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Alison M Gurney - One of the best experts on this subject based on the ideXlab platform.

  • pulmonary vasoconstrictor action of kcnq Potassium Channel Blockers
    Respiratory Research, 2006
    Co-Authors: Shreena Joshi, Prabhu Balan, Alison M Gurney
    Abstract:

    KCNQ Channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ Channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ Channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ Channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ Channel Blockers, linopirdine and XE991, to promote pulmonary vasoconstriction. The tension developed by rat and mouse intrapulmonary or mesenteric arteries was measured using small vessel myography. Contractile responses to linopirdine and XE991 were measured in intact and endothelium denuded vessels. Experiments were also carried out under conditions that prevent the contractile effects of nerve released noradrenaline or ATP, or block various Ca2+ influx pathways, in order to investigate the mechanisms underlying contraction. Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim. The KCNQ Channel Blockers are potent and powerful constrictors of pulmonary arteries. This action may be selective for the pulmonary circulation as mesenteric arteries showed little response. The results imply that the drugs act directly on smooth muscle cells and contraction requires voltage-dependent Ca2+ influx. It is concluded that the drugs probably act by blocking KCNQ Channels in pulmonary artery myocytes, leading to membrane depolarization and Ca2+ influx through L-type Ca2+ Channels. This implies a functional role for KCNQ Channels in regulating the resting membrane potential of pulmonary artery myocytes.

Shreena Joshi - One of the best experts on this subject based on the ideXlab platform.

  • pulmonary vasoconstrictor action of kcnq Potassium Channel Blockers
    Respiratory Research, 2006
    Co-Authors: Shreena Joshi, Prabhu Balan, Alison M Gurney
    Abstract:

    KCNQ Channels have been widely studied in the nervous system, heart and inner ear, where they have important physiological functions. Recent reports indicate that KCNQ Channels may also be expressed in portal vein where they are suggested to influence spontaneous contractile activity. The biophysical properties of K+ currents mediated by KCNQ Channels resemble a current underlying the resting K+ conductance and resting potential of pulmonary artery smooth muscle cells. We therefore investigated a possible role of KCNQ Channels in regulating the function of pulmonary arteries by determining the ability of the selective KCNQ Channel Blockers, linopirdine and XE991, to promote pulmonary vasoconstriction. The tension developed by rat and mouse intrapulmonary or mesenteric arteries was measured using small vessel myography. Contractile responses to linopirdine and XE991 were measured in intact and endothelium denuded vessels. Experiments were also carried out under conditions that prevent the contractile effects of nerve released noradrenaline or ATP, or block various Ca2+ influx pathways, in order to investigate the mechanisms underlying contraction. Linopirdine and XE991 both contracted rat and mouse pulmonary arteries but had little effect on mesenteric arteries. In each case the maximum contraction was almost as large as the response to 50 mM K+. Linopirdine had an EC50 of around 1 μM and XE991 was almost 10-fold more potent. Neither removal of the endothelium nor exposure to phentolamine or α,β-methylene ATP, to block α1-adrenoceptors or P2X receptors, respectively, affected the contraction. Contraction was abolished in Ca2+-free solution and in the presence of 1 μM nifedipine or 10 μM levcromakalim. The KCNQ Channel Blockers are potent and powerful constrictors of pulmonary arteries. This action may be selective for the pulmonary circulation as mesenteric arteries showed little response. The results imply that the drugs act directly on smooth muscle cells and contraction requires voltage-dependent Ca2+ influx. It is concluded that the drugs probably act by blocking KCNQ Channels in pulmonary artery myocytes, leading to membrane depolarization and Ca2+ influx through L-type Ca2+ Channels. This implies a functional role for KCNQ Channels in regulating the resting membrane potential of pulmonary artery myocytes.

Igor D.g. Duarte - One of the best experts on this subject based on the ideXlab platform.

