Effects Of Potassium Channel Openers Research Articles

Involvement of Mitochondrial Intermediate Conductance Ca2+-Activated K+ Channels in DCEBIO-Induced C2C12 Skeletal Muscle Cell Hypertrophy

Differentiation of skeletal muscle stem cells to myofibers is a critical step for muscle maintenance and repair. Although potassium channels play pivotal roles in myogenic differentiation, the effect of potassium channel openers on myogenic differentiation is unclear. Our study examined the change of differentiation rate of muscle stem cells and mass of differentiated myotubes induced by DCEBIO, a small molecule opener of intermediate conductance Ca2+-activated K+ channel (IKCa channel) which abundantly expressed in skeletal muscle stem cells.

The Relaxant Effect of Plantago Major on Rat Tracheal Smooth Muscles and Its Possible Mechanisms.

This study was conducted to evaluate the possible mechanisms of the relaxant effects of hydroalcoholic extract of Plantago major (P. major) on tracheal smooth muscle (TSM) in rats. The effects of cumulative concentrations of P. major (5, 10, 20 and 40 mg/mL) and theophylline (0.2, 0.4, 0.6 and 0.8 mM) were evaluated on pre-contracted TSM with 10 μΜ methacholine or 60 mM KCl. To determine the possible mechanisms, the relaxant effect of the plant was also examined on incubated TSM with atropine, indomethacin, chlorpheniramine, glibenclamide, diltiazem, papaverine, and propranolol. The results indicated concentration-dependent relaxant effects for P. major in non-incubated TSM contracted by methacholine or KCl. There was no statistically significant difference in the relaxant effects of P. major between non-incubated and incubated tissues with indomethacin, papaverine, and propranolol. However, the relaxant effects of P. major in incubated tissues with atropine (p<0.01 to p<0.001), chlorpheniramine (p<0.05 to p<0.001), glibenclamide (p<0.05), or diltiazem (p<0.01) were significantly lower than non-incubated TSM. P. major indicated relatively potent relaxant effects which were lower than those of theophylline. Muscarinic and histamine (H1) receptors inhibition, as well as calcium channel blocking and potassium channel opening effects are suggested to contribute to the TSM relaxant effect of the plant.

Role of nitric oxide donor in methotrexate-induced testicular injury via modulation of pro-inflammatory mediators, eNOS and P-glycoprotein.

Methotrexate (MTX) is a widely used chemotherapeutic agent but its clinical use is challenged with different forms of toxicities including testicular injury. The aim of the current study was to evaluate the potential protective effect of potassium channel opener, nicorandil (NIC) (3 and 10 mg/kg/day) on MTX-induced testicular injury in a rat model. Rats were randomly divided into four groups (nine rats each) and treated for 2 weeks as follows: (I) normal control (CON group) received vehicle, (II) model group (MTX group) given MTX (20 mg/kg) single intraperitoneal (i.p.) injection dose on 11th day, (III) MTX + NLD group treated with NIC (3 mg/kg/day) orally for 2 weeks and MTX (20 mg/kg) single i.p. dose on 11th day, and (IV) MTX + NHD group treated with NIC (10 mg/kg/day) orally for 2 weeks and MTX (20 mg/kg) single i.p. injection on the 11th day. The testicular injury was assessed biochemically via serum testosterone, total antioxidant capacity, testicular oxidative stress parameters, P-glycoprotein, tumor necrosis factor-alpha, and interleukin-1β. Furthermore, histopathological evaluation, endothelial nitric oxide synthase (eNOS) immunoexpression, and detection of p53 expression level using Western blotting were performed. Results showed that MTX induced testicular injury which was proved by both biochemical and histopathological evaluations. Our results concluded that NIC pretreatment attenuated MTX-induced testicular injury via significantly increased eNOS immunoexpression, antiapoptotic, anti-inflammatory, and antioxidant properties. Interestingly, NIC high dose is more protective than low dose.

Role of ATP-Sensitive Potassium Channel (KATP) and eNOS in Mediating the Protective Effect of Nicorandil in Cyclophosphamide-Induced Cardiotoxicity.

