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PubMed2005

Bepridil, an antiarrhythmic drug, opens mitochondrial KATP channels, blocks sarcolemmal KATP channels, and confers cardioprotection.

Bepridil, which is clinically useful in the treatment of arrhythmias, has been reported to inhibit sarcolemmal ATP-sensitive K(+) (sarcK(ATP)) channels. However, the effect of bepridil on mitochondrial ATP-sensitive K(+) (mitoK(ATP)) channels remains unclear. The objective of the present study was to determine whether bepridil activates mitoK(ATP) channels and confers cardioprotection. SarcK(ATP) channels composed of Kir6.2+SUR2A in human embryonic kidney (HEK) 293 cells were examined using the patch-clamp technique. Flavoprotein fluorescence in guinea pig ventricular cells and matrix volume in isolated rat heart mitochondria were measured to assay mitoK(ATP) channel activity. Mitochondrial Ca(2+) concentration ([Ca(2+)](m)) was measured by loading cells with rhod-2 fluorescence. Coronary-perfused guinea pig ventricular muscles were subjected to 35-min no-flow ischemia followed by 60-min reperfusion. Bepridil (10 microM) completely inhibited the pinacidil-induced Kir6.2+SUR2A channel current expressed in HEK 293 cells. Bepridil reversibly oxidized the flavoprotein and increased mitochondrial matrix volume in a concentration-dependent manner. Furthermore, bepridil significantly attenuated the ouabain-induced increase of [Ca(2+)](m). Pretreatment with bepridil for 5 min before ischemia improved the recovery of developed tension measured after 60 min of reperfusion. These effects of bepridil were abolished by the mitoK(ATP) channel blocker 5-hydroxydecanoate (500 microM) and by the nonselective K(ATP) channel blocker glisoxepide (10 microM). Our results indicate that bepridil is an opener of mitoK(ATP) channels but an inhibitor of sarcK(ATP) channels and exerts a direct cardioprotective effect on native cardiac myocytes. This is the first report of a unique modulator of K(ATP) channels; bepridil would be expected to mitigate ischemic injury while blunting arrhythmias.

Algorithms↗
PubMed1999

Role of KATP channel in heat shock and pharmacological preconditioning.

Heat shock (HS) and 4-monophosphoryl lipid A (MLA, a non-toxic analogue of endotoxin) protects the myocardium against ischemia-reperfusion injury. We studied the involvement of ATP-sensitive potassium channel (KATP channel) in ischemic protection induced by these stimuli. Anesthetized rabbits were preconditioned with either HS (by raising temperature to 42 degrees C for 15 min) or intravenous pretreatment with MLA (35 micrograms/kg). After 24 h, animals were re-anesthetized and subjected to 30-min regional ischemia followed by 180-min reperfusion (I/R). KATP channel blockers glibenclamide and/or 5-hydroxydecanoate (5-HD) were used to inhibit channel function. The 72 kD heat shock protein (HSP-72) was measured by Western blots. HS produced a marked reduction in infarct size (39.4 +/- 8.1% to 14.3 +/- 2.5%, p < 0.05) that was abolished by glibenclamide (42.3 +/- 3.2%) and 5-HD (33.7 +/- 4.8%) when given before I/R. These drugs failed to block HS protection when given before HS. Expression of HSP-72 was increased in all HS groups as compared to non-HS groups in both glibenclamide and 5-HD-treated rabbits. Similarly, pretreatment with MLA reduced infarct size from 40 +/- 8.6% to 15.1 +/- 1.5% (p < 0.05). The infarct size increased to 51.9 +/- 5.8 with 5-HD in MLA-treated rabbits. 5-HD did not alter infarct size significantly when given in vehicle-treated control rabbits. These data suggest that HS and MLA exert their anti-ischemic effect through activation of KATP channel.

ATP-Binding Cassette Transporters↗
PubMed2003

Roles of KATP channels in delayed cardioprotection and intracellular Ca(2+) in the rat heart as revealed by kappa-opioid receptor stimulation with U50488H.

