Selective ATP-sensitive Potassium Research Articles

Evaluation of the Potential Effect of Iptakalim Hydrochloride on the QT Interval in Single- and Multiple-Ascending-Dose Studies Using Concentration-QTc Analysis.

Cardiotoxicity has been one of the most common causes of withdrawal of drugs from the market, and prolongation of the QT interval is one of the manifestations of drug cardiotoxicity. Iptakalim hydrochloride (ITKL) is a selective ATP-sensitive potassium channel opener used to treat hypertension. It is crucial to assess the risk of cardiac repolarization of ITKL in clinical trials. This study was conducted to determine the effect of ITKL on corrected QT (QTc) interval. A randomized, double-blind, placebo-controlled single- and multidose regimen was carried out to investigate the QTc and ITKL concentration correlation. ITKL was administered at doses of 5, 10, 15, and 20 mg with single oral administration and 10 and 20 mg with multiple oral administration, along with placebo, in 83 healthy subjects. Electrocardiograms (ECGs) and blood samples were collected on a preset time schedule. A ΔΔQTcF effect above 10 milliseconds was excluded at all observed plasma levels. Among them, the highest dose was 20 mg, which is twice the therapeutic dose. We concluded that ITKL did not prolong the QT interval in healthy subjects within the therapeutic dose. Retrospectively registered: The study was registered at Chinese Clinical Trial Registry with registration number ChiCTR1800014466.

The role of potassium channels and calcium in the relaxation mechanism of magnesium sulfate on the isolated rat uterus

MgSO4 is used as a tocolytic agent. It is considered to be a calcium channel antagonist, but a different mechanism of its action might be involved. The aim of this study was to examine the contribution of calcium concentrations and potassium channels in the mechanism of MgSO4-mediated uterine relaxation. Isolated uteri from female Wister rats were treated with increasing MgSO4 concentrations (0.1-30 mM). MgSO4 induced dose-dependent inhibition of spontaneous activity. Addition of Ca2+ (6 mM and 12 mM) stimulated uterine contractile activity and attenuated the inhibitory activity of MgSO4. In order to analyze the role of different subtypes of potassium channels, Ca2+-stimulated uteri were pretreated with glibenclamide (Glib), a selective ATP-sensitive potassium channel inhibitor (KATP), tetraethylammonium (TEA), a non-specific inhibitor of large conductance calcium-activated potassium channels (BKCa), and 4-aminopyridine (4-AP), a voltage-sensitive potassium channel inhibitor (Kv), at concentrations that had no effect per se. Pretreatment with 4-AP had no effect on MgSO4-mediated relaxation of Ca2+-stimulated uteri. The relaxing effect of MgSO4 was potentiated by pretreatment with glibenclamide. Pretreatment with TEA attenuated the MgSO4-mediated decrease in frequency. Our results suggest that MgSO4 acts as a general calcium antagonist that influences Ca2+-mediated potassium channels. Furthermore, it seems that MgSO4 uterine relaxation activity is partially mediated by selective ATP-sensitive potassium channels, suggesting an ATP-dependent role.

Melatonin receptor and KATP channel modulation in experimental vascular dementia

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

Protective effects of phosphodiesterase-1 (PDE1) and ATP sensitive potassium (KATP) channel modulators against 3-nitropropionic acid induced behavioral and biochemical toxicities in experimental Huntington׳s disease

