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PubMed1994

Reversibility of electrophysiologic abnormalities of subendocardial Purkinje fibers induced by ischemia.

INTRODUCTION: During the subacute phase of infarction in the canine heart, the subendocardial Purkinje fibers subtended by the infarct show depolarization greater than can be accounted for by the decrease in [K+]i, and generate abnormal action potentials and spontaneous rhythms due to abnormal automaticity. We have used pinacidil to hyperpolarize these fibers and evaluate the extent to which an increase in resting potential can normalize action potential generation. METHODS AND RESULTS: Twenty-four hours after two-stage ligation of the canine left anterior descending coronary artery, preparations of subendocardial Purkinje fibers were studied in vitro by recording transmembrane potentials through standard microelectrodes and exposing the preparation to pinacidil and increases in [K+]o. Pinacidil increased resting potential to the estimated value of EK, abolished the abnormal automaticity, and restored action potentials of normal amplitude with normal values of Vmax. This effect often persisted after washout of pinacidil. Elevation of [K+]o from 4.0 to 20.0 mM slightly increased maximum diastolic potential, suggesting that the excess (over the change in EK) depolarization was caused by a decrease in gK1. CONCLUSION: The ventricular arrhythmias seen during the subacute stage of infarction probably are caused by abnormal automaticity. Our findings support the conclusion that this abnormal automaticity arises in partially depolarized subendocardial Purkinje fibers. This loss of resting potential is due in large part to a decrease in gK1. Restoration of resting potential to the value of EK permits the Purkinje fibers to develop essentially normal action potentials. An agent capable of reversing the partial block of IK,1 thus might be an effective drug for some types of arrhythmias.

Adenosine Triphosphate↗
PubMed2005

Evidence that activation following failed defibrillation is not caused by triggered activity.

BACKGROUND: Earliest postshock activation following failed defibrillation shocks slightly lower than the defibrillation threshold (DFT) in large animals appears to arise from a focus. We tested the hypothesis that these foci are caused by early or delayed afterdepolarizations (EADs or DADs) by performing epicardial electrical mapping and giving the EAD inhibitor pinacidil or the DAD inhibitor flunarizine to see if the foci were extinguished or altered in timing or location. METHODS AND RESULTS: A sock containing 504 electrodes was placed over the entire ventricular epicardium of 12 open-chested pigs. After the DFT was determined and additional shocks given, pinacidil was administered to 6 pigs and flunarizine to 6 pigs. Then, the DFT was again determined and additional shocks were given. Pinacidil significantly shortened the effective refractory period (ERP) (162 +/- 16 vs 130 +/- 28 msec) and action potential duration (APD(90)) (179 +/- 6 vs 149 +/- 19 msec) and significantly increased the peak frequency of the power spectrum of a left ventricle (LV) electrode during ventricular fibrillation (VF) (9.3 +/- 0.6 vs 10.5 +/- 1.0 Hz), while flunarizine did not significantly alter the ERP (162 +/- 8 vs 167 +/- 18 msec) or APD(90) (187 +/- 12 vs 191 +/- 20) but significantly reduced the peak frequency (9.2 +/- 0.5 vs 7.5 +/- 1.0 Hz). These findings suggest the drugs had their expected electrophysiological effects. However, the DFT was not significantly changed by either drug. Following the same strength shock 10% below the predrug DFT, earliest postshock activation arose in a focal epicardial pattern from the anterior-apical LV both before and after the drugs. The time from the shock until the appearance of this activation was not significantly different before and after either drug. CONCLUSION: The lack of change in DFT as well as the lack of change in the incidence, location, and timing of the postshock focus with sub-DFT strength shocks before and after pinacidil and flunarizine provide evidence that these foci are not caused by triggered activity.

Analysis of Variance↗
PubMed2002

K(ATP) channel-independent targets of diazoxide and 5-hydroxydecanoate in the heart.