The effect of preconditioning with U50488 H (UP), a selective kappa-opioid receptor (kappa-OR) agonist, on infarct size and intracellular Ca2+ ([Ca2+]i) in the heart subjected to ischaemic insults were studied and evaluated. U50488 H administered intravenously reduced the infarct size 18-48 h after administration in isolated hearts subjected to regional ischaemia/reperfusion (I/R). The effect was dose dependent. A peak effect was reached at 10 mg x kg-1 U50488 H and at 24 h after administration. The effect of 10 mg x kg-1 U50488 H at 24 h after administration was abolished by nor-binaltorphimine (nor-BNI), a selective kappa-OR antagonist, indicating the effect was kappa-OR mediated. The infarct reducing effect of U50488 H was attenuated when a selective blocker of mitochondrial (5-hydroxydecanoic acid, 5-HD) or sarcolemmal (HRM-1098) ATP-sensitive potassium channel (KATP) was coadministered with U50488 H 24 h before ischaemia or when 5-HD was administered just before ischaemia. U50488 H also attenuated the elevation in [Ca2+]i and reduction in electrically induced [Ca2+]i transient in cardiomyocytes subjected to ischaemic insults. The effects were reversed by blockade of KATP channel, which abolished the protective effect of preconditioning with U50488 H. The results indicated that mitochondrial KATP channel serves as both a trigger and a mediator, while sarcolemmal KATP channel as a trigger only, of delayed cardioprotection of kappa-OR stimulation. The effects of these channels may result from prevention/attenuation of [Ca2+]i overload induced by ischaemic insults.

3,4-Dichloro-N-methyl-N-(2-(1-pyrrolidinyl)-cycloh↗
PubMed1999

Characterization of the ATP-sensitive potassium channels (KATP) expressed in guinea pig bladder smooth muscle cells.

ATP-sensitive K+ (KATP) channels play an important role in the regulation of smooth muscle membrane potential. To investigate the properties of KATP channels in guinea pig urinary bladder smooth muscle cells, fluorescence-based assays were carried out with the membrane potential-sensitive probe bis-(1,3-dibutylbarbituric acid)trimethine oxonol [DiBAC4(3)]. The prototypical channel openers, including pinacidil, (-)-cromakalim, and diazoxide, elicited concentration-dependent decreases in membrane potential that were attenuated by glyburide. Similar responses were evoked by a reduction in intracellular ATP levels by metabolic inhibition. The observed rank order potency (EC50) for evoking membrane potential changes by potassium channel openers, P1075 (53 nM) approximately Bay X 9228 > (-)-cromakalim approximately ZD6169 approximately pinacidil > Bay X 9227 approximately ZM244085 > diazoxide (59 microM), showed a good correlation with that of bladder smooth muscle relaxation, as assessed by isolated tissue bath studies. The maximal efficacies of (-)-cromakalim, pinacidil, Bay X 9228, and ZD6169 were comparable with the response achieved by the reference activator P1075. Whole cell currents in bladder smooth muscle cells were increased in both inward and outward directions by P1075 and were reversed by glyburide to control levels. The molecular composition assessed by reverse transcriptase-polymerase chain reaction analysis using subunit-specific primers revealed the presence of mRNA for inward rectifying potassium channel (KIR6.2) and sulfonylurea receptors (SUR)2B and SUR1. The subunit profile together with pharmacological properties suggests that the KATP channel in bladder smooth muscle cells could be composed of SUR2B associated with a single inward rectifier, KIR6.2. In summary, these studies have characterized the pharmacological profile using fluorescent imaging plate reader-based membrane potential techniques and provide evidence for the molecular identity of KATP channels expressed in guinea pig bladder smooth muscle cells.

Adenosine Triphosphate↗
PubMed1999

Pharmacological evidence for a KATP channel in renin-secreting cells from rat kidney.

