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Noriyoshi Teramoto - One of the best experts on this subject based on the ideXlab platform.

  • effects of zd0947 a novel and potent atp sensitive k Channel Opener on smooth muscle type atp sensitive k Channels
    European Journal of Pharmacology, 2016
    Co-Authors: Keisuke Mori, Noriyoshi Teramoto, Yoshio Yamashita
    Abstract:

    Abstract The effects of ZD0947, a novel ATP-sensitive K+ Channel (KATP Channel) Opener, on the activity of reconstituted KATP Channels were investigated using cell-attached recordings. KATP Channels were studied in HEK 293 cells by co-expression of inwardly rectifying-6 family K+ Channel subunits (Kir6.x: Kir6.1 and Kir6.2) with 3 different types of sulphonylurea receptors (SUR.x: SUR1, SUR2A and SUR2B). ZD0947 (100 µM) activated SUR2B/Kir6.2 Channels in a concentration-dependent manner, but caused only weak activation of SUR1/Kir6.2 Channels and SUR2A/Kir6.2 Channels expressed in HEK 293 cells. ZD0947 reversibly suppressed diazoxide-elicited SUR1/Kir6.2 Channels activity and pinacidil-elicited SUR2A/Kir6.2 Channel activity. However, ZD0947 did not affect SUR2B/Kir6.2 Channels fully activated by 100 µM pinacidil. ZD0947 had little inhibitory effects on the activity of Kir6.2ΔC26 Channels (a truncated isoform of Kir6.2) or its mutant Channels (i.e. Kir6.2ΔC26C166A) expressed in HEK 293 cells. ZD0947 also elicited activity in SUR2B/Kir6.1 Channels expressed in HEK 293 cells, in a concentration-dependent manner. Therefore, ZD0947 is a relatively effective activator of smooth muscle-type KATP Channels (SUR2B/Kir6.1 and SUR2B/Kir6.2) but is a partial antagonist of pancreatic-type KATP Channels (i.e. SUR1/Kir6.2) and cardiac-type KATP Channels (i.e. SUR2A/Kir6.2). These results suggest that a pharmacological agent can possess either agonist or antagonist actions on the activity of KATP Channels, depending on the subtype of SUR.x.

  • Comparative studies of ZD0947, a novel ATP-sensitive K^+ Channel Opener, on guinea pig detrusor and aortic smooth muscles
    Naunyn-Schmiedeberg's Archives of Pharmacology, 2008
    Co-Authors: Takakazu Yunoki, Kazuomi Iwasa, Toshihisa Tomoda, Manami Aishima, Atsushi Shibata, Seiji Naito, Noriyoshi Teramoto
    Abstract:

    The effects of ZD0947, a novel urinary bladder selective ATP-sensitive potassium Channel (K_ATP Channel) Opener, on carbachol-induced contractions of isolated guinea pig urinary bladder strips were investigated to compare its ability to relax norepinephrine-induced contraction of the aorta. Electrophysiological techniques were also utilized to compare the effects of ZD0947 on membrane currents between guinea pig detrusor and aortic myocytes. ZD0947 caused a significant reduction of the carbachol-induced contractile activity, demonstrating a biphasic relaxation (the first and second components). Although glibenclamide antagonized the effects of two components for the ZD0947-induced relaxation, gliclazide, a selective sulphonylurea receptor 1 (SUR1) antagonist, reduced the effects of the first component but not the second component of the ZD0947-induced relaxation. ZD0947 also reduced the norepinephrine-induced contraction of the aorta. ZD0947 reduced electrical excitability of detrusor smooth muscles, inhibiting spike discharges and also hyperpolarizing the membrane as measured with microelectrodes. In conventional whole-cell configuration, ZD0947 caused a glibenclamide-sensitive K^+ current (i.e., K_ATP current) at a holding potential of −60 mV in guinea pig detrusor and aortic myocytes. The current density of ZD0947-induced K_ATP currents in guinea pig detrusor myocytes was significantly larger than that in aortic smooth muscle cells. These results show that ZD0947 caused a significant relaxation through the activation of K_ATP Channels in detrusor muscle.

