Sodium potassium and calcium ions regulate the shape and frequency of action potentials in skeletal muscles, cardiac muscles and neurons.
Mutations in genes are related to andersontawil syndrome, dm, episodic ataxia, epilepsy and erectile dysfunctionGenes encoding the potassium channels are subject to spontaneous mutations and are associated with channelopathies like andersontawil syndrome , diabtes mellitus, epilepsy, episodic ataxia , erectile dysfunction etc. Anderson syndrome is accompanied by cardiac arrhythmias reminiscent of long QT syndrome, periodic paralysis, and dysmorphic bone structure in face and fingers . The syndrome is an autosomal dominant disorder and is caused by mutations in KCNJ2 gene which encodes the Kir2.1subunit. The symptoms in the heart are caused by reduction in Kir2.1 subunit: function that prolongs the plateau phase of action potential and trigger arrhythmias, abnormal bone structure in the disease would be caused by provoking dysfunction of osteoclasts. Low extracellular pH in extracellular matrix maintained by H+ SECRETION via ATP driven proton pump is critical for proper degradation of the bone by osteoclasts. Since H+ secretion is achieved in exchange for potassium transport through Kir channels disrution of these channels causes osteoclast dysfunction that could lead to svere bone deformity
In humans potassium channel subunits are coded by atleast 75 genes and all of these have a sequence of 5 amino acids (TVGYG), THREONINE, VALINE, GLYCINE, TYROSINE, GLYCINE . Forming potassium selectivity filter . This forms signature of thechannel and allows only potassium channels to pass
Standard nomenclature of these channels is proposed by Nomenclature and Drug classification International Union of basic clinical pharmacology committee on receptor nomenclature and drug classification subcommitees on K channels.
Differs from 2 tm in having two pores rather than one and forms functional dimers in contrast to usual potassium channel tetramers
The subfamilies TREK and task are sensitive to both volatile and inhalational anesthetic agentsSUBTYPE TASK SEEMS TO BE SENSITIVE TO CHANGES IN EXTERNAL Ph . This family appears to play a important role in regulating cell volume. These potassium channels are insensitive to k channel blockers like tetraethyl ammonium and 4-aminopyrodine Anandamide: endogenous cannabinoid neurotransmitter. The name is taken from the Sanskrit word ananda, which means "bliss, delight", and amide
4AP: 4 AMINO PYRIDINE, TEA: TETRAETHYL AMMONIUM, RETIGABINE A NOVEL ANTICONVULSANT OPENS NEURONAL Kv channels KCNQ2-5This family includes voltage gated channels like Kv, KCNQ, EAG, and calcium activated slo and Sk subfamilies
IF YOU HAVE ALOOK AT ALL THE TABLES CURRNETLY THE MOST EXPLORED POTASSIUM CHANNELS ARE THE ATP SENSITIVE POTASSIUM CHANNELS AND AND VOLTAGE GATED POTASSIUM CHANNELS
SUR2A AND 2B DIFFER ONLY IN COOH TERMINAL 42 AMINOACIDS
These channels show inter tissue variation in their sensitivity to Kcblockers and openers . This varied response is attributed to diffwerent combinations of KIR6.X and SUR subunits in a given tissueSUR2A isoform predominantly expressed in cardiac and skeletal muscles and SUR2B in smooth muscle are activated by broad range of potassium channel openersWhereas SUR1 isoform present in beta cells and neurons is activated by a limited number of openers The distribution of SUR isoforms with differential responsiveness to potassium channel openers provides unique targets for development of tissue specific therapeutics KATP channels in brain and β cells are predominately composed of KIR6.2 and SUR1, while in heart and skeletal muscle it is KIR6.2 and SUR2A. The combination of KIR6.1 with SUR2B is seen in vascular smooth muscle, with KIR6.2 making a contribution in some smooth muscles. Both KIR6.1 and KIR6.2 have been shown to have 70 per cent similarity in their amino acid sequences15. SUR1 and KIR6.2 are located on chromosome 11 (11p15.1) and are encoded by the genes ABCC8 and KCNJ11, respectively14. The other subunits of this channel namely KIR6.1 and SUR2 are coded by the genes KCNJ8 and ABCC9, respectively.
insulin release following KATP channel blockade in pancreatic β cells.