  • Involvement of GABAA receptor-associated chloride Channels in the peripheral antinociceptive effect induced by GABAA receptor agonist muscimol
    European Journal of Pharmacology, 2007
    Co-Authors: Gláucia Maria Lopes Reis, Daniela Da Fonseca Pacheco, Janetti N. Francischi, Maria Salete De A Castro, Andrea C. Perez, Igor D.g. Duarte
    Abstract:

    Abstract The effect of chloride and Potassium Channel Blockers on the antinociception induced by GABAA receptor agonist muscimol was investigated using the paw pressure test. Muscimol (1, 2, 4, 8 ng/paw) elicited a peripheral antinociceptive effect that was antagonized by bicuculline (10, 20, 40, 80 ng/paw), suggesting a specific effect. The muscimol effect was reverted by the chloride Channel coupled GABAA receptor blocker, picrotoxin (0.4, 0.6, 0.8, 2 μg/paw). Potassium Channel Blockers did not modify the peripheral antinociception induced by muscimol. This study provides evidence that the peripheral antinociceptive effect of muscimol results from the activation of GABAA receptor-associated chloride Channels.

  • dibutyryl cyclic gmp induces peripheral antinociception via activation of atp sensitive k Channels in the rat pge2 induced hyperalgesic paw
    British Journal of Pharmacology, 2001
    Co-Authors: Adriana C Soares, Igor D.g. Duarte
    Abstract:

    1. Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E2, we studied the action of several K(+) Channel Blockers in order to determine what types of K(+) Channels could be involved in the peripheral antinociception induced by dibutyrylguanosine 3 : 5'-cyclic monophosphate (DbcGMP), a membrane permeable analogue of cyclic GMP. 2. DbcGMP elicited a dose-dependent (50, 75, 100 and 200 microg paw(-1)) peripheral antinociceptive effect. The effect of the 100 microg dose of DbcGMP was considered to be local since only a higher dose (300 microg paw(-1)) produced antinociception in the contralateral paw. 3. The antinociceptive effect of DbcGMP (100 microg paw(-1)) was dose-dependently antagonized by intraplantar administration of the sulphonylureas tolbutamide (20, 40 and 160 microg) and glibenclamide (40, 80 and 160 microg), selective Blockers of ATP-sensitive K(+) Channels. 4. Charybdotoxin (2 microg paw(-1)), a selective blocker of high conductance Ca(2+)-activated K(+) Channels, and apamin (10 microg paw(-1)), a selective blocker of low conductance Ca(2+)-activated K(+) Channels, did not modify the peripheral antinociception induced by DbcGMP. 5. Tetraethylammonium (2 mg paw(-1)), 4-aminopyridine (200 microg paw(-1)) and cesium (800 paw(-1)), non-selective voltage-gated Potassium Channel Blockers, also had no effect. 6. Based on this experimental evidence, we conclude that the activation of ATP-sensitive K(+) Channels could be the mechanism by which DbcGMP induces peripheral antinociception, and that Ca(2+)-activated K(+) Channels and voltage-dependent K(+) Channels appear not to be involved in the process.

Christopher T Bever - One of the best experts on this subject based on the ideXlab platform.

  • Potassium Channel Blockers and openers as cns neurologic therapeutic agents
    Recent Patents on Cns Drug Discovery, 2007
    Co-Authors: Susan I V Judge, Paul J Smith, Peggy E Stewart, Christopher T Bever
    Abstract:

    Potassium (K+) Channels are the most heterogeneous and widely distributed class of ion Channels. K+ Channels are dynamic pore-forming transmembrane proteins known to play important roles in all cell types underlying both normal and pathophysiological functions. Essential for such diverse physiological processes as nerve impulse propagation, muscle contraction, cellular activation and the secretion of biologically active molecules, various K+ Channels are recognized as potential therapeutic targets in the treatment of multiple sclerosis, Alzheimers disease, Parkinsons disease, epilepsy, stroke, brain tumors, brain/spinal cord ischemia, pain and schizophrenia, migraine, as well as cardiac arrhythmias, pulmonary hypertension, diabetes, cervical cancer, urological diseases and sepsis. In addition to their importance as therapeutic targets, certain K+ Channels are gaining attention for their beneficial roles in anesthesia, neuroprotection and cardioprotection. The K+ Channel gene families (subdividing into multiple subfamilies) include voltage-gated (Kv: Kv1-Kv12 or KCNA-KCND, KCNF-KCNH, KCNQ, KCNS), calcium-activated (KCa: KCa1-KCa5 or KCNM-KCNN), inwardly rectifying (Kir: Kir1- Kir7 or KCNJ) and background/leak or tandem 2-pore (K2P: K2P1-K2P7, K2P9-K2P10, K2P12-K2P13, K2P15-K2P18 or KCNK) K+ Channels. Worldwide, the pharmaceutical industry is actively developing better strategies for targeting ion Channels, in general, and K+ Channels, in particular, already generating over $6 billion in sales per annum from drugs designed to block or modulate ion Channel function. This review provides an overview of recent patents on emerging K+ Channel Blockers and activators (openers) with potential for development as new and improved nervous system therapeutic agents.