  • comparative studies of zd0947 a novel atp sensitive k Channel Opener on guinea pig detrusor and aortic smooth muscles
    Naunyn-schmiedebergs Archives of Pharmacology, 2008
    Co-Authors: Takakazu Yunoki, Kazuomi Iwasa, Toshihisa Tomoda, Manami Aishima, Atsushi Shibata, Seiji Naito, Noriyoshi Teramoto
    Abstract:

    The effects of ZD0947, a novel urinary bladder selective ATP-sensitive potassium Channel (KATP Channel) Opener, on carbachol-induced contractions of isolated guinea pig urinary bladder strips were investigated to compare its ability to relax norepinephrine-induced contraction of the aorta. Electrophysiological techniques were also utilized to compare the effects of ZD0947 on membrane currents between guinea pig detrusor and aortic myocytes. ZD0947 caused a significant reduction of the carbachol-induced contractile activity, demonstrating a biphasic relaxation (the first and second components). Although glibenclamide antagonized the effects of two components for the ZD0947-induced relaxation, gliclazide, a selective sulphonylurea receptor 1 (SUR1) antagonist, reduced the effects of the first component but not the second component of the ZD0947-induced relaxation. ZD0947 also reduced the norepinephrine-induced contraction of the aorta. ZD0947 reduced electrical excitability of detrusor smooth muscles, inhibiting spike discharges and also hyperpolarizing the membrane as measured with microelectrodes. In conventional whole-cell configuration, ZD0947 caused a glibenclamide-sensitive K+ current (i.e., KATP current) at a holding potential of −60 mV in guinea pig detrusor and aortic myocytes. The current density of ZD0947-induced KATP currents in guinea pig detrusor myocytes was significantly larger than that in aortic smooth muscle cells. These results show that ZD0947 caused a significant relaxation through the activation of KATP Channels in detrusor muscle.

  • actions of zd0947 a novel atp sensitive k Channel Opener on membrane currents in human detrusor myocytes
    British Journal of Pharmacology, 2006
    Co-Authors: Manami Aishima, Takakazu Yunoki, Toshihisa Tomoda, Seiji Naito, Toshiaki Nakano, Narihito Seki, Yoshikazu Yonemitsu, Katsuo Sueishi, Noriyoshi Teramoto
    Abstract:

    Background and purpose: ATP-sensitive K+ Channels (KATP Channels) play important roles in regulating the resting membrane potential of detrusor smooth muscle. Actions of ZD0947, a novel KATP Channel Opener, on both carbachol (CCh)-induced detrusor contractions and membrane currents in human urinary bladder myocytes were investigated. Experimental approach: Tension measurements and patch-clamp techniques were utilized to study the effects of ZD0947 in segments of human urinary bladder. Immunohistochemistry was also performed to detect the expression of the sulphonylurea receptor 1 (SUR1) and the SUR2B antigens in human detrusor muscle. Key results: ZD0947 (≥0.1 μM) caused a concentration-dependent relaxation of the CCh-induced contraction of human detrusor, which was reversed by glibenclamide. The rank order of the potency to relax the CCh-induced contraction was pinacidil>ZD0947>diazoxide. In conventional whole-cell configuration, ZD0947 (≥1 μM) caused a concentration-dependent inward K+ current which was suppressed by glibenclamide at -60 mV. When 1 mM ATP was included in the pipette solution, application of pinacidil or ZD0947 caused no inward K+ current at -60 mV. Gliclazide (≤1 μM), a selective SUR1 blocker, inhibited the ZD0947-induced currents (Ki=4.0 μM) and the diazoxide-induced currents (high-affinity site, Ki1=42.4 nM; low-affinity site, Ki2=84.5 μM) at -60 mV. Immunohistochemical studies indicated the presence of SUR1 and SUR2B proteins, which are constituents of KATP Channels, in the bundles of human detrusor smooth muscle. Conclusions and Implications: These results suggest that ZD0947 caused a glibenclamide-sensitive detrusor relaxation through activation of glibenclamide-sensitive KATP Channels in human urinary bladder. British Journal of Pharmacology (2006) 149, 542–550. doi:10.1038/sj.bjp.0706893

Jennifer S Lawton - One of the best experts on this subject based on the ideXlab platform.