Endothelin is a potent vasoconstrictor peptide able to close KATP MORE RECENTLY TWO PEPTIDES ALPHA AND BETA ENDOSULFINE HAVE BEEN IDENTIFIED WHICH DISPLACE GLIBENCLAMIDE FROM RAT CEREBRAL CORTEX MEMBRANESIt is speculated that endosulfine may regulate beta cell secretion and proliferation and the lack of this peptide may may lead to NIDDM. IT IS ALSO SPECULATED THAT ENDOSULFINE MAY HAVE ROLE IN REGLATING K atp CHANNEL ACTIVITY IN THE cns , PERHAPS PLAYING A ROLE IN RESPONSE TO CEREBRAL ISCHEMIA
VIP stimulates contractility in the heart, causes vasodilation, increases glycogenolysis, lowers arterial blood pressure and relaxes the smooth muscle of trachea, stomach and gall bladder. In humans, the vasoactive intestinal peptide is encoded by the VIP gene.The hyperpolarization of acetylcholine appears to be mediated by EDHF. at present it is not clear whether edhf activates k ATP channels. THE Ach mediated hyperpolarization and vasorelaxation are partly sensitive to glibenclamideMyocardial ischemia can result in increased resistance to subsequent more severe episodes of ischemia. This ischemic preconditioning refers to a brief coronary occlusion which confers some measure of ischemic tolerance to subsequent more prolonged occlusion. The exact mechanism is not known but it appears that release of adenosine during preconditioning phase initiates the protection probably through KATP activation . Glienclamide inhibits this action. Adenosine is able to reduce infarct size when administered at reperfusion and infarct size was shoen to decrease using both A1 and A2 specific analogue3s given at reperfusion . Thus as in reasctive hyperemia and during ischemia adenosine may act as an endogenous activator of K atp channels THE Ach mediated hyperpolarization and vasorelaxation are partly sensitive to glibenclamide (cerebral rabbit artery, but not mesentric arteries in rat)
C2 and C3 are intolerable to the structural changes , c4 is markedly flexible in type of substituent it can accommodate. COMBINING STRUCTURAL FEATURES OF CROMAKALIM AND PINACIDIL LED TO SYNTHESIS OF compounds exhibited cardiac and vasvular properties of these drugs Selectivity between different smooth muscle types has been reported for example simple modification in the 6 –position of benzofuran structure cromakalim has led to apparent respiratory smooth muscle selective agents Rimakalim
Currently there is some debate over mechanisms involved in the production of vascular smooth muscle relaxation by potassium channel openers. Initially it was assumed that hyperpolarization caused by potassium efflux produced closure of voltage operated calcium channels thus preventing depolarization induced calcium entry which ultimately produced relaxation
K channel openers may have direct effect on intracellular calcium stores this inference was derived as cromakalim appeared equieffective in many tissues against number of vasoconstrictors that utilized voltage operated calcium channels to varying extent. These additional actions may be linked to the hyperpolarization induced by potassium channel openers Decreased neurotransmitter release from nerve terminals this may be related to hyperpolarization of nerve terminal me3mbrane Potassium channel openers may also activate calcium activated potassium channels in vascular smooth muscles . Colectively this means that mode of asction of potassium channel openers may notr be as simple as thought first and a great deal of research is required in this area
SARCOLEMMAL atp SENSITIVE POTASSIUM CHANNELS ARE INVOLVED IN THE MAINATAINEN E OF THE BASAL
Because of hetrogenous effect of shortening How ever on thought is that K Channel openers will produce vasodilation increase the coronary blood flow thus diluting the drug causing arrhythmia so drug induced arrhythmias may be reduced
, Nicorandil causes venodilationalsoUnder normal conditions β-cell pancreatic KATP channels are spontaneously open In contrast smooth muscle KATP are closed due to sufficiently high ATP Levels and they have no regulatory effect on smooth muscle tone. Only in cells with depleted levels of ATP like (hypoxia and/or ischaemia) KATP channels open and therefore affect resting membrane potential. KATP channels may play a role in the prevention of cell injury under these circumstances.