Huntington׳s disease (HD), a devastating neurodegenerative disorder, is characterized by weight loss, impairment of motor function, cognitive dysfunction, neuropsychiatric disturbances and striatal damage. Phosphodiesterase-1 (PDE1) has been implicated in various neurological diseases. Mitochondrial potassium channels in the brain take part in neuroprotection. This study has been structured to investigate the role of vinpocetine, a selective PDE1 inhibitor as well as nicorandil, selective ATP sensitive potassium (KATP) channel opener in 3-nitropropionic acid (3-NP) induced HD symptoms in rats. Systemic administration of 3-NP significantly, reduced body weight, impaired locomotion, grip strength and impaired cognition. 3-NP elicited marked oxidative stress in the brain (enhanced malondialdehyde-MDA, reduced glutathione-GSH content, superoxide dismutase-SOD and catalase-CAT), elevated brain acetylcholinesterase activity and inflammation (myeloperoxidase-MPO), with marked nitrosative stress (nitrite/nitrate) in the brain. 3-NP has also induced mitochondrial dysfunction (impaired mitochondrial NADH dehydrogenase-complex I, succinate dehydrogenase-complex II and cytochrome oxidase-complex IV) activities in the striatum of the rat. Tetrabenazine was used as a positive control. Treatment with vinpocetine, nicorandil and tetrabenazine ameliorated 3-NP induced reduction in body weight, impaired locomotion, grip strength and impaired cognition. Treatment with these drugs reduced brain striatum oxidative (MDA, GSH, SOD and CAT) and nitrosative (nitrite/nitrate) stress, acetylcholinesterase activity, inflammation and mitochondrial dysfunctions. These results indicate that vinpocetine, a selective PDE1 inhibitor and nicorandil, a KATP channel opener have attenuated 3-NP induced experimental HD. Hence, pharmacological modulation of PDE1 as well as KATP channels may be considered as potential research targets for mitigation of HD.

Early potassium channel blockade improves sepsis‐induced organ damage and cardiovascular dysfunction

There is increasing evidence that potassium channels are involved in the cardiovascular dysfunction of sepsis. This evidence was obtained after the systemic inflammation, cardiovascular dysfunction and organ damage had developed. Here we have studied the consequences of early interference with potassium channels on development of sepsis. Sepsis was induced by caecal ligation and puncture (CLP) or sham surgery in Wistar rats. Four hours after surgery, animals received tetraethylammonium (TEA; a non-selective potassium channel blocker) or glibenclamide (a selective ATP-sensitive potassium channel blocker). Twenty-four hours after surgery, inflammatory, biochemical, haemodynamic parameters and survival were evaluated. Sepsis significantly increased plasma NO(x) levels, expression of inducible nitric oxide synthase (NOS-2) protein in lung and thigh skeletal muscle, lung myeloperoxidase, urea, creatinine and lactate levels, TNF-α and IL-1β, hypotension and hyporesponsiveness to phenylephrine and hyperglycemia followed by hypoglycemia. TEA injected 4 h after surgery attenuated the increased NOS-2 expression, reduced plasma NO(x) , lung myeloperoxidase activity, levels of TNF-α and IL-1β, urea, creatinine and lactate levels, prevented development of hypotension and hyporesponsiveness to phenylephrine, the alterations in plasma glucose and reduced late mortality by 50%. Glibenclamide did not improve any of the measured parameters and increased mortality rate, probably due to worsening the hypoglycemic phase of sepsis. Early blockade of TEA-sensitive (but not the ATP-sensitive subtype) potassium channels reduced organ damage and mortality in experimental sepsis. This beneficial effect seems to be, at least in part, due to reduction in NOS-2 expression.

Comparative studies of ZD0947, a novel ATP-sensitive K+ channel opener, on guinea pig detrusor and aortic smooth muscles

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.

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

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

S.05.03 Treatment of bipolar depression

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

Preparation and pharmacological evaluation of the R- and S-enantiomers of 3-(2′-butylamino)-4H- and 3-(3′-methyl-2′-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide, two tissue selective ATP-sensitive potassium channel openers

The preparation and the pharmacological evaluation of the R- and S-isomers of 3-(2′-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 42) and 3-(3′-methyl-2′-butylamino)-4H-pyrido[4,3-e]-1,2,4-thiadiazine 1,1-dioxide (BPDZ 44), two potassium channel openers, is described. Their optical purity was estimated by means of capillary electrophoresis (R- and S-BPDZ 42) and chiral HPLC (R- and S-BPDZ 44). The absolute configuration of each isomer of BPDZ 44 was deduced from crystallographic data. Pharmacological assays performed with the R- and S-isomers of BPDZ 44 revealed only slight differences in their activity on pancreatic B-cells but significant differences in their activity on vascular smooth muscle cells; the R-isomer being sixfold more potent than its corresponding S-isomer. The R-isomer of BPDZ 42 was shown to be more potent than its corresponding S-isomer on the endocrine pancreas. S-BPDZ 44 as well as R- and S-BPDZ 42 were found to exhibit tissue selectivity for the pancreatic versus the vascular smooth muscle tissue.