Cyclophosphamide (CP) is a widely used chemotherapeutic agent but its clinical usefulness is challenged with different forms of toxicities. No studies have evaluated the possible protective effect of nicorandil (NIC) in CP-induced cardiotoxicity. Our study aimed to investigate this effect by using NIC (3mg/kg/day) orally for 5days, in the presence or absence of cardiotoxicity induced by intraperitoneal (i.p.) injection of CP (150mg/kg) on 4th and 5th days. We confirmed the role of ATP-sensitive potassium channel (KATP) by coadministration of glibenclamide (GP) (5mg/kg/day) 2h before NIC (3mg/kg/day) for 5days. Moreover, the role of endothelial nitric oxide synthase (eNOS) was confirmed by coadministration of nitro-ω-L-arginine (L-NNA) (25mg/kg/day) for 5days. Results showed that CP succeeded in induction of cardiotoxicity which manifested by a significant increase in heart weights, creatine kinase-MB (CK-MB), lactate dehydrogenase (LDH), troponin I, cardiac tissue malondialdehyde (MDA), tumor necrosis factor alpha (TNF-α), interleukin 1β (IL1 β), and caspase-3 levels. Furthermore, CP group showed toxic histopathological changes of marked cardiac damage in addition to a significant decrease in total antioxidant capacity (TAC), superoxide dismutase (SOD), eNOS gene expression, and B cell lymphoma 2 (Bcl2) immunoexpression. NIC succeeded in reversing CP-induced cardiotoxicity by its potassium channel opening effect, stimulating eNOS gene expression, anti-inflammatory, antiapoptotic, and antioxidant properties. Coadministration of GP or L-NNA could diminish the protective effect of NIC. This proves the important role of KATP and eNOS in mediating such protection.

Neuroprotective effects of potassium channel openers on cerebral ischemia–reperfusion injury in diabetic rats

ObjectivesThis study was done to estimate the potential neuroprotective role of potassium channel openers in cerebral ischemia–reperfusion (IR) injury in streptozotocin (STZ) induced type-I diabetic rats (T1DR). MethodsPotassium channel openers – cromakalim, cinnarizine and nicorandil; potassium channel blocker –glibenclamide, insulin (as an antidiabetic standard), telmisartan (as an anti-hypertensive standard agent) and vitamin E (as an antioxidant and antiapoptotic standard agent) were given for 3days in streptozotocin (45mg/kg i.v.) induced type I diabetic rats along with middle cerebral artery occlusion. After 24h of surgery, plasma glucose, neurobehavioral score, cerebral infarct volume, blood pressure and caspase-3 levels were measured to evaluate the mechanism of potassium channel openers (KCOs) for neuroprotection. ResultsFollowing STZ administration and ischemia–reperfusion, blood sugar, neurobehavioral score, cerebral infarct volume and caspase-3 levels were significantly high in diabetic-IR groups. Treatment with cromakalim, cinnarizine, nicorandil, insulin and vitamin E significantly reduce neurobehavioral score while nicorandil and vitamin E significantly reduced cerebral infarct volume. Caspase-3 levels were significantly reduced by cromakalim and nicorandil treated animals. Except insulin and glibenclamide, none of the agents significantly reduce plasma glucose levels. ConclusionTreatment of ischemic stroke with potassium channel openers in T1DR is neuroprotective. Inhibition of apoptosis may contribute to their neuroprotective effects after stroke in T1DR.