1. Openers of the ATP-sensitive potassium channel (KATP channel) increase and blockers decrease renin secretion. Here we report the effects of levcromakalim (LCRK, a channel opener) and glibenclamide (GBC, a blocker) on membrane potential, whole-cell current and the cytoplasmic Ca2+ concentration of renin-secreting cells (RSC). Studies were performed on afferent arterioles from the kidney of Na+-depleted rats. 2. As monitored with the fluorescent oxonol dye DiBAC4(3), LCRK (0.3 and 1 microM) induced a hyperpolarization of approximately 15 mV which was abolished by GBC (1 microM). 3. Whole-cell current-clamp experiments showed that RSC had a membrane potential of -61 +/- 1 mV (n = 16). LCRK (1 microM) induced a hyperpolarization of 9.9 +/- 0.2 mV (n = 16) which, in the majority of cells, decreased slowly with time. 4. Capacitance measurements showed a strong electrical coupling of the cells in the preparation. 5. At -60 mV, LCRK induced a hyperpolarizing current in a concentration-dependent manner with an EC50 of 152 +/- 31 nM and a maximum current of about 200 pA. 6. Application of GBC (1 microM) produced no effect; however, when applied after LCRK (300 nM), GBC inhibited the opener-induced hyperpolarizing current with an IC50 of 103 +/- 36 nM. 7. LCRK (0.3 and 1 microM) did not significantly affect the cytoplasmic Ca2+ concentration either at rest or after stimulation by angiotensin II. 8. The data show that LCRK induces a GBC-sensitive hyperpolarizing current in rat RSC. This current presumably originates from the activation of KATP channels which pharmacologically resemble those in vascular smooth muscle cells. The stimulatory effect of KATP channel opening on renin secretion is not mediated by a decrease in intracellular Ca2+ concentration.

Angiotensin II↗
PubMed2002

Modulation of force development by Na+, K+, Na+ K+ pump and KATP channel during muscular activity.

Extracellular K+ concentration increases during exercise and especially during fatigue development. It has been proposed that K+ is an important factor in the etiology of skeletal muscle fatigue because it suppresses membrane excitability and eventually force development. Based on the effect of K+, it has then been proposed the Na+ K+ pump reduces increases in extracellular K+ concentration while the ATP-sensitive K+ channel (KATP channel) allows for rapid increases in extracellular K+ to suppress force development when ATP levels start to fall or when the levels of metabolic end-products become high. However, recent studies have now demonstrated that an increase in extracellular K+ concentration can be advantageous to muscle during exercise because it not only stimulates vasodilation and the exercise pressor reflex, but it also potentiates force development when the Na+ concentration gradient is maintained. A new hypothesis is therefore proposed in which the Na+ K+ pump is important in maintaining the Na+ concentration gradient (and not the K+ concentration gradient as previously suggested), while the activation of KATP channels is important to increase the K+ efflux and extracellular concentration. This situation then optimizes the development of force during exercise. Another hypothesis is proposed in which more KATP channels are activated while the activity of the Na+ K+ pump is reduced when ATP levels start to decrease to allow for an accumulation of intracellular Na+ and further increases in extracellular K+ concentration. These concentration changes then reduce membrane excitability and force development (i.e., fatigue) to protect muscle against large ATP depletion and function impairment.

Action Potentials↗
PubMed1998

Effect of KATP channel blocker U37883A on renal function in experimental diabetes mellitus in rats.

An increase in glomerular filtration rate (GFR) in early diabetes mellitus is considered a risk factor for the development of diabetic nephropathy. Insulin deficiency may increase the activity of ATP-sensitive potassium channels (KATP), which could promote afferent arteriolar vasodilation und thus contribute to glomerular hyperfiltration in early diabetes mellitus. To further elucidate this hypothesis we performed renal clearance experiments in anesthetized rats at 2 and 6 weeks after onset of streptozotocin-induced insulin-treated diabetes mellitus and studied the acute effect of the putative KATP channel blocker 4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexylhydr ochloride (U37883A) on renal function. In control rats, application of U37883A (1.5 mg/kg i.v. bolus plus 1.5 mg/kg/hr) induced a significant reduction in heart rate, but did not affect or even slightly increased mean arterial blood pressure. Furthermore, U37883A did not significantly affect renal vascular resistance, renal blood flow or GFR, but caused an eukaliuretic diuresis and natriuresis and lowered plasma renin activity. Diabetic rats at both 2 or 6 weeks after streptozotocin exhibited essentially an identical response to U37883A; in particular, RVR and glomerular hyperfiltration remained unchanged. These results show that in both control and diabetic rats, the renal excretory function, renin secretion and pace setting in the heart were sensitiv to U37883A, implying a functional contribution of KATP channel activity. However, in both control and diabetic rats, renal vascular resistance, renal blood flow, or GFR were not altered by U37883A. These results argue against a substantial role for KATP channels in the basal control of renal hemodynamics in both nondiabetic and diabetic rats.