  • superior diastolic function with katp Channel Opener diazoxide in a novel mouse langendorff model
    Journal of Surgical Research, 2018
    Co-Authors: Carol M Makepeace, Richard B Schuessler, Evelyn M Kanter, Colin G Nichols, Alejandro Suarezpierre, Jennifer S Lawton
    Abstract:

    Abstract Background Adenosine triphosphate–sensitive potassium (KATP) Channel Openers have been found to be cardioprotective in multiple animal models via an unknown mechanism. Mouse models allow genetic manipulation of KATP Channel components for the investigation of this mechanism. Mouse Langendorff models using 30 min of global ischemia are known to induce measurable myocardial infarction and injury. Prolongation of global ischemia in a mouse Langendorff model could allow the determination of the mechanisms involved in KATP Channel Opener cardioprotection. Methods Mouse hearts (C57BL/6) underwent baseline perfusion with Krebs-Henseleit buffer (30 min), assessment of function using a left ventricular balloon, delivery of test solution, and prolonged global ischemia (90 min). Hearts underwent reperfusion (30 min) and functional assessment. Coronary flow was measured using an inline probe. Test solutions included were as follows: hyperkalemic cardioplegia alone (CPG, n = 11) or with diazoxide (CPG + DZX, n = 12). Results Although the CPG + DZX group had greater percent recovery of developed pressure and coronary flow, this was not statistically significant. Following a mean of 74 min (CPG) and 77 min (CPG + DZX), an additional increase in end-diastolic pressure was noted (plateau), which was significantly higher in the CPG group. Similarly, the end-diastolic pressure (at reperfusion and at the end of experiment) was significantly higher in the CPG group. Conclusions Prolongation of global ischemia demonstrated added benefit when DZX was added to traditional hyperkalemic CPG. This model will allow the investigation of DZX mechanism of cardioprotection following manipulation of targeted KATP Channel components. This model will also allow translation to prolonged ischemic episodes associated with cardiac surgery.

  • abstract 15629 superior myocardial protection with adenosine triphosphate sensitive potassium Channel Opener diazoxide in a novel mouse langendorff model
    Circulation, 2016
    Co-Authors: Carol M Makepeace, Richard B Schuessler, Evelyn M Kanter, Colin G Nichols, Jennifer S Lawton
    Abstract:

    Introduction: Adenosine triphosphate - sensitive potassium (K ATP ) Channel Openers are cardioprotective via an unknown mechanism. Mouse models allow genetic manipulation of K ATP Channel components for investigation of this mechanism. Mouse Langendorff models utilizing 30 min of global ischemia are known to induce myocardial infarction. In such models, the benefit of a K ATP Channel Opener over traditionally utilized hyperkalemic cardioplegia solutions has not been demonstrated. Hypothesis: Prolongation of global ischemia in a mouse Langendorff model will allow demonstration of superior protection with K ATP Channel Opener diazoxide when added to traditional hyperkalemic cardioplegia solutions. Methods: Wild type mouse hearts underwent 30 min baseline perfusion with Krebs-Henseleit solution (KH), 1.5 hours global ischemia following infusion of test solution, followed by 30 min reperfusion with KH solution. Test solutions were hyperkalemic cardioplegia (CPG) (N=11) or CPG + K ATP Channel Opener diazoxide (CPG + DZX) (N=12). Pressure measurements were taken at baseline, during ischemia, and following reperfusion via a left ventricular balloon, and coronary flow was measured. Results: CPG + DZX group had improved recovery of developed pressure and coronary flow, although this did not reach statistical significance (Table). Ischemic end diastolic pressure (EDP) was similar between groups at 30 mins. At a mean of 74 min (CPG) or 77 min (CPG+ DZX), an additional increase in EDP was noted (plateau) (Figure) and was higher in the CPG group. Similarly, EDP at reperfusion and end of experiment were higher in the CPG group. Conclusions: Prolongation of global ischemia in a mouse Langendorff model demonstrated additional benefit when DZX was added to hyperkalemic cardioplegia. This model allows investigation of K ATP Channel components and their role in DZX cardioprotection as well as translation to prolonged ischemic episodes associated with cardiac surgery.

