kir6 pore-forming subunits associated with four sulphonylurea receptor subunits. The exact subunit composition differs between the tissues in which the channels are expressed, which include pancreas, cardiac, smooth and skeletal muscle and brain. K(ATP) channels are targets for antidiabetic sulphonylurea blockers, and for channel opening drugs that are used as antianginals and antihypertensives. This review focuses on non-pancreatic K(ATP) channels. In vascular smooth muscle, K(ATP) channels are extensively regulated by signalling pathways and cause vasodilation, contributing both to resting blood flow and vasodilator-induced increases in flow. Similarly, K(ATP) channel activation relaxes smooth muscle of the bladder, gastrointestinal tract and airways. In cardiac muscle, sarcolemmal K(ATP) channels open to protect cells under stress conditions such as ischaemia or exercise, and appear central to the protection induced by ischaemic preconditioning (IPC). Mitochondrial K(ATP) channels are also strongly implicated in IPC, but clarification of their exact role awaits information on their molecular structure. Skeletal muscle K(ATP) channels play roles in fatigue and recovery, K+ efflux, and glucose uptake, while neuronal channels may provide ischaemic protection and underlie the glucose-responsiveness of hypothalamic neurones. Current therapeutic considerations include the use of K(ATP) openers to protect cardiac muscle, attempts to develop openers selective for airway or bladder, and the question of whether block of extra-pancreatic K(ATP) channels may cause adverse cardiovascular side-effects of sulphonylureas.

Small molecule mitochondrial F1F0 ATPase hydrolase inhibitors as cardioprotective agents. Identification of 4-(N-arylimidazole)-substituted benzopyran derivatives as selective hydrolase inhibitors.

In this paper we show that 4-aryl-CH2-imidazole-substituted benzopyran compounds with 3S,4R-stereochemistry are cardioprotective by inhibiting the F1F0 mitochondrial ATP hydrolase. Compounds (e.g., 13) with 3R,4S-stereochemistry act as mitochondrial KATP openers. This resulted from an inversion of stereochemistry for the F1F0 mitochondrial ATP hydrolase vs mitochondrial KATP. Structure-activity relationships for the inhibition of mitochondrial ATP hydrolase are also delineated. It is not clear how 13 (3R,4S) can selectively inhibit the hydrolytic activity of the F1F0 mitochondrial enzyme without interfering with the synthase activity.

Identification of a Novel Antiangiogenic Agent; 4‐(N‐Imidazol‐2‐ylmethyl)amino Benzopyran Analogues.

AbstractFor Abstract see ChemInform Abstract in Full Text.