Adamantane↗
PubMed2000

Diadenosine tetraphosphate (AP4A) mimics cardioprotective effect of ischemic preconditioning in the rat heart: contribution of KATP channel and PKC.

Diadenosine tetraphosphate (AP4A) administration is reported to mimic the effect of ischemic preconditioning (PC) via purine 2y receptors (P2yR) and adenosine receptors. This study was designed to test the contributions of the ATP-sensitive potassium channel (KATP channel) and protein kinase C (PKC), two of the main regulator in PC, to the effect of AP4A. Isolated buffer-perfused rat hearts were subjected to 20 min of global ischemia (37 degrees C) and 20 min of reperfusion. Three cycles of 1-min ischemia and 3-min reperfusion induced PC. Chemicals were administrated for 2 min before 20 min of ischemia. AP4A (10 microM) administration was as effective as PC in improving the recovery of post-ischemic contractile function and reducing creatine kinase leakage after reperfusion, whereas adenosine (10 and 100 microM) have not effect. AP4A had not effect on reperfusion-induced arrhythmia, whereas PC significantly prevented it. These effects of AP4A and PC were reversed by co-administration of glibenclimade (KATP channel blocker, 100 microM) and GF109203X (PKC inhibitor, 10 microM); the effects of AP4A but not PC were reversed by co-administration of reactive blue (P2yR antagonist, 13 nM). AP4A appears to activate the KATP channel and PKC via P2yR mimic the effects of PC in part. The role of P2yR indicated that trigger mechanism of the effect of PC and AP4A administration might differ in rat hearts.

Adenosine Triphosphate↗
PubMed1994

Contribution of prostaglandins in hypoxia-induced vasodilation in isolated rabbit hearts. Relation to adenosine and KATP channels.

The mechanism of hypoxia-induced coronary vasodilation was studied in isolated, saline-perfused rabbit hearts under constant flow conditions. Reduction in the perfusion solution PO2 (from 520 +/- 6 to 103 +/- 9 mm Hg) under control conditions halved the coronary resistance and was accompanied by a significant release of the prostaglandin (PG) 6-keto-PGF1 alpha (from 1.8 +/- 0.3 to a maximum of 4.4 +/- 0.9 pmol min-1 g-1). The cyclooxygenase inhibitor, diclofenac (1 microM), blocked the release of PGI2 and reduced hypoxia-induced vasodilation (from 47 +/- 8% to 25 +/- 5%, P < 0.05). The relative contribution of adenosine, prostaglandins, and adenosine triphosphate (ATP)-sensitive K+ channel (KATP channel) activation in hypoxia-induced vasodilation was assessed by comparing the differential change (control response minus response after treatment) in coronary perfusion pressure (CPP) during infusion of 8-phenyltheophylline (8-PT), diclofenac, and glibenclamide, respectively. The differential change in CPP with 8-PT and diclofenac given together (-48 +/- 7%) was found to be equivalent to the sum of their respective effects (-24 +/- 7 and -19 +/- 4%, respectively). Glibenclamide (0.3 microM) reduced significantly hypoxia-induced vasodilation (differential change in CPP of -27 +/- 6%) as well as the dilator response to 10 microM adenosine and to the stable PGI2-analogue, iloprost. Forskolin-induced coronary vasodilation in arrested hearts was slightly, but significantly, reduced by glibenclamide. Our results suggest that both cyclooxygenase products and adenosine, acting independently, and concomitantly, contribute to the dilator response of coronary resistance vessels to hypoxia, in part through the activation of KATP channels.(ABSTRACT TRUNCATED AT 250 WORDS)

Adenosine↗
PubMed1997

An ATP-sensitive potassium (KATP) channel opener, nicorandil, lowers the threshold for ischemic preconditioning in barbital-anesthetized dogs.