  • cardioprotective benefits of adenosine triphosphate sensitive potassium Channel Opener diazoxide are lost with administration after the onset of stress in mouse and human myocytes
    Journal of The American College of Surgeons, 2014
    Co-Authors: Burhan M Janjua, Richard B Schuessler, Carol M Makepeace, Colin G Nichols, Melissa M Anastacio, Jennifer S Lawton
    Abstract:

    Background Adenosine triphosphate-sensitive (K ATP ) potassium Channel Opener diazoxide (DZX) maintains myocyte volume and contractility during stress via an unknown mechanism when administered at the onset of stress. This study was performed to investigate the cardioprotective potential of DZX when added after the onset of the stresses of hyperkalemic cardioplegia, metabolic inhibition, and hypo-osmotic stress. Study Design Isolated mouse ventricular and human atrial myocytes were exposed to control Tyrode's solution (TYR) for 10 to 20 minutes, test solution for 30 minutes (hypothermic hyperkalemic cardioplegia [CPG], CPG + 100uM diazoxide [CPG+DZX], metabolic inhibition [MI], MI+DZX, mild hypo-osmotic stress [0.9T], or 0.9T + DZX), with DZX added after 10 or 20 minutes of stress, followed by 20 minutes of re-exposure to TYR (±DZX). Myocyte volume (human + mouse) and contractility (mouse) were compared. Results Mouse and human myocytes demonstrated significant swelling during exposure to CPG, MI, and hypo-osmotic stress that was not prevented by DZX when administered either at 10 or 20 minutes after the onset of stress. Contractility after the stress of CPG in mouse myocytes significantly declined when DZX was administered 20 minutes after the onset of stress (p Conclusions To maintain myocyte volume homeostasis and contractility during stress (hyperkalemic cardioplegia, metabolic inhibition, and hypo-osmotic stress), K ATP Channel Opener diazoxide requires administration at the onset of stress in this isolated myocyte model. These data have potential implications for any future clinical application of diazoxide.

  • myocyte volume and function in response to osmotic stress observations in the presence of an adenosine triphosphate sensitive potassium Channel Opener
    Circulation, 2005
    Co-Authors: Shinichi Mizutani, Sandip M Prasad, Angela D Sellitto, Richard B Schuessler, Ralph J Damiano, Jennifer S Lawton
    Abstract:

    Background— Hypothermic hyperkalemic cardioplegia results in significant myocyte swelling and impaired contractility. These detrimental effects may be eliminated by the addition of an adenosine triphosphate-sensitive potassium (K ATP ) Channel Opener. This study evaluated the hypothesis that a K ATP Channel Opener (diazoxide) would benefit volume homeostasis by limiting volume and subsequent contractility changes during osmotic stress. Methods and Results— Isolated rabbit ventricular myocyte volume and contractility were evaluated using video microscopy and field stimulation after exposure to osmotic stress at 37°C. Myocytes were exposed to Tyrode’s physiological solution for 20 minutes and test solution for 20 minutes, and then reexposed to Tyrode’s for 20 minutes. Test solutions included control Tyrode’s (1T) and osmotically altered Tyrode’s (2.6T, 0.9T, and 0.6T) solutions with or without the K ATP Channel Opener diazoxide. Severe osmotic stress (2.6T and 0.6T) resulted in significant cell shrinkage and swelling, respectively. This was unchanged by the addition of diazoxide. Mild hyposmotic stress (0.9T) resulted in significant cell swelling that was eliminated by the addition of diazoxide. Cell swelling was associated with reduced contractility. Conclusions— Cell swelling, but not shrinkage, was detrimental to myocyte contractility. Diazoxide eliminated volume change due to mild hyposmotic stress, similar to that previously noted with hyperkalemic cardioplegia, but did not alter volume change secondary to severe osmotic stress.