Effect of potassium channel openers in acute and chronic models of glaucoma

PurposeGlaucoma is characterized by increased intraocular pressure (IOP). The effect of nicorandil and pinacidil on IOP in experimentally induced acute and chronic models of glaucoma and the mechanism of action involved were studied. MethodsNew Zealand white rabbits were used for the study. After the measurement of IOP, nicorandil (1%), pinacidil (1%), and pilocarpine as standard (1%) were instilled topically into the left eye. The other eye served as control. Dextrose (5%) was used to induce acute glaucoma. IOP changes were recorded every 15 minutes until the pressure became normal. Freshly prepared α-chymotrypsin solution was introduced in the posterior chamber to induce chronic glaucoma. Rabbits with ocular hypertension were selected for the study. Similar drug solutions were used to study the effect on IOP. Glibenclamide, pilocarpine, and indomethacin (1%) were used to study the mechanism of action of both drugs. The IOPs were measured just prior to drug instillation and at suitable time intervals using a tonometer. ResultsPretreatment with topical nicorandil and pinacidil significantly lowered the rise in IOP in the acute model. Nicorandil and pinacidil initially caused rise in IOP for 15–30 minutes in chronic glaucoma. This was followed by reduction in IOP. Pretreatment with indomethacin and pilocarpine did not modify the effect of nicorandil and pinacidil on IOP. Pretreatment with glibenclamide blocked IOP from the lowering effect of nicorandil and pinacidil. ConclusionThe oculohypotensive effect shown by these drugs appears to be attributable to enhancement of the aqueous humor outflow. This effect is perhaps mediated through potassium channels.

Synthesis and Biological Evaluation of New Tricyclic Dihydropyridine Based Derivatives on Potassium Channels.

The present study reports a microwave-assisted method for the synthesis of twelve novel tricyclic 1,4-dihydropyridine derivatives in which dimethyl-substituted cyclohexane and / or tetrahydrothiophene rings are fused to the DHP ring. The structures of the compounds were confirmed by spectral methods and elemental analysis. The potassium channel opening effects of the compounds were determined on rat mesenteric arteries and urinary bladders. The obtained results indicated that some compounds produced mesenteric artery-selective relaxant properties and the effects of these compounds were mediated through ATP-sensitive potassium channels. The replacement of the second tetrahydrothiophene ring with dimethyl-substituted cyclohexane ring led to more active compounds. Docking studies were carried out to understand the interactions of the compounds with the active site of potassium channel. The unsubstituted nitrogen atom on the 1,4-dihydropyridine ring and one of the sulfonyl oxygens were found to be important for the formation of hydrogen bonds to stabilize the compound in the center of the cavity. The nature and position of phenyl ring substituents were also effective on the activity of the compounds. Finally, a theoretical study was established to predict the ADME of the most active compounds.

The Effects of Potassium Channels in Human Internal Mammary Artery

Background: Structural and functional changes in potassium channels of vascular smooth muscle cells may contribute to the development of diseases such as hypertension. We aim to investigate the vascular effects of potassium channel openers and blockers in human internal mammary artery (HIMA). Methods: Remaining segments of HIMA from 18 consecutive patients undergoing coronary artery bypass surgery were obtained to examine the vascular effects of various potassium channel openers (staurosporine, hydrochlorothiazide and cromakalim) and potassium channel blockers (4-aminopyridin [4-AP], charybdotoxin [CTX] and glibenclamide [GLBC]). Results: Noradrenaline (NA)-induced maximal contractions were inhibited by all 3 K⁺-channel blockers but only fully inhibited by 4-AP (95.6%). Only NA-induced contractions were reversed by CTX. Only K⁺-induced maximal contractions were significantly inhibited by 4-AP (95.6%, p < 0.05). Only acetylcholine-induced relaxation was fully inhibited by CTX. Only sodium nitroprusside-induced relaxations in potassium chloride-precontracted strips could be reversed by GLBC. Conclusions: Drugs affecting potassium channels may be useful in the treatment of hypertension and management of perioperative vasospasm during the coronary artery bypass surgery.

A Systematic Review of the Uterine Relaxant Effect of Potassium Channel Openers

Despite significant advances in the understanding of uterine physiology, preterm labor is still a predicament with a high incidence. The mechanism that triggers uterine contraction is currently unclear. ATP-sensitive potassium (KATP) channel stimulation has an inhibitory effect on uterine contractile pursuit through hyperpolarization of myometrial cells where KATP channels openers (KCOs) act as a tocolytic. In this review, studies that report the effects of KCOs on the contractile activity of the myometrium have been collected and evaluated. All electronic databases were searched up to 1(st)December 2012 with the most relevant keywords. Studies related to the effect of KCOs on the human or animal myometrium both in vivo and in vitro were included. Of initial search, 45 records were reviewed and finally, 23 were included. All of these studies found that KCOs have an inhibitory effect on the myometrium contractions, but different sample size and inconsistencies in reporting the effects make the absolute judgment about efficacy of these compounds too difficult. Of course, we can state that the inhibitory effects of KCOs were greater in myometrium of non-labor group. Conclusion is that although some positive effects are expected, yet further placebo-controlled studies are needed to reach a consensus.