To determine whether the adenosine triphosphate (ATP)-sensitive potassium channel (KATP channel) opener, nicorandil, lowers the threshold for the infarct-reducing effect of preconditioning (PC), barbital-anesthetized dogs were subjected to 60-min occlusion (60'OC) of left anterior descending coronary artery (LAD) followed by 3-h reperfusion (3h-RP). At the end of the 3h-RP, heart was resected to measure infarct size. Infarct size was determined by triphenyltetrazolium chloride (TTC) staining, calculated gravimetrically and was expressed as a percent age of area at risk (AAR). Myocardial blood flow was measured by radioactive microspheres. Single 5-min LAD occlusion 10 min before 60'OC (5'PC group) markedly reduced infarct size, compared to the controls (11.8 +/- 3.7% versus 26.8 +/- 4.7%; P < 0.05). Neither 2.5-min PC (2.5'PC group), nor 2.5-min intracoronary infusion with 0.5 microgram/kg per min of nicorandil followed by a 10-min drug-free period (2.5'NC group), showed a cardioprotective effect (26.5 +/- 1.7% and 20.7 +/- 2.8%, respectively). However, when nicorandil was administered during the 2.5-min LAD occlusion period (2.5'PC + 2.5'NC group), infarct size was significantly reduced to an extent similar to that in 5'PC group (13.6 +/- 1.2%). There were no significant differences in hemodynamics, collateral circulation, or AAR between groups. These results suggest that nicorandil lowers the threshold for the infarct-reducing effect of PC in dogs by, at least in part, activation of myocardial KATP channels.

Animals↗
PubMed1999

Pharmacological and histochemical distinctions between molecularly defined sarcolemmal KATP channels and native cardiac mitochondrial KATP channels.

A variety of direct and indirect techniques have revealed the existence of ATP-sensitive potassium (KATP) channels in the inner membranes of mitochondria. The molecular identity of these mitochondrial KATP (mitoKATP) channels remains unclear. We used a pharmacological approach to distinguish mitoKATP channels from classical, molecularly defined cardiac sarcolemmal KATP (surfaceKATP) channels encoded by the sulfonylurea receptor SUR2A and the pore-forming subunit Kir6.2. SUR2A and Kir6.2 were expressed in human embryonic kidney (HEK)293 cells, and their activities were measured by patch-clamp recordings of membrane current. SurfaceKATP channels are activated potently by 100 microM pinacidil but only weakly by 100 microM diazoxide; in addition, they are blocked by 10 microM glibenclamide, but are insensitive to 500 microM 5-hydroxydecanoate. This pharmacology, which was confirmed with patch-clamp recordings in intact rabbit ventricular myocytes, contrasts with that of mitoKATP channels as indexed by flavoprotein oxidation. MitoKATP channels in myocytes are activated equally by 100 microM diazoxide and 100 microM pinacidil. In contrast to its lack of effect on surfaceKATP channels, 5-hydroxydecanoate is an effective blocker of mitoKATP channels. Glibenclamide's effects on mitoKATP channels are difficult to assess, because it independently activates flavoprotein fluorescence, consistent with a previously described primary uncoupling effect. Confocal imaging of the subcellular distribution of expressed fluorescent Kir6.2 in HEK cells and in myocytes revealed no targeting of mitochondrial membranes. The differences in drug sensitivity and subcellular localization indicate that mitoKATP channels are distinct from surface KATP channels at a molecular level.

Animals↗
PubMed1999

Regulation of mitochondrial KATP channel by redox agents.