Potassium channel openers primarily vasodilate arterioles and arteries Venodilationdoesnot occur with most potassium channel openers but nicoradil by means of nitrate moeity also dilates venous capacitance vessels and there by reduce cardiac preload
Despite potent vasodilator effect, do not cause decrease blood supply to ischemic tissues so do not cause coronary steal phenomnenon
DECREASE bp in DOSE DEPENDENT MANNER IN BOTH NORMOTENSIVES AND HYPERTENSIVES. CAN CONTROL BLOOD PRESSURE IN 75-85% OF PATOENTS LEVOCROMAKALIM SELECTIVELY DILATES VESSELS WHERE ENDOTHELIUM IS DYSFUNCTIONAL FOR example in hypertension, atherosclerosis or hypercholesterolemia
Due to hyperpolarization of smooth muscles, neurons and secretory cells
Development odbroncho-selective KCOs with higher efficacy and inhaled drug preparations with poor systemic absorption may limit these adverse effects
Clinical trials of potassium channel openers in the treatment of bronchial asthma . The actions of these drugs was complicated by cardiovascular side effects like postural hypotension and headache. U-89,232 appears to be a K channel opener with selective cardiac actions , that is lacking cardiovascular effects
Prokinetic drugs like cisapride, mosapride, metoclopramide, erythromycin and domperidone have been used to overcome morphine-induced gastrointestinal delay. These drugs act through receptors like serotonergic, cholinergic and motilin. However it is not known if these have any action through Ca2+ and K+ channels. There is a possibility to think that prokinetic drugs may be acting by enhancing ‘L’ type Ca2+ channels and blocking KATP channels
In an in vitro study, glibenclamide was shown to antagonize the relaxant effect of levcromakalim on longitudinal smooth muscle of rat ileum47. Moreover, glibenclamide has been found to increase small intestinal transit in mice48. Similarly in an in vivo study conducted by us in mice, glibenclamide significantly decreased small intestinal transit when administered along with morphine and mosapride. This shows that concurrent administration of glibenclamide (K+ channel blocker) with mosapride (a prokinetic agent) and morphine counteracts the effect of mosapride46.
Urinary incontinence caused by detrusor muscle hyperactivity and involuntary contraction of bladder is very common in elderly Detrusor muscle hyperactivity is due to supersensitivity to neurogenic and myogenic stimuli causing depolarization and increased membrane excitability . Hyperpolarization of membrane through opening of K+ channels provides an approach to supress bladder hyperreactivity in hypertrophic bladder including outflow obstruction Due to lack of selectivity and the resultant side effects, KCOs used to relax urinary bladder, may also relax vascular smooth muscle resulting in hypotension and reflex tachycardia Thus exploring the subtypes of K+ channels can lead to the discovery of highly selective KCOs with minimal side effects. Such drugs are under current development
Intracorporealvasorelaxants used currently produce priapism, local fibrosis and pain Especially of vascular etiology Guanylatecyclase stimulation , further clinical investigation needed to demonstrate the efficacy of topical and or oral KCO alone or in combination with other vasoactive agents
During labour forceful contractions of the uterus can occlude its blood supply which may lead to hypoxia . Hypoxia can reduce or even abolish uterine force in in isolated human uterus More work is needed in this area to increase our understanding of KATP channels in this response