Jens D Mikkelsen - One of the best experts on this subject based on the ideXlab platform.

  • the pan kv7 kcnq Channel Opener retigabine inhibits striatal excitability by direct action on striatal neurons in vivo
    Basic & Clinical Pharmacology & Toxicology, 2017
    Co-Authors: Henrik H Hansen, Maria D Mikkelsen, Frederik Rode, Pia Weikop, Jens D Mikkelsen
    Abstract:

    : Central Kv7 (KCNQ) Channels are voltage-dependent potassium Channels composed of different combinations of four Kv7 subunits, being differently expressed in the brain. Notably, striatal dopaminergic neurotransmission is strongly suppressed by systemic administration of the pan-Kv7 Channel Opener retigabine. The effect of retigabine likely involves the inhibition of the activity in mesencephalic dopaminergic neurons projecting to the striatum, but whether Kv7 Channels expressed in the striatum may also play a role is not resolved. We therefore assessed the effect of intrastriatal retigabine administration on striatal neuronal excitability in the rat determined by c-Fos immunoreactivity, a marker of neuronal activation. When retigabine was applied locally in the striatum, this resulted in a marked reduction in the number of c-Fos-positive neurons after a strong excitatory striatal stimulus induced by acute systemic haloperidol administration in the rat. The relative mRNA levels of Kv7 subunits in the rat striatum were found to be Kv7.2 = Kv7.3 = Kv7.5 > >Kv7.4. These data suggest that intrastriatal Kv7 Channels play a direct role in regulating striatal excitability in vivo.

  • the neuronal kcnq Channel Opener retigabine inhibits locomotor activity and reduces forebrain excitatory responses to the psychostimulants cocaine methylphenidate and phencyclidine
    European Journal of Pharmacology, 2007
    Co-Authors: Henrik H Hansen, Naheed Mirza, Jorgen Scheelkruger, Jesper T. Andreasen, Pia Weikop, Jens D Mikkelsen
    Abstract:

    Abstract Many central stimulating drugs have a pronounced stimulatory effect on striatal and cortical activity which is associated to enhanced function of mesencephalic dopaminergic neurons. Mesencephalic KCNQ (also termed Kv7) potassium Channels suppress the basal activity of dopaminergic neurons in the substantia nigra and ventral tegmental area. These regions have extensive dopaminergic projections to the striatum and cortex, and positive modulation of KCNQ Channel function may therefore potentially reduce the reinforcing impact of central stimulating drugs. We studied the effects of the principal neuronal KCNQ Channel Opener, retigabine, in rats exposed acutely to cocaine, methylphenidate (dopamine reuptake inhibitors) or phencyclidine (PCP, a psychotomimetic NMDA receptor antagonist). Retigabine (≥ 1.0 mg/kg) inhibited cocaine, methylphenidate and PCP-stimulated locomotor activity. Also, retigabine reduced spontaneous locomotor activity. The inhibitory effect of retigabine on psychostimulant-induced locomotor activity was accompanied by a marked reduction in c-Fos expression, in particular the nucleus accumbens and primary motor cortex were responsive to retigabine pre-treatment. Notably, retigabine also reduced basal extracellular levels of striatal dopamine metabolites and partially prevented dopamine overflow in the striatum induced by dopamine reuptake blockade. In combination, these data suggest that retigabine reduces striatal and cortical excitability, thereby attenuating excitatory effects of central stimulating drugs in dopamine-rich areas of the rat forebrain. KCNQ Channel Openers may therefore be of potential relevance in the treatment of addiction states caused by abuse of psychostimulants.