Hirsutism in a Female Adolescent Induced by Long-Acting Injectable Risperidone

Hirsutism in a Female Adolescent Induced by Long-Acting Injectable Risperidone

1002 EFFECTS OF COMBINED USE OF PHOSPHODIESTERASE 5 INHIBITOR AND MEDICATIONS FOR HYPERTENSION, LOWER URINARY TRACT SYMPTOMS AND DYSLIPIDEMIA ON TONE OF CORPORAL TISSUE

INTRODUCTION AND OBJECTIVES: To establish theoretical basis of choosing an appropriate medication for ED and concomitant disease, we examined the effects of combination Phosphodiesterase 5 inhibitor (PDE5I) with drug for ED comorbidities (hypertension, lower urinary tract symptoms, and dyslipidemia) on relaxation of rabbit corpus cavernosum (CC). METHODS: Contractility of CC strips was studied in organ baths. Concentration-response curves to mirodenafil were generated on phenylephrine (PE) (10 M)-precontracted strips before and after preincubation of losartan (10, 10 M), amlodipine (10, 10 M), nifedipine (10, 10 M), enalapril (10, 10 M), doxazosin (10, 10 M), tamsulosin (10, 10 M), or simvastatin(10, 10 M). Another organ bath studies were done to determine the losartan/nitric oxide interaction on CC smooth muscle function. We also determined role of potassium channel opening in synergistic effect of mirodenafil and alpha adrenergic blockers. RESULTS: The effect of mirodenafil to relax PE-induced CC tone was significantly enhanced by preincubation of losartan, nifedipine, amlodipine, tamsulosin, and doxazosin. The maximal effect was 35.8 2.0% of inhibition of PE-induced tone for mirodenafil alone vs. 47.2 3.8% for preincubation of 10 M losartan, 57.6 2.6% for 10 M nifedipine, 64.0 3.7% for 10 M amlodipine, 76.1 5.7% for 10 M doxazosin, and 71.7 5.4% for 10 M tamsulosin. But enalapril and simvastatin had no additional effect. Relaxation of CC smooth muscle induced by the nitric oxide donor sodium nitroprusside (SNP) was potentiated by losartan (p 0.05). The maximal responses to SNP alone (39.0 4.0%) were significantly enhanced in the presence of the 10 M losartan (66.0 6.0%). Nonselective K inhibitor tetraethylammonium (1mM) significantly inhibited enhancement effect of tamsulosin or doxazosin on mirodenafil-induced relaxation. CONCLUSIONS: Amlodipine, nifedipine, losartan, doxazosin, and tamsulosin enhancd relaxation effect of mirodenafil in CC. Losartan seems to exert enhancing effect by interaction with nitric oxide. And potassium channel opening effect of PDE5I and alpha adrenergic blocker could be one of action mechanism for enhancing effect. Combination of PDE5I with losartan, nifedipine, amlodipine, doxazosin, or tamsulosin could be a possible pharmacologic strategy to simultaneously treat erectile dysfunction and its comorbidities and to increase response rate to PDE5I.