Also familial persistanthyperinsulinemic hypoglycemia of infancy due to mutations in Katp subunits Katp channels in Beta cells of pancreasPotassium channel openers can be useful in insulinoma – hypoglycemia Currently evidence is their that KATP channels present in the adenohypophysis are involved in the release of growth hormone secretion with responses parellel to that seen in pancreatic beta cells. Somatostatin is known to regulate insulin secretion from insulinoma cells via activation of KATPSomatostatin has been proposed to regulate prolactin secretion from pitutary via the same mechanism
Cromakalim and diazoxide prevent signs of morphine withdrawlppt by naloxone may have role in chronic pain syndromes , may be used for management of narcotic withdrawl in addicted patients , substitute for morphine by decreasing withdrawl symptoms in morphine dependent patients
Cromakalim and bimakalimsupressmjyotonic activity and after contractions and spontaneous twitches
Problem of selectivity can be easily overcome by direct topical application of drug to skin Mechanism of action Indirect: peripheral vasodilation-> improvement in blood circulation Increased DNA synthesis which converts balding hair follicles into non balding hair follicles This is postulated to be linked to KATP channels present in follicular keratinocytes
Minoxidil decreased period of baldness from maximal hair loss to first regrowth AFTER CHEMOTHERAPY THE ROLE OF THESE AGENTS IN PROMOTING HAIR GROWTH AND STABILIZING HAIR LOSS ESPECIALLY MALE PATTERN BALDNESS IS HIGHLY PROMOSING
Effect is not permanent , on stoppage loss after 4-6 months Vertex balding more than frontal balding
Among the KCOs used therapeutically, minoxidil is the most potent vasodilator but is reserved mainly for severe resistant hypertension. Minoxidil also has cardioprotective action mediated through mitochondrial KATP channel These agents could contribute to their cardioprotective effects by improving coronary blood flow.Another KCO, nicorandil has been approved for angina, hypertension and cardiac ischaemia. However, KATP channels in vascular and non vascular smooth muscle are 10 - 100 times more sensitive to KCOs compared to that in heart
Other drugs likemeclofenamic acid and diclofenac also have antiepileptic action
Potassium channel openers Dr. Naser Ashraf Tadvi Associate Professor Dept. of Pharmacology Kamineni Institute of Medical Sciences, Narketpally
Ion Channels• Ion channels are protein molecules that form pores on the plasma membrane and intracellular organelle of all cells.• They exploit the ionic gradient between cytosolic side and Extracellular space• Responsible for transfer of ions• Regulate the shape and frequency of Action potential• Potassium channels form most abundant and diverse class of ion channels
Potassium channels• They are membrane spanning proteins allowing efflux of potassium ions through K+ selective pore.• Their activity may be regulated by voltage, calcium, or neurotransmitters• Play important role in cellular and cardiac repolarization, smooth muscle relaxation, neurotransmitter and insulin release.
Classification of potassium channels• Grouped into families based on their structure as well as physiological & pharmacological criteria .• Mainly classified into three families – 2 TM: Inward rectifier potassium channels – 4 TM : Underlying cause for leak currents in neuronal cells – 6 TM: includes voltage gated channels• These channels are composed of two subunits namely primary pore forming α-subunit and an associated regulatory subunit.
α –subunit β –subunitsComposite model of a voltage-dependent K+ channel.