  • Potassium Channel Blockers in multiple sclerosis neuronal kv Channels and effects of symptomatic treatment
    Pharmacology & Therapeutics, 2006
    Co-Authors: Susan I V Judge, Christopher T Bever
    Abstract:

    Abstract Multiple sclerosis (MS) is an inflammatory disease of the central nervous system (CNS) characterized by demyelination, with a relative sparing of axons. In MS patients, many neurologic signs and symptoms have been attributed to the underlying conduction deficits. The idea that neurologic function might be improved if conduction could be restored in CNS demyelinated axons led to the testing of Potassium (K+) Channel Blockers as a symptomatic treatment. To date, only 2 broad-spectrum K+ Channel Blockers, 4-aminopyridine (4-AP) and 3,4-diaminopyridine (3,4-DAP), have been tested in MS patients. Although both 4-AP and 3,4-DAP produce clear neurologic benefits, their use has been limited by toxicity. Here we review the current status of basic science and clinical research related to the therapeutic targeting of voltage-gated K+ Channels (Kv) in MS. By bringing together 3 distinct but interrelated disciplines, we aim to provide perspective on a vast body of work highlighting the lengthy and ongoing process entailed in translating fundamental Kv Channel knowledge into new clinical treatments for patients with MS and other demyelinating diseases. Covered are (1) Kv Channel nomenclature, structure, function, and pharmacology; (2) classic and current experimental morphology and neurophysiology studies of demyelination and conduction deficits; and (3) a comprehensive overview of clinical trials utilizing 4-AP and 3,4-DAP in MS patients.

Moo Yeol Lee - One of the best experts on this subject based on the ideXlab platform.

  • A Novel Pathway Underlying the Inhibitory Effects of Melatonin on Isolated Rat Urinary Bladder Contraction
    2013
    Co-Authors: June Hyun Han, Soon Chul Myung, Shin Young Lee, Moo Yeol Lee, In Ho Chang, Won Yong Kim, Seo Yeon Lee, Seung Wook Lee, Kyung Do Kim
    Abstract:

    The aim of the present study was to elucidate the direct effects of melatonin on bladder activity and to determine the mechanisms responsible for the detrusor activity of melatonin in the isolated rat bladder. W e evaluated the effects of melatonin on the contractions induced by phenylephrine (PE), acetylcholine (ACh), bethanechol (BCh), KCl, and electrical field stimulation (EFS) in 20 detrusor smooth muscle samples from Sprague-Dawley rats. To determine the mechanisms underlying the inhibitory responses to melatonin, melatonin-pretreated muscle strips were exposed to a calcium Channel antagonist (verapamil), three Potassium Channel Blockers [tetraethyl ammonium (TEA), 4-aminopyridine (4-AP), and glibenclamide], a direct voltage-dependent calcium Channel opener (Bay K 8644), and a specific calcium/calmodulin-dependent kinase II (CaMKII) inhibitor (KN-93). Melatonin pretreatment (10- 8 ∼ 10- 6 M) decreased the contractile responses induced by PE (10-9 ∼ 10- 4 M) and Ach (10-9 ∼10-4 M) in a dose-dependent manner. Melatonin (10-7 M) also blocked contraction induced by high KCl ([KCl]ECF; 35 mM, 70 mM, 105 mM, and 140 mM) and EFS. Melatonin (10-7 M) potentiated the relaxation response of the strips by verapamil, but other Potassium Channel Blockers did not change melatonin activity. Melatonin pretreatment significantly decreased contractile responses induced by Bay K 8644 (10- 11-