Diazoxide and 5-hydroxydecanoate (5-HD; C10:0) are reputed to target specifically mitochondrial ATP-sensitive K(+) (K(ATP)) channels. Here we describe K(ATP) channel-independent targets of diazoxide and 5-HD in the heart. Using submitochondrial particles isolated from pig heart, we found that diazoxide (10-100 microM) dose-dependently decreased succinate oxidation without affecting NADH oxidation. Pinacidil, a non-selective K(ATP) channel opener, did not inhibit succinate oxidation. However, it selectively inhibited NADH oxidation. These direct inhibitory effects of diazoxide and pinacidil cannot be explained by activation of mitochondrial K(ATP) channels. Furthermore, application of either diazoxide (100 microM) or pinacidil (100 microM) did not decrease mitochondrial membrane potential, assessed using TMRE (tetramethylrhodamine ethyl ester), in isolated guinea-pig ventricular myocytes. We also tested whether 5-HD, a medium-chain fatty acid derivative which blocks diazoxide-induced cardioprotection, was 'activated' via acyl-CoA synthetase (EC 6.2.1.3), an enzyme present both on the outer mitochondrial membrane and in the matrix. Using analytical HPLC and electrospray ionisation mass spectrometry, we showed that 5-HD-CoA (5-hydroxydecanoyl-CoA) is indeed synthesized from 5-HD and CoA via acyl-CoA synthetase. Thus, 5-HD-CoA may be the active form of 5-HD, serving as substrate for (or inhibiting) acyl-CoA dehydrogenase (beta-oxidation) and/or exerting some other cellular action. In conclusion, we have identified K(ATP) channel-independent targets of 5-HD, diazoxide and pinacidil. Our findings question the assumption that sensitivity to diazoxide and 5-HD implies involvement of mitochondrial K(ATP) channels. We propose that pharmacological preconditioning may be related to partial inhibition of respiratory chain complexes.

Acyl Coenzyme A↗
PubMed2003

KATP channels depress force by reducing action potential amplitude in mouse EDL and soleus muscle.

Although ATP-sensitive K+ (KATP) channel openers depress force, channel blockers have no effect. Furthermore, the effects of channel openers on single action potentials are quite small. These facts raise questions as to whether 1) channel openers reduce force via an activation of KATP channels or via some nonspecific effects and 2) the reduction in force by KATP channels operates by changes in amplitude and duration of the action potential. To answer the first question we tested the hypothesis that pinacidil, a channel opener, does not affect force during fatigue in muscles of Kir6.2-/- mice that have no cell membrane KATP channel activity. When wild-type extensor digitorum longus (EDL) and soleus muscles were stimulated to fatigue with one tetanus per second, pinacidil increased the rate at which force decreased, prevented a rise in resting tension, and improved force recovery. Pinacidil had none of these effects in Kir6.2-/- muscles. To answer the second question, we tested the hypothesis that the effects of KATP channels on membrane excitability are greater during action potential trains than on single action potentials, especially during metabolic stress such as fatigue. During fatigue, M wave areas of control soleus remained constant for 90 s, suggesting no change in action potential amplitude for half of the fatigue period. In the presence of pinacidil, the decrease in M wave areas became significant within 30 s, during which time the rate of fatigue also became significantly faster compared with control muscles. It is therefore concluded that, once activated, KATP channels depress force and that this depression involves a reduction in action potential amplitude.

Action Potentials↗
PubMed2001

Denervation enhances the physiological effects of the K(ATP) channel during fatigue in EDL and soleus muscle.

The objective was to determine whether denervation reduces or enhances the physiological effects of the K(ATP) channel during fatigue in mouse extensor digitorum longus (EDL) and soleus muscle. For this, we measured the effects of 100 microM of pinacidil, a channel opener, and of 10 microM of glibenclamide, a channel blocker, in denervated muscles and compared the data to those observed in innervated muscles from the study of Matar et al. (Matar W, Nosek TM, Wong D, and Renaud JM. Pinacidil suppresses contractility and preserves energy but glibenclamide has no effect during fatigue in skeletal muscle. Am J Physiol Cell Physiol 278: C404-C416, 2000). Pinacidil increased the (86)Rb(+) fractional loss during fatigue, and this effect was 2.6- to 3.4-fold greater in denervated than innervated muscle. Pinacidil also increased the rate of fatigue; for EDL the effect was 2.5-fold greater in denervated than innervated muscle, whereas for soleus the difference was 8.6-fold. A major effect of glibenclamide was an increase in resting tension during fatigue, which was for the EDL and soleus muscle 2.7- and 1.9-fold greater, respectively, in denervated than innervated muscle. A second major effect of glibenclamide was a reduced capacity to recover force after fatigue, an effect observed only in denervated muscle. We therefore suggest that the physiological effects of the K(ATP) channel are enhanced after denervation.