  • the kcnq Channel Opener retigabine inhibits the activity of mesencephalic dopaminergic systems of the rat
    Journal of Pharmacology and Experimental Therapeutics, 2006
    Co-Authors: Henrik H Hansen, Lars Christian Biilmann Ronn, Christina Ebbesen, Claus Mathiesen, Vincent Seutin, Olivier Waroux, Jacqueline Scuveemoreau, Pia Weikop, Jens D Mikkelsen
    Abstract:

    Homo- and heteromeric complexes of KCNQ Channel subunits are the molecular correlate of the M-current, a neuron-specific voltage-dependent K + current with a well established role in control of neural excitability. We investigated the effect of KCNQ Channel modulators on the activity of dopaminergic neurons in vitro and in vivo in the rat ventral mesencephalon. The firing of dopaminergic neurons recorded in mesencephalic slices was robustly inhibited in a concentration-dependent manner by the KCNQ Channel Opener N -(2-amino-4-(4-fluorobenzylamino)-phenyl) carbamic acid ethyl ester (retigabine). The effect of retigabine persisted in the presence of tetrodotoxin and simultaneous blockade of GABA A receptors, small-conductance calcium-activated K + (SK) Channels, and hyperpolarization-activated (I h ) Channels, and it was potently reversed by the KCNQ Channel blocker 4-pyridinylmethyl-9(10 H )-anthracenone (XE991), indicating a direct effect on KCNQ Channels. Likewise, in vivo single unit recordings from dopaminergic neurons revealed a prominent reduction in spike activity after systemic administration of retigabine. Furthermore, retigabine inhibited dopamine synthesis and c-Fos expression in the striatum under basal conditions. Retigabine completely blocked the excitatory effect of dopamine D 2 autoreceptor antagonists. Again, the in vitro and in vivo effects of retigabine were completely reversed by preadministration of XE991. Dual immunocytochemistry revealed that KCNQ4 is the major KCNQ Channel subunit expressed in all dopaminergic neurons in the mesolimbic and nigrostriatal pathways. Collectively, these observations indicate that retigabine negatively modulates dopaminergic neurotransmission, likely originating from stimulation of mesencephalic KCNQ4 Channels.

Karlerik Andersson - One of the best experts on this subject based on the ideXlab platform.

  • effects of intravesical administration of the k Channel Opener zd6169 in conscious rats with and without bladder outflow obstruction
    The Journal of Urology, 1999
    Co-Authors: Raj Kumar Pandita, Karlerik Andersson
    Abstract:

    AbstractPurpose: To investigate the urodynamic effects of the new KATP Channel Opener, ZD6169, given intravesically, in rats with and without bladder outflow obstruction.Materials and Methods: Female, conscious Sprague-Dawley rats, normal or with bladder hypertrophy and overactivity secondary to bladder outflow obstruction, were given ZD6169 intravesically (10 or 100 ng./ml.), and intra-arterially (1 mg./kg.). Continuous cystometry was performed.Results: In normal and obstructed rats, intravesical ZD6169 had similar, dose-dependent effects on bladder function. In obstructed rats, ZD6169 (100 ng./ml.) significantly decreased micturition pressure (17%), and increased bladder capacity (32%), micturition volume (18%), residual volume (145%), and inter-contraction interval (71%). There was a marked decrease in both frequency (40%) and amplitude (43%) of the spontaneous bladder activity. When given intra-arterially in obstructed rats ZD6169 increased bladder capacity (19%) and residual volume (47%) and decrease...

Hai Wang - One of the best experts on this subject based on the ideXlab platform.

  • targeting hypertension with a new adenosine triphosphate sensitive potassium Channel Opener iptakalim
    Journal of Cardiovascular Pharmacology, 2010
    Co-Authors: Jinghui Huang, Chaoliang Long, Yanfang Zhang, Hai Wang
    Abstract:

    : 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.