Effect of potassium channel openers on intraocular pressure in rabbits

Effect of potassium channel openers on intraocular pressure in rabbits

Effect of potassium channel openers on hypoxic pulmonary vasoconstriction

The ATP-sensitive potassium channel (K+ATP) has been suggested as an important mechanism for the reactivity of vascular smooth muscle. We investigated the effects of K+ channel openers (lemakalim, pinacidil) on hypoxic pulmonary vasoconstriction (HPV) and angiotensin II (Ag II) induced vasoconstriction in isolated rat lungs (Sprague-Dawley rats: 300-450 g). Ventilation with hypoxic gas (2% O2, 5% CO2) was performed for 6 min after the injection of Ag II (0.1 microgram). Isolated lungs were perfused under constant flow (0.04 ml/g/min) using 20 ml of blood from donor rat. The perfusion pressure was used as the pulmonary artery pressure. Lemakalim or pinacidil was pre-administered through the reservoir. Pretreatment with pinacidil (10(-4) M) or lemakalim (10(-5) M) inhibited the pressor response to hypoxia, but did not inhibit the response to angiotensin II. Although the effect of lemakalim on HPV was reversed by administration of glibenclamide (10(-5) M) or tolbutamide (10(-3) M), the effect of pinacidil on HPV was not influenced by either drug. These results suggest that 1) K+ channel openers (lemakalim and pinacidil) inhibit the pressor response to hypoxia, and 2) lemakalim seems to act through K+ATP, whereas pinacidil may have other mechanisms of inhibition of vascular smooth muscle contraction. K+ATP may play an important role in the regulation of pulmonary vascular reactivity to hypoxia.

Effect of Potassium Channel Modulators on Morphine Withdrawal in Mice

The present study was conducted to investigate the effect of potassium channel openers and blockers on morphine withdrawal syndrome. Mice were rendered dependent on morphine by subcutaneous injection of morphine; four hours later, withdrawal was induced by using an opioid antagonist, naloxone. Mice were observed for 30 minutes for the withdrawal signs ie, the characteristic jumping, hyperactivity, urination and diarrhea. ATP-dependent potassium (K+ATP) channel modulators were injected intraperitoneally (i.p.) 30 minutes before the naloxone. It was found that a K+ATP channel opener, minoxidil (12.5–50 mg/kg i.p.), suppressed the morphine withdrawal significantly. On the other hand, the K+ATP channel blocker glibenclamide (12.5–50 mg/kg i.p.) caused a significant facilitation of the withdrawal. Glibenclamide was also found to abolish the minoxidil’s inhibitory effect on morphine withdrawal. The study concludes that K+ATP channels play an important role in the genesis of morphine withdrawal and K+ATP channel openers could be useful in the management of opioid withdrawal. As morphine opens K+ATP channels in neurons, the channel openers possibly act by mimicking the effects of morphine on neuronal K+ currents.

Differential K ATP channel pharmacology in intact mouse heart

Classically, cardiac sarcolemmal K ATP channels have been thought to be composed of Kir6.2 (KCNJ11) and SUR2A (ABCC9) subunits. However, the evidence is strong that SUR1 (sulfonylurea receptor type 1, ABCC8) subunits are also expressed in the heart and that they play a significant functional role in the atria. To examine this further, we have assessed the effects of isotype-specific potassium channel-opening drugs, diazoxide (specific to SUR1 > SUR2A) and pinacidil (SUR2A > SUR1), in intact hearts from wild-type mice (WT, n = 6), SUR1 −/− ( n = 6), and Kir6.2 −/− mice ( n = 5). Action potential durations (APDs) in both atria and ventricles were estimated by optical mapping of the posterior surface of Langendorff-perfused hearts. To confirm the atrial effect of both openers, isolated atrial preparations were mapped in both WT ( n = 4) and SUR1 −/− ( n = 3) mice. The glass microelectrode technique was also used to validate optical action potentials. In WT hearts, diazoxide (300 μM) decreased APD in atria (from 33.8 ± 1.9 ms to 24.2 ± 1.1 ms, p < 0.001) but was without effect in ventricles (APD 60.0 ± 7.6 ms vs. 60.8 ± 7.5 ms, respectively, NS), consistent with an atrial-specific role for SUR1. The absence of SUR1 resulted in loss of efficacy of diazoxide in SUR1 −/− atria (APD 36.8 ± 1.9 ms vs. 36.8 ± 2.8 ms, respectively, NS). In contrast, pinacidil (300 μM) significantly decreased ventricular APD in both WT and SUR1 −/− hearts (from 60.0 ± 7.6 ms to 29.8 ± 3.5 ms in WT, p < 0.001, and from 63.5 ± 2.1 ms to 24.8 ± 3.8 ms in SUR1 −/−, p < 0.001), but did not decrease atrial APD in either WT or SUR1 −/− hearts. Glibenclamide (10 μM) reversed the effect of pinacidil in ventricles and restored APD to control values. The absence of Kir6.2 subunits in Kir6.2 −/− hearts resulted in loss of efficacy of both openers (APD 47.2 ± 2.2 ms vs. 47.6 ± 2.1 ms and 50.8 ± 2.4 ms, and 90.6 ± 5.7 ms vs. 93.2 ± 6.5 ms and 117.3 ± 6.4 ms, for atria and ventricle in control versus diazoxide and pinacidil, respectively). Collectively, these results indicate that in the same mouse heart, significant differential K ATP pharmacology in atria and ventricles, resulting from SUR1 predominance in forming the atrial channel, leads to differential effects of potassium channel openers on APD in the two chambers.