2TM family subtypes (Inward rectifier)2TM Family Subtype Activators InhibitorsKIR1.X 1.1KIR2.X 2.1 to 2.4 Mg2+, polyaminesKIR3.X 3.1 to 3.4 PIP2G ProteinactivatedKIR4.X 4.1-4.2KIR5.X 5.1KIR6.X 6.1 – 6.2 Minoxidil , Glibenclamide,ATP Associated cromakalim, tolbutamidesensitive subunit SUR1, diazoxide, SUR2A,2B nicorandilKIR7.X 7.1
4TM family of K channels• This family is underlying cause of leak currents in the neuronal cells• The primary pore forming α-subunit has two pore domains• These two pore domain channels have emerged as potential target for inhalational anaesthetic agents.• Halothane seems to highly efficacious in activating these subtypes TREK AND TASK
4TM family subtypes4TM family Subtypes Activators inhibitorsTWIK 1-3 Acid PHTREK TREK 1,2 & Halothane, Riluzole, Heat, TRAAK Arachidonic Acid,pHTASK 1,3,5 Halothane, alkaline PH AnandamideTALK 1,2,4 ALKALINE PHTHIK 1-2 HalothaneTRESK 1 Arachidonic acidTWIK: TANDOM OF PORE DOMAINS IN A WEAK INWARD RECTIFYING K CHANELTREK:TWIK RELATED POTASSIUM CHANNELTASK: TWIK RELATED ACID SENSITIVE POTASSIUM CHANNELTALK: TWIK RELATED ALKALINE PH ACTIVATED K CHANNELTHIK: TANDEM PORE DOMAIN HALOTHANE INHIBITED CHANNELTRESK: TWIK RELATED SPINAL CORD POTASSIUM CHANNEL
ATP sensitive potassium channels• Present in the pancreas , heart, brain, smooth muscle, and skeletal muscle.• close when ↑ATP , ↑ ADP: opens the channels• Structure : octameric with – 4 KIR6 subunits and 4 SUR subunits
Structure of KATP channels SUR subunit has 3 transmembrane domains. TMD0,TMD1 & TMD2 , and 2 nucleotide binding domains NBD1 in between TMD1 & TMD2 , NBD2: in COOH terminus
Tissue specific distribution of different subunits of KATPTISSUE SUBUNITSPancreatic β- cells SUR1 KIR6.2Neurons SUR1 KIR6.2Cardiac & skeletal SUR2A KIR6.2musclesVascular & smooth SUR2B Kir6.1/kir6.2muscles
MOA of potassium channel openers Potassium channel openers Open KATP Enhance K+ efflux Membrane Hyperpolarization ↓ Ca 2+ entry Reduced intracellular calcium Smooth muscle relaxation
Other mechanisms of action of K+ channel openers• Hyperpolarization induced by K ATP CO inhibits production of 1,4,5 IP3and hence Ca2+ release from intracellular stores• Hyperpolarization may also be linked with ↓ sensitivity of contractile elements of vascular smooth muscles• ↓ neurotransmitter release from nerve terminals
Pharmacological actions & Uses of potassium channel openers
Actions on heart• Sarcolemmal KATP – shorten duration of cardiac action potential – Negative ionotrophic effect in cardiomyocytes and vasodilation of blood vessels• Mitochondrial KATP – Channels open in response to ischemia – Trigger ↑mitochondrial ROS production amplify cell signalling pathway – Leads to gene transcription and cell growth – Also prevents disruption of mitochondrial structure and function
Actions on heart• Cardiac preconditioning effect – Brief episode of ischemia can result in an increase resistance to subsequent more severe episodes of ischemia – This ischemic preconditioning to brief ischemia may occur due to adenosine by activation of KATP
Actions on heart• Antiarrhythmic actions – Prevent arrhythmias related to triggered activity , abnormal repolarization and early or delayed after depolarization – Prolonged QT syndrome, drug induced ventricular arrhythmias nicorandil and pinacidil were effective – ↑ K+ conductance shortens APD and contributes to extracellular K accumulation . This may be responsible for ischemia induced arrhythmias – May also facilitate re-entrant arrhythmias
Actions on blood vessels• Mainly arteriolar vasodilation
Therapeutic uses in cardiovascular conditions• Ishemic heart disease : – Angina , Myocardial infarction• Hypertension• Pulmonary hypertension• Perioperative cardiac protection• Organ perfusion and preservation for transplant• Rhythm disturbances• Peripheral vascular disease
Respiratory system• In bronchial asthma – Hyperpolarization of smooth muscles, neurons and secretory cells – Reduce bronchial hyper-responsiveness by direct effect on smooth muscle relaxation and through inhibition of excitatory NANC transmission
Role in bronchial asthma• Broncho-relaxation• Prevention of bronchoconstriction• ↓ microvascular leakage & goblet cell secretion• ↓ dyspnoea evoked by inflammatory mediators & airway hyperesponsiveness• Do not develop bronchial hyper-reactivity & tolerance on long term use
Comparison of potencies Potassiumchannel openers used in Bronchial AsthmaCompound IC-AHR Ozone – MAP AHRLevocromakalim 22 - 10Bimakalim 0.5 0.3 2Rilmakalim 0.2 - 10
Action on intestines• Minoxidil ↑the effect of morphine on gastrointestinal delay in presence of mosapride• Pinacidil and cromakalim administered orally, inhibited the intestinal propulsion of charcoal, and castor oil-induced diarrhoea in mice.• This confirms the presence of KATP channels in the intestine and suggests a new approach for the symptomatic treatment of diarrhoea.