  • iptakalim a vascular atp sensitive potassium katp Channel Opener closes rat pancreatic β cell katp Channels and increases insulin release
    Journal of Pharmacology and Experimental Therapeutics, 2007
    Co-Authors: Naoko Misaki, Hai Wang, Sechiko Suga, Guohui Li, Yongchang Chang, Makoto Wakui, Jie Wu
    Abstract:

    Sulfonylureas have been the leading oral antihyperglycemic agents, and they presently continue to be the most popular antidiabetic drugs prescribed for treatment of type 2 diabetes. However, concern has arisen over the side effects of sulfonylureas on the cardiovascular system. Here, we tested the hypothesis that iptakalim, a novel vascular ATP-sensitive potassium (KATP) Channel Opener, closes rat pancreatic β-cell KATP Channels and increases insulin release. Rat pancreatic β-cell KATP Channels and heterologously expressed KATP Channels in both human embryonic kidney (HEK) 293 cells and Xenopus oocytes were used to test the pharmacological effects of iptakalim. Patch-clamp recordings, Ca2+ imaging, and measurements of insulin release were applied. Patch-clamp whole-cell recordings revealed that iptakalim depolarized β-cells, induced action potential firing, and reduced KATP Channel-mediated currents. Single-Channel recordings revealed that iptakalim reduced the open probability of KATP Channels without changing Channel sensitivity to ATP. By closing β-cell KATP Channels, iptakalim elevated intracellular Ca2+ concentrations and increased insulin release. In addition, iptakalim decreased the open probability of recombinant Kir6.2FL4A (a trafficking mutant of the Kir6.2) KATP Channels heterologously expressed in HEK 293 cells, suggesting that iptakalim suppressed the function of β-cell KATP Channels by directly inhibiting the Kir6.2 subunit. Finally, iptakalim inhibited Kir6.2/SUR1, but it activated Kir6.1/SUR2B (vascular-type), KATP Channels heterologously expressed in Xenopus oocytes. Iptakalim bidirectionally regulated pancreatic-type and vascular-type KATP Channels, and this unique pharmacological property suggests the potential use of iptakalim as a new therapeutic strategy for treating type 2 diabetes with the additional benefit of alleviating vascular disorders.

  • systematic administration of iptakalim an atp sensitive potassium Channel Opener prevents rotenone induced motor and neurochemical alterations in rats
    Journal of Neuroscience Research, 2005
    Co-Authors: Yong Yang, Yan Long, Fang Wang, Jianhua Ding, Hai Wang, Jie Wu, Gang Hu
    Abstract:

    Our previous studies revealed that iptakalim, a novel ATP-sensitive potassium Channel Opener, has a significant neuroprotective function against ischemia in vivo or rotenone-induced neurotoxicity in vitro. To investigate the potential pharmaceutical benefit of ATP-sensitive potassium Channel Openers on neurodegenerative diseases, we studied the effects of iptakalim and diazoxide, a selective mitochondrial ATP-sensitive potassium Channel Opener, on the rotenone-induced nigrostriatal degeneration in rats. Iptakalim (1.5 mg/kg/day, orally) or diazoxide (1.5 mg/kg/day, orally) alone was administered to rats for 3 days, and then for 4 weeks was used daily with an injection of rotenone (2.5 mg/kg/day, subcutaneously) 1 hr later each time. The results showed that rotenone-infused rats exhibited parkinsonian symptoms and had dopamine depletion in the striatum and substantia nigra. Pretreatment with iptakalim or diazoxide prevented rotenone-induced catalepsy and the reduction of striatum dopamine contents. Moreover, iptakalim and diazoxide reduced the enzymatic activities and mRNA levels of inducible nitric oxide synthase elicited by chronic administration of rotenone. These neuroprotective effects of iptakalim and diazoxide were abolished by 5-hydroxydecanoate, a selective mitochondrial ATP-sensitive potassium Channel blocker. In conclusion, our data suggested that mitochondrial ATP-sensitive potassium Channels might play a key role in preventing both parkinsonian symptoms and neurochemistry alterations induced by rotenone in rats. The selective activation of mitochondrial ATP-sensitive potassium Channels may provide a new therapeutic strategy for prevention and treatment of neurodegenerative disorders such as Parkinson's disease. © 2005 Wiley-Liss, Inc.