The use of microelectrode array (MEA) to study the protective effects of potassium channel openers on metabolically compromised HL-1 cardiomyocytes

The microelectrode array (MEA) was used to evaluate the cardioprotective effects of adenosine triphosphate sensitive potassium (KATP) channel activation using potassium channel openers (KCOs) on HL-1 cardiomyocytes subjected to acute chemically induced metabolic inhibition. Beat frequency and extracellular action potential (exAP) amplitude were measured in the presence of metabolic inhibitors (sodium azide (NaN3) or 2-deoxyglucose (2-DG)) or KCOs (pinacidil (PIN, a cyanoguanidine derivative, activates sarcolemmal KATP channels) or SDZ PCO400 (SDZ, a benzopyran derivative, activates mitochondrial KATP channels)). The protective effects of these KCOs on metabolically inhibited HL-1 cells were subsequently investigated. Signal shapes indicated that NaN3 and 2-DG reduced the rate of the sodium (Na+) influx signal as reflected by a reduction in beat frequency. PIN and SDZ appeared to reduce both rate of depolarization and extent of the Na+ influx signals. Pre-treating cardiomyocytes with PIN (0.1 mM), but not SDZ, prevented the reduction of beat frequency associated with NaN3- or 2-DG-induced metabolic inhibition. The exAP amplitude was not affected by either KCO. The cardioprotective effect of PIN relative to SDZ may be due to the opening of different KATP channels. This metabolic inhibition model on the MEA may provide a stable platform for the study of cardiac pathophysiology in the future.

Pursuing the goal to improve downstream myocardial tissue perfusion

The coronary slow flow phenomenon is an angiographic finding characterized by delayed distal vessel opacification in the absence of significant epicardial coronary disease. Extensively studied both in the experimental and clinical setting, it was clearly associated with unfavourable clinical outcome and prognosis.1,2 Several hypotheses, including embolization of platelet-rich thrombi or atherosclerotic plaque debris that can ‘sludge’ the distal vessel, and release of vasoconstrictive substances causing intense vasospasm of the distal microcirculation, were advocated to justify this event in the context of percutaneous coronary intervention. If the principal mechanism of the slow flow phenomenon is vasoconstriction, this would explain the favourable response seen with intracoronary administration of calcium antagonists such as verapamil, or vasodilators such as nitroprusside, papaverine, and adenosine. Nicorandil, a nicotinamide ester, is a vasodilator agent approved as an antianginal agent, with a compound and balanced mechanism of action which relaxes coronary vascular smooth muscle by stimulating guanylyl cyclase and increasing cGMP levels as well as by a second mechanism resulting in activation of K+ channels and hyperpolarization.3 Potassium channel opening effects a titratable and sustained dilating action on both coronary artery conductance and resistance vessels. Kawai et al. have provided evidence that a prophylactic bolus of 6 mg of nicorandil administered i.v. immediately prior to percutaneous coronary intervention (PCI) reduces the incidence of the slow flow phenomenon without any side effects.4 Conceptually, this strategy improves coronary flow and myocardial perfusion by dilating those vessels with loss of endothelial integrity and reducing capillary and arteriolar blockages resulting from the presence of leukocytes … *Corresponding author. Tel: +39 0957436201, Fax: +39 095362429, Email: tambucor{at}unict.it