Adenosine Triphosphate↗
PubMed1997

Increased myogenic tone and diminished responsiveness to ATP-sensitive K+ channel openers in cerebral arteries from diabetic rats.

Diabetes mellitus has profound adverse effects on vascular and, in particular, endothelial function. Although pressure-induced constriction ("myogenic tone") is a major contributor to the regulation of blood flow, little is known about the effects of diabetes on this response. Diabetes has been shown to diminish the dilation of cerebral arteries to synthetic ATP-sensitive K+ (KATP) channel openers. In this study, we explored the effects of diabetes induced in rats by streptozotocin on cerebral artery (250 to 300 microns) myogenic tone and on vasodilations to the synthetic KATP channel openers pinacidil and levcromakalim. Elevation of intravascular pressure caused a graded membrane potential depolarization and constriction, which was greater in arteries from diabetic rats compared with normal rats (at 60 mm Hg, 5 mV more depolarized and 22 microns more constricted). Pressurized arteries (at 60 mm Hg) from diabetic rats were 5- to 15-fold less sensitive to pinacidil and levcromakalim than were control arteries (EC50 values for pinacidil and levcromakalim were 1.4 and 0.6 mumol/L, respectively, in diabetic animals and 0.3 and 0.04, respectively, in control animals; P < .05). Removal of the endothelium or addition of a NO synthase inhibitor, NG-nitro-L-arginine (LNNA), in control arteries decreased the sensitivity to KATP channel openers and depolarized and constricted control arteries to levels similar to those observed in arteries from diabetic animals. Sodium nitroprusside caused a membrane potential hyperpolarization and enhanced the response to pinacidil in arteries from diabetic animals. Removal of the endothelium or LNNA had little effect on the apparent KATP channel opener sensitivity, the membrane potential, and pressure-induced constrictions of arteries from diabetic animals. The results are consistent with the hypothesis that this type of diabetes leads to a decrease in tonic NO release from the endothelium, which in turn causes membrane potential depolarization and vasoconstriction, resulting in a diminished response to KATP channel openers.

Acetylcholine↗
PubMedDate not supplied

[Role of ATP-sensitive potassium channel activators in liver mitochondrial function in rats with different resistance to hypoxia].

Effects of ATP-sensitive potassium (KATP) channels opener pinacidil (0.06 mg/kg) and inhibitor glibenclamide (1 mg/kg) in rats with different resistance to hypoxia on indices of ADP-stimulation of mitochondrial respiration by Chance, calcium capacity and processes of lipid peroxidation in liver has been investigated. We used next substrates of oxidation: 0.35 mM succinate, 1 mM alpha-ketoglutarate. Additional analyses contain the next inhibitors: mitochondrial fermentative complex I-10 mkM rotenone, succinate dehydrogenase 2 mM malonic acid. It was shown that effects of pinacidil induced the increasing of oxidative phosporylation efficacy and ATP synthesis together with lowering of calcium capacity in rats with low resistance to hypoxia. Effects of pinacidil were leveled by glibenclamide. These changes are connected with the increasing of respiratory rate, calcium overload and intensification of lipid peroxidation processes. A conclusion was made about protective effect of pinacidil on mitochondrial functioning by economization of oxygen-dependent processes, adaptive potentialities of organisms with low resistance to hypoxia being increased.

Adenosine Triphosphate↗
PubMed2004

[Iptakalim enhances astrocytic glutamate uptake activity].