Thiopental and propofol impair relaxation produced by ATP-sensitive potassium channel openers in the rat aorta

ATP-sensitive potassium channel openers are used as vasodilators in the treatment of cardiovascular disorders. The effects of i.v. anaesthetics on arterial relaxation induced by ATP-sensitive potassium channel openers have not been studied. Therefore, in this study, we have examined if thiopental (thiopentone) and propofol affect the vascular response to the ATP-sensitive potassium channel openers, cromakalim and pinacidil, in the isolated rat aorta. Rings of rat thoracic aortas without endothelium were suspended for isometric force recording. Concentration-response curves were obtained in a cumulative manner. During submaximal contractions with phenylephrine 0.3 mumol litre-1, relaxation after cromakalim 0.1-30 mumol litre-1, pinacidil 0.1-30 mumol litre-1 and papaverine 0.1-300 mumol litre-1 was demonstrated. Thiopental 30-300 mumol litre-1, propofol 10-100 mumol litre-1, 10% Intralipid 45 microliters or glibenclamide 5 mumol litre-1 were applied 15 min before addition of phenylephrine. During contractions with phenylephrine, cromakalim and pinacidil induced concentration-dependent relaxation. A selective ATP-sensitive potassium channel antagonist, glibenclamide 5 mumol litre-1, abolished this relaxation, whereas it did not affect relaxation produced by papaverine. Thiopental concentrations > 30 mumol litre-1 significantly impaired relaxation produced by cromakalim or pinacidil. Propofol concentrations > 10 mumol litre-1 also significantly reduced relaxation produced by cromakalim or pinacidil, whereas Intralipid was ineffective. Thiopental 300 mumol litre-1 and propofol 100 mumol litre-1 did not alter relaxation produced by papaverine. These results suggest that the i.v. anaesthetics, thiopental and propofol, impaired vasodilatation mediated by ATP-sensitive potassium channels in vascular smooth muscle cells.

Cardioselective anti-ischemic ATP-sensitive potassium channel openers. 3. Structure-activity studies on benzopyranyl cyanoguanidines: modification of the cyanoguanidine portion.

Structure-activity relationships for the cyanoguanidine portion of the lead cardiac selective ATP-sensitive potassium channel (KATP) opener (3) are described. The cyanoguanidine moity appears to be optimal since increasing or decreasing the distance between the aniline nitrogen and the pendant aromatic ring attenuates anti-ischemic potency/selectivity. Similarly, unfavorable results are obtained by replacement of the aniline nitrogen with other linkers (CH2, S, O). Replacement of the phenyl ring with a methyl group diminishes cardiac selectivity. Constraining the urea moiety into a benzimidazolone or imidazolone ring retains anti-ischemic potency with significant improvement in cardiac selectivity. As shown by the ratio of vasorelaxant and anti-ischemic potencies, the cardiac selectivity in vitro varies over 3 orders of magnitude. These data are in agreement with previous results indicating that distinct structure-activity relationships exist for the anti-ischemic and vasorelaxant activities. Since the anti-ischemic effects of this series of compounds are abolished by pretreatment with structurally different KATP blockers (glyburide, sodium 5-hydroxydecanoate, meclofenamic acid), the mechanism for the anti-ischemic actions of these compounds still appears to involve the opening of KATP.

An ATP-sensitive potassium channel blocker abolishes the potentiating effect of morphine on the bicuculline-induced convulsion in mice.

ICV bicuculline, a selective GABAA antagonist, dose-dependently induced clonic-tonic convulsions in mice. Coadministration of ICV morphine (mu opioid agonist) significantly potentiated ICV bicuculline-induced convulsions, and this effect of morphine was completely blocked by pretreatment with beta-funaltrexamine (beta-FNA), a mu antagonist. ICV glibenclamide, a selective ATP-sensitive potassium (KATP) channel blocker, at a dose which alone did not affect the convulsive threshold of bicuculline, was capable of blocking the exacerbation of ICV bicuculline-induced convulsions by morphine. The present data further suggest that KATP channels may play a tonic regulatory role in the potentiative effect of morphine on ICV bicuculline-induced convulsions.