The ATP-dependent K+ channel (KATP) was purified from the inner mitochondrial membrane and reconstituted into lipid bilayer membranes. KATP activity was inhibited by high concentrations of ATP and ADP, but activated by low concentrations (up to 200 microM) of ADP. p-Diethylaminoethylbenzoate (DEB) acted as a KATP opener: at micromolar concentrations, it reversed inhibition by ATP and ADP and it also prevented KATP rundown. Pelargonidine, extracted from flowers of Pelargonium, reduced spontaneous activity of KATP channels and diminished their potentiation by DEB. Their opposite action on KATP corresponded with their opposite redox properties in reactions with free radicals: DEB behaved as an electron donor, whereas pelargonidine acted as an electron acceptor. We hypothesize that thiol groups on mitoKATP are targets for redox-active ligans.

Adenosine Diphosphate↗
PubMed1995

The risk of myocardial stunning is decreased concentration-dependently by KATP channel activation with nicorandil before high K+ cardioplegia.

BACKGROUND: Drug-induced opening of the adenosine triphosphate-sensitive potassium channel (KATP) during hypoxia and/or ischemia, achieved significant myocardial protection in several in vitro and in vivo models. Pretreatment with KATP openers simulated preconditioning and thus enhanced recovery from ischemia. We have demonstrated that the risk of hypoxia-induced myocardial stunning is reversed by KATP activation with 1 mmol/l nicorandil before cold cardioplegic arrest. Whether lower concentrations were effective is not known. METHODS: In guinea pig papillary muscle preparations contracting isometrically (driven at 1600 ms cycle), nicorandil was superfused (15 min) either 1 mumol/l (n = 4), 30 mumol/l (n = 4), 100 mumol/l (n = 4), or 1 mmol/l (n = 8) in Tyrode's solution (oxygen content 16 ml/l, 37 degrees C, 5 ml/min). Controls were superfused with saline (Tyrode's solution: n = 8). A group containing vehicle (DMSO 1%, n = 8) was also studied. In four preparations the KATP channel blocker glibenclamide 1 mumol/l was given before nicorandil 1 mmol/l. Then, long-lasting (120 min) but moderately hypoxic (oxygen content 5 ml/l: 31% of Tyrode's solution) superfusion with hypothermic (20 degrees C) high K+ (16 mmol/l) cardioplegic solution (5 ml/min) was performed. Recovery of contractility was evaluated after further 60 min of reoxygenation with Tyrode's solution based on DT/TPT (developed tension divided by time to peak tension) as percent of prehypoxia basal values (%DT/TPT60). DT/TPT was also studied following 15 min of inotropic stimulation with dobutamine 10 mumol/l (%DT/TPT75). To assess the risk of stunning, we used a multivariate linear model by all possible subsets analysis (BMDP-9R) aimed at predicting both %DT/TPT60 and %DT/TPT75 (as continuous dependent variables). RESULTS: During cardioplegia induction, time to arrest (TTA) was (mean +/- S.D.) 103 +/- 48s in control preparations which had poor recovery of contractility (stunning) after reoxygenation (%DT/TPT60: 71 +/- 20%; %DT/TPT75: 443 +/- 272%). Nicorandil (1 mumol/l-1 mmol/l) abbreviated TTA concentration-dependently (163 +/- 74, 149 +/- 103, 82 +/- 20, and 56 +/- 27s) and improved both %DT/TPT60 (63 +/- 9, 78 +/- 17, 87 +/- 13, and 98 +/- 11%) and %DT/TPT75 (587 +/- 333, 619 +/- 107, 971 +/- 301, and 666 +/- 400%). Glibenclamide reversed the effects of nicorandil 1 mmol/l (TTA: 165 +/- 30 s, P < 0.01; %DT/TPT60: 43 +/- 12, P < 0.01; %DT/TPT75: 272 +/- 147, P < 0.05). Multivariate prediction of myocardial stunning at both 60 and 75 min reoxygenation showed that nicorandil (30 mumol/l-1 mmol/l) was a significant (P < 0.001) protectant whereas glibenclamide was a significant risk factor (P = 0.009). It is unclear whether negative inotropic effects of nicorandil (%DT/TPT at the end of pretreatment) was mechanistically related to reduced risk of stunning since contribution was seen only to predict %DT/TPT75 (t = 3.24, P = 0.003) whereas a positive association was observed with %DT/TPT60 (t = 1.89, P = 0.068). CONCLUSION: Pretreatment with nicorandil concentration-dependently enhanced the cardioprotective effect of hypothermic high K+ cardioplegia. The risk of myocardial stunning was decreased by KATP opening with nicorandil and increased by KATP block with glibenclamide. Inotropic stimulation with dobutamine might unravel the role of negative inotropic effect of KATP opening as a contributory factor to explain the efficacy of nicorandil in our model.