  • a novel pathway underlying the inhibitory effects of melatonin on isolated rat urinary bladder contraction
    The Korean Journal of Physiology and Pharmacology, 2012
    Co-Authors: June Hyun Han, Soon Chul Myung, Shin Young Lee, Moo Yeol Lee, In Ho Chang, Won Yong Kim, Seo Yeon Lee, Seung Wook Lee, Kyung Do Kim
    Abstract:

    The aim of the present study was to elucidate the direct effects of melatonin on bladder activity and to determine the mechanisms responsible for the detrusor activity of melatonin in the isolated rat bladder. We evaluated the effects of melatonin on the contractions induced by phenylephrine (PE), acetylcholine (ACh), bethanechol (BCh), KCl, and electrical field stimulation (EFS) in 20 detrusor smooth muscle samples from Sprague-Dawley rats. To determine the mechanisms underlying the inhibitory responses to melatonin, melatonin-pretreated muscle strips were exposed to a calcium Channel antagonist (verapamil), three Potassium Channel Blockers [tetraethyl ammonium (TEA), 4-aminopyridine (4-AP), and glibenclamide], a direct voltage-dependent calcium Channel opener (Bay K 8644), and a specific calcium/calmodulin-dependent kinase II (CaMKII) inhibitor (KN-93). Melatonin pretreatment (10(-8)~10(-6) M) decreased the contractile responses induced by PE (10(-9)~10(-4) M) and Ach (10(-9)~10(-4) M) in a dose-dependent manner. Melatonin (10(-7) M) also blocked contraction induced by high KCl ([KCl](ECF); 35 mM, 70 mM, 105 mM, and 140 mM) and EFS. Melatonin (10(-7) M) potentiated the relaxation response of the strips by verapamil, but other Potassium Channel Blockers did not change melatonin activity. Melatonin pretreatment significantly decreased contractile responses induced by Bay K 8644 (10(-11)~10(-7) M). KN-93 enhanced melatonin-induced relaxation. The present results suggest that melatonin can inhibit bladder smooth muscle contraction through a voltage-dependent, calcium-antagonistic mechanism and through the inhibition of the calmodulin/CaMKII system.

  • effects of l norgestrel on the endothelium dependent relaxation response of rabbit clitoral cavernous smooth muscles
    Fertility and Sterility, 2006
    Co-Authors: Soon Chul Myung, Saechul Kim, Shin Young Lee, Ji Yup Han, Moo Yeol Lee
    Abstract:

    Objective To determine the effect of a popular oral contraceptive, l-norgestrel (a synthetic progestogen), on relaxing response of clitoral cavernous smooth muscles. Design Prospective, randomized study. Setting Academic facility. Animal(s) Thirty adult female New Zealand White rabbits. Intervention(s) We conducted isometric tension studies with norepinephrine, endothelium-dependent (acetylcholine) and endothelium-independent (sodium nitroprusside) vasodilators, and l-norgestrel. The effects of nonspecific nitric oxide synthase inhibitor ( N w -nitro-l-arginine methyl ester) and the Potassium Channel Blockers (1 and 10 mM tetraethylammonium as well as 10 μM glibenclamide) on the reactivities of clitoral cavernous strips were investigated. Main Outcome Measure(s) Causation and power of developed tension after treatment. Result(s) Acetylcholine, sodium nitroprusside, and l-norgestrel produced concentration-dependent relaxation of the norepinephrine-precontracted strips. Both endothelium removal and treatment with 10 μM N w -nitro-l-arginine methyl ester completely inhibited the relaxation response to acetylcholine and l-norgestrel, and supplementation with 10 mM l-arginine partially reversed the inhibition. Incubation with either tetraethylammonium (TEA) or glibenclamide reduced the l-norgestrel-induced relaxation in a dose-independent manner. Conclusion(s) The l-norgestrel–induced relaxation of the clitoral cavernous smooth muscle is endothelium and nitric oxide dependent and may be related to more than two types of Potassium Channels activation.