Actions on urinary bladder• KATP channels also found in the bladder smooth muscle.• A-251179, a potent novel KATP channel opener related to pinacidil has shown high selectivity towards these channels• ↓ed spontaneous contractions in urinary bladder.• prolongs the time interval between voids by ↑ bladder capacity without affecting voiding efficiency• This novel compound represents an interesting area to be explored for the application of KATP channel openers
Role in erectile dysfunction• Potassium channel openers hyperpolarize and relax corpus cavernosum• Produce penile tumescene and erection• Minoxidil lubricating gel on glans penis was more effective than placebo or NTG in facilitating erection with less side effects• Nicorandil like compounds additional vasodilation due to NO release
Actions on uterus• Capable of producing glibenclamide sensitive relaxation of uterine smooth muscle• May be of used as uterine relaxants & have some place in treatment of dysmenorrhoea, and preterm labour• Hypoxia may contribute to uterine dystocia KATP channels may be involved in this effect.
Actions on endocrine system• KATP Channels essential in regulating insulin secretion from pancreatic β-cells• Diazoxide used in management of hypoglycemia due to hyperinsulinemia in inoperable islet cell adenoma, & islet cell hyperplasia• Interesting finding is that diazoxide has also demonstrated antidiabetic activity on prolonged use in type II diabetes
Actions on nervous system• Strong neuroprotective effect when injected prior to ischemic or epileptic insult• Inhibit release of Aspartate and glutamate, which are released during hypoxia with neuronal depolarization• Also inhibit Ca2+ loading , decreases excitability and prevent neuronal injury
Uses of KCOs in neurological diseases• Subarachnoid haemorrhage : – prevent and reverse vasospasm by relaxing basilar artery without affecting systemic hemodynamics• Epilepsy• Alzheimers disease• Antinociceptive effect – Mediated through release of endorphins and enkephalins and activation of opioid receptors
Role in muscular diseases• Cromakalim and pinacidil shown effect in Myotonia congenita and myotonic dystrophy• Hypokalemic periodic paralysis• Peripheral vascular disease
Action on hair growth• Promote hair growth by direct effect on hair follicles and also by improving blood supply to hair follicles (vasodilation)• Minoxidil stimulates DNA synthesis in epidermal keratinocytes and hair follicles• ↑ proliferation and differentiation of epithelial hair shaft• ↑hair density by induction of anagen phase and ↑ anagen duration
Diazoxide• Compound related to chlorthiazide• Potent direct vasodilator• Pharmacokinetics: – 95% protein bound, should be injected IV – T ½ = 36 hrs• Uses: – malignant and pulmonary hypertension – Hypoglycemia – Uterine hyperactivity
Minoxidil• Prodrug activated to active metabolite minoxidil sulfate• Pharmacokinetics – Well absorbed orally – T ½ = 3-4 hrs – 85 % metabolized rest excreted unchanged• Uses – Alopecia areata & alopecia androgenita – Malignant / refractory hypertension – Impotence
Minoxidil• Dose: – 2.5 mg – 80 mg BD orally – 2% gel or 5 % gel also available apply 1 ml BD in alopecia• Adverse effects – Hypertrichosis – Pleural, pericardial effusion – Reflex tachycardia – Fluid and salt retention