Adenosine Triphosphate↗
PubMed1997

KATP channel modulators increase survival rate during coronary occlusion-reperfusion in anaesthetized rats.

We investigated the effect of ATP-sensitive K+ channel (KATP) openers (pinacidil and cromakalim), and a KATP blocker (glibenclamide) on reperfusion-induced arrhythmias in pentobarbitone-anaesthetized rats. Arrhythmias were induced by reperfusion following a 6 min ligation of the left main coronary artery. Rats were pretreated with pinacidil (0.1 or 0.3 mg/kg), or cromakalim (28 or 56 micrograms/kg), or glibenclamide (5 mg/kg), or vehicle. Pinacidil and cromakalim produced dose-related reductions in blood pressure. Pinacidil (0.1 mg/kg) and cromakalim (56 micrograms/kg) significantly decreased the incidence of reperfusion-induced ventricular fibrillation and increased survival. Glibenclamide did not decrease ventricular fibrillation incidence, yet improved survival by increasing the possibility of recovery from ventricular fibrillation. The present study suggests that both opening and blocking KATP channels may increase survival during coronary occlusion and reperfusion in anaesthetized rats.

Action Potentials↗
PubMed1999

Effects of ischemic preconditioning on reperfusion arrhythmias and electrophysiology in isolated rat hearts: it is not a role of KATP(+) channels.

OBJECTIVE: To investigate the effects of ischemic preconditioning (PC) and ATP sensitive K+ channels (KATP(+) opener nicorandil on reperfusion arrhythmias and electrophysiology. METHODS: Langendorff-perfused rat hearts were subjected to ischemic PC with three cycles of 2 minutes of global ischemia or infusion of KATP(+) opener nicorandil with subsequent 5 minutes global ischemia and reperfusion. The incidence of reperfusion arrhythmias, ventricular fibrillation threshold (VFT), effective refractory period (ERP) and monophasic action potential duration (MAPD) of the left and right ventricles were compared to those from control rat hearts. RESULTS: The results indicated that PC reduced the incidence of total arrhythmias and ventricular fibrillation during reperfusion (P < 0.05, vs controls). PC markedly delayed the onset of arrhythmia after reperfusion (P < 0.01, vs controls). PC significantly enhanced the VFT values during reperfusion and shortened the ERP and the MAPD during ischemia. VFT was restored more rapidly than that in controls. KATP+ opener nicorandil neither reduced the incidence of total arrhythmias and VF nor delayed arrhythmia onset. Nicorandil shortened ERP and MAPD90 without enhancing the VFT values, and VFT returned to normal as slowly as that in controls. CONCLUSIONS: We conclude that PC protects the globally ischemic rat hearts from reperfusion arrhythmias. The antiarrhythmic effect of PC is likely to be related to a significant increase of VFT. KATP(+) opener nicorandil has no potential antiarrhythmic action and KATP(+) channels may not play a major role in the antiarrhythmic effects of ischemic PC in isolated rat hearts.

Animals↗
PubMed1995

Effects of a novel KATP channel blocker on renal tubule function and K channel activity.

ATP-sensitive potassium channels (KATP) modulate Na, K and Cl reabsorption in the thick ascending limb of the loop of Henle and K secretion in the cortical collecting tubule. Inhibition of potassium recycling in the apical membrane of the thick ascending limb of the loop of Henle interferes with sodium reabsorption and suppression of the apical potassium conductance in principal cells of the cortical collecting tubule and reduces potassium secretion. Both potassium recycling and potassium secretion depend critically on the activity of KATP, and recent studies indicate that the sulfonylurea compound glyburide, a known KATP channel blocker, is diuretic but does not produce kaliuresis.