BK channel openers inhibit ROS production of isolated rat brain mitochondria

To delineate the potential mechanism of neuroprotective effects of potassium channel openers we have investigated, how Ca 2+-activated large conductance potassium channel (BK Ca channel) openers influence the production of reactive oxygen species (ROS) by rat brain mitochondria, since mitochondrial generation of ROS is known to have a crucial influence on neuronal survival. We studied the effects of BK Ca channel openers CGS 7184 and NS 1619 on hydrogen peroxide production rate of isolated rat brain mitochondria. In K +-containing media 3 μM of both channel openers reduced the hydrogen peroxide production rates by approximately 20%. This effect was not observed in Na +-containing media. This potassium-dependent partial inhibition of hydrogen peroxide production was found to be sensitive to the selective blockers of BK Ca channel iberiotoxin and charybdotoxin applied in nanomolar concentrations. Taken together, our data are compatible with the viewpoint that the opening of a Ca 2+-activated large conductance potassium channel being localised in the inner membrane of brain mitochondria inhibits ROS production by respiratory chain complex I. This finding is suggested to explain the beneficial effects of BK potassium channel openers on neuronal survival.

Effects of potassium channel openers in the isolated perfused hypokalaemic murine heart

AimWe explored the anti-arrhythmic efficacy of K+ channel activation in the hypokalaemic murine heart using NS1643 and nicorandil, compounds which augment IKr and IKATP respectively.MethodsLeft ventricular epicardial and endocardial monophasic action potentials were compared in normokalaemic and hypokalaemic preparations in the absence and presence of NS1643 (30 μm) and nicorandil (20 μm).ResultsSpontaneously beating hypokalaemic hearts (3 mm K+) all elicited early afterdepolarizations (EADs) and episodes of ventricular tachycardia (VT). Perfusion with NS1643 and nicorandil suppressed EADs and VT in 7 of 13 and five of six hypokalaemic hearts. Provoked arrhythmia studies using programmed electrical stimulation induced VT in all hypokalaemic hearts, but failed to do so in 7 of 13 and five of six hearts perfused with NS1643 and nicorandil respectively. These anti-arrhythmic effects were accompanied by reductions in action potential duration at 90% repolarization (APD90) and changes in the transmural gradient of repolarization, reflected in ΔAPD90. NS1643 and nicorandil reduced epicardial APD90 from 68.3 ± 1.1 to 56.5 ± 4.1 and 51.5 ± 1.5 ms, respectively, but preserved endocardial APD90 in hypokalaemic hearts. NS1643 and nicorandil thus restored ΔAPD90 from −9.6 ± 4.3 ms under baseline hypokalaemic conditions to 3.9 ± 4.1 and 9.9 ± 2.1 ms, respectively, close to normokalaemic values.ConclusionThese findings demonstrate, for the first time, the anti-arrhythmic efficacy of K+ channel activation in the setting of hypokalaemia. NS1643 and nicorandil are anti-arrhythmic through the suppression of EADs, reductions in APD90 and restorations of ΔAPD90.

Effects of Pinacidil on Reentrant Arrhythmias Generated During Acute Regional Ischemia: A Simulation Study

Many experimental studies have pointed out the controversy involving the arrhythmogenic effects of potassium channel openers (KCOs) in ischemia. KCOs activate the ATP-sensitive potassium current [IK(ATP)], resulting in action potential duration (APD) shortening, especially under pathological conditions such as ischemia. Acute myocardial ischemia leads to electrophysiological inhomogeneities in APD, conduction velocity, and refractoriness, which provide the substrate for reentry initiation and maintenance and may lead to malignant arrhythmias. The aim of this work is to analyze the effect of the KCO pinacidil on vulnerability to reentry during acute regional ischemia using computer simulations. We use a two-dimensional virtual heart tissue with implementation of acute regional ischemia conditions. Membrane kinetics are represented by a modified version of Luo-Rudy (phase II) action potential model that incorporates the effect of pinacidil on IK(ATP). The vulnerable window (VW) for reentry is quantified for different doses of pinacidil. Our results show that for doses below 3 micromol/l the VW widens with increasing pinacidil concentration, whereas for higher doses of pinacidil the VW decreases, becoming zero for concentrations above 10 micromol/l. The ionic mechanisms involved in this behavior are explored. This study demonstrates that the effect of pinacidil on arrhythmogenesis is strongly dose-dependent, and that high doses of pinacidil exert a strong antiarrhythmic effect.