Nicorandil• In addition to acting as KCO also produces vasodilation by acting as NO donor• Decreases preload as well as after load• Pharmacokinetics: – Well absorbed orally, no significant first pass metabolism – T ½ = 50 min• Uses: Angina, Arrhythmias
Pinacidil• Similar to nicorandil in use, properties and adverse effects• Oral bioavailability 57% , T 1/2 = 1-3 hrs• Metabolized by CYP450• Can cause fluid retention• Dose: – 12.5 mg BD , in combination with diuretic – 37.5 mg controlled release tablet available
Flupirtine• Selective Neuronal KCO (SNEPCO)• Triaminopyridine recently marketed in Italy• Opens Kv7.2 –Kv 7.5 Potassium channels• Uses: – Mild to moderate pain especially associated with muscle tension – Retinal ischemia, stroke, migraine – Neurodegenerative disorder• Dose: – 100-300 mg/day
Retigabine• Structural analog of flupirtine• Used in epilepsy (broad spectrum antiepileptic)• Mechanism of action – Activates voltage dependent neuronal potassium channels Kv7.2-Kv7.6 – Hyperpolarizes neuronal resting membrane potential leading to inhibition of spontaneous or synaptically trigerred neuronal activity
Retigabine• Pharmacokinetics – 60 % bioavailability , Low first pass metabolism – 80% plasma protein binding , T ½ = 8 hrs – Does not induce or inhibit CYP450 – Metabolized by acetylation• Dose: 600-1200 mg/day• Adverse effects – Somnolence, confusion, dizziness, headache
Iptakalim• Novel ATP sensitive KCO• Strong antihypertensive effect• Antipsychotic action• Mechanism : – Inhibitory function on excess dopamine and glutamate release – Highly lipophilic crosses BBB• Dose: 5 – 20 mg
Take home message• Potential area of research• Multi- utility drugs but lack specificity in action• Need of developing selective drugs• Most important uses are alopecia, angina, hypertensive crisis• Newer KCOs like retigabine, flupirtine iptakalim are promising drugs
References1. Hibino H, Inanobe A, Furutani K, Murukami S, Findlay I, Kurachi Y. Inwardly rectifying potassium channels: Their structure, function and physiological roles.Physiol Rev. 2010;90:291-366.2. Enyedi P, Czirjak G. molecular background of leak K+ currents: two pore domain potassium channels. Physiol Rev. 2010;90:559-605.3. Barrese V, Miceli F, Soldovieri MV, Ambrosino P, Lannotti FA, Cilio MR, et.al. Neuronal Potassium channel openers in the management of epilepsy: Role potential of retigabine. Clinical Pharmacology: Advances and Applications. 2010;2:225-36.
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References7. Pollesello P, Mebazaa A. ATP dependent potassium channels as key target for the treatment of myocardial and vascular dysfunction. Current Opinion in Critical Care. 2004;10:436-41.8. Challinor Rogers JL, McPherson GA. Potassium channel openers and other regulators of KATP channels. Clinical and Experimental Pharmacology and Physiology. 1994;21:583-97.
References9. Fozart JR, Manley PW. Potassium channel openers: Agents for the treatment of airway hyperreactivity . Prog Respir Res. 2001;31:77-80.10. Graffi M, Longobardi C, Giovannini A, Viscardi D, Costa F, Palomba R. Analgesia and S.N.E.P.C.O. (Selective Neuronal Potassium Channel Openers): our experience with flupirtine. 5th International Meeting - Dialogues on anaesthesia and intensive care (Napoli, 18-19 november 2011).11. Sun T, Zhao C, Gang Hu, Ming li. Iptakalim: A potential antipsychotic drug with novel mechanisms?. European Journal of Pharmacology. 2010; 634: 68–76.