Adamantane↗
PubMed2003

Hypercapnic acidosis activates KATP channels in vascular smooth muscles.

ATP-sensitive K+ channels (KATP) couple intermediary metabolism to cellular activity, and may play a role in the autoregulation of vascular tones. Such a regulation requires cellular mechanisms for sensing O2, CO2, and pH. Our recent studies have shown that the pancreatic KATP isoform (Kir6.2/SUR1) is regulated by CO2/pH. To identify the vascular KATP isoform(s) and elucidate its response to hypercapnic acidosis, we performed these studies on vascular smooth myocytes (VSMs). Whole-cell and single-channel currents were studied on VSMs acutely dissociated from mesenteric arteries and HEK293 cells expressing Kir6.1/SUR2B. Hypercapnic acidosis activated an inward rectifier current that was K+-selective and sensitive to levcromakalim and glibenclamide with unitary conductance of approximately 35pS. The maximal activation occurred at pH 6.5 to 6.8, and the current was inhibited at pH 6.2 to 5.9. The cloned Kir6.1/SUR2B channel responded to hypercapnia and intracellular acidification in an almost identical pattern to the VSM current. In situ hybridization histochemistry revealed expression of Kir6.1/SUR2B mRNAs in mesenteric arteries. Hypercapnia produced vasodilation of the isolated and perfused mesenteric arteries. Pharmacological interference of the KATP channels greatly eliminated the hypercapnic vasodilation. These results thus indicate that the Kir6.1/SUR2B channel is a critical player in the regulation of vascular tones during hypercapnic acidosis.

ATP-Binding Cassette Transporters↗
PubMed2001

Phorbol ester impairs electrical excitation of rat pancreatic beta-cells through PKC-independent activation of KATP channels.

BACKGROUND: Phorbol 12-myristate 13-acetate (PMA) is often used as an activating phorbol ester of protein kinase C (PKC) to investigate the roles of the kinase in cellular functions. Accumulating lines of evidence indicate that in addition to activating PKC, PMA also produces some regulatory effects in a PKC-independent manner. In this study, we investigated the non-PKC effects of PMA on electrical excitability of rat pancreatic beta-cells by using patch-clamp techniques. RESULTS: In current-clamp recording, PMA (80 nM) reversibly inhibited 15 mM glucose-induced action potential spikes superimposed on a slow membrane depolarization and this inhibition can not be prevented by pre-treatment of the cell with a specific PKC inhibitor, bisindolylmaleimide (BIM, 1 microM). In the presence of a subthreshold concentration (5.5 mM) of glucose, PMA hyperpolarized beta-cells in a concentration-dependent manner (0.8-240 nM), even in the presence of BIM. Based on cell-attached single channel recordings, PMA increased ATP-sensitive K+ channel (KATP) activity. Based on inside-out patch-clamp recordings, PMA had little effect on KATP activity if no ATP was in the bath, while PMA restored KATP activity that was suppressed by 10 microM ATP in the bath. In voltage-clamp recording, PMA enhanced tolbutamide-sensitive membrane currents elicited by repetitive ramp pulses from -90 to -50 mV in a concentration-dependent manner, and this potentiation could not be prevented by pre-treatment of cell with BIM. 4alpha-phorbol 12,13-didecanoate (4alpha-PDD), a non-PKC-activating phorbol ester, mimicked the effect of PMA on both current-clamp and voltage-clamp recording configurations. With either 5.5 or 16.6 mM glucose in the extracellular solution, PMA (80 nM) increased insulin secretion from rat islets. However, in islets pretreated with BIM (1 microM), PMA did not increase, but rather reduced insulin secretion. CONCLUSION: In rat pancreatic beta-cells, PMA modulates insulin secretion through a mixed mechanism: increases insulin secretion by activation of PKC, and meanwhile decrease insulin secretion by impairing beta-cell excitability in a PKC-independent manner. The enhancement of KATP activity by reducing sensitivity of KATP to ATP seems to underlie the PMA-induced impairment of beta-cells electrical excitation in response to glucose stimulation.

ATP-Binding Cassette Transporters↗