AIM: To investigate the effect of iptakalim (Ipt), a novel ATP-sensitive potassium channel opener (KATPCO), on astrocyte glutamate uptake activity. The mechanism of action involved was also examined. METHODS: Primary cultures of astrocytes were prepared from cerebral cortexes of 1 to 2 days old Sprague-Dawley rats. Cultures were preincubated with iptakalim of various concentrations with the absence or presence of 6-hydroxydopamine (6-OHDA, 50 micromol x L(-1)). Then, the cells were treated with pinacidil (10 micromol x L(-1), K+ channel opener) instead of iptakalim and pretreated with glibenclamide (20 micromol x L(-1), ATP-sensitive K+ channel inhibitor) before pinacidil or iptakalim was added into the medium so that the mechanism of action of iptakalim could be analysed. Astrocyte glutamate uptake activity was determined by intracellular concentration of 3H labeled D,L-glutamate, using isotope techniques. RESULTS: Both iptakalim and pinacidil were shown to increase glutamate uptake activity of astrocytes and reverse inhibitory effect induced by 6-OHDA. But the increased and reversed effects of iptakalim or pinacidil on astrocytic glutamate uptake were found to be completely antagonized by glibenclamide. CONCLUSION: These data indicated that iptakalim can enhance astrocytic glutamate uptake activity due to its K+ channel opening properties and lessen glutamate excitotoxicity. Iptakalim may be useful for the therapy of Parkinson's disease.

Animals↗
PubMed2005

[Effects of iptakalim on intracellular calcium concentrations, PKA and PKC activities in rat tail artery smooth muscle cells].

AIM: To investigate the effects of iptakalim, a new structural potassium channel opener (KCO), on intracellular calcium concentration ([Ca2+]i), protein kinase C (PKC), and cAMP-dependent kinase (PKA) activities in rat tail artery smooth muscle cells (RTA-SMC), and to analyze mechanisms involved in iptakalim reversing hypertensive vascular remodeling. METHODS: RTA-SMC was cultured and passages 3-4 were used for experiment. [Ca2+] i was measured by laser scanning confocal microscope after loaded with fluorescent indicator fluo-3-acetoxymethylester, and activities of PKA and PKC were detected by commercial assay kits (the nonradioactive PepTag system) following instructions. RESULTS: Compared with baseline, [Ca2+] i reduced significantly after iptakalim- or pinacidil-treatment at concentrations of 0.1, 1 and 10 micromol x L(-1), while diazoxide caused significant decrease at concentration of 1 and 10 micromol x L(-1). After preincubation with 1 micromol x L(-1) glibenclamide, [Ca2+] i was not significantly changed when iptakalim, pinacidil or diazoxide were added at concentration of 0.1 and 1 micromol x L(-1). Activities of PKA and PKC increased significantly by 1 micromol x L(-1) iptakalim- or pinacidil-treatment, while 1 micromol x L(-1) diazoxide induced significant change in activity of PKC but not in that of PKA. CONCLUSION: The characteristics of iptakalim on [Ca2+] i, PKA and PKC are more or less similar to those of pinacidil. Iptakalim decreased [Ca2+] i while increased PKA and PKC activities of RTA-SMCs, which may contribute to its ability to reverse antihypertensive vascular remodeling.

Animals↗
PubMed2006

Involvement of potassium channels in hypoglycemic effect of sertraline.

Effect of 21 days administration of sertraline (30 mg/kg, po) in streptozotocin (55 mg/kg, ip) induced diabetic and non-diabetic rats produced hypoglycemia in diabetic and non-diabetic rats. Pinacidil (1mg/kg, po), when co-administered with sertraline or glimepiride antagonized the decrease in glucose levels in diabetic rats. Pinacidil (10(-6)-10(-3) M) produced dose dependent relaxation (EC50-1.58 x 10(-5) M). Neither sertraline nor glimepiride had any effect on the resting tension of ileum preparation. Both sertraline and glimepiride antagonized competitively the pinacidil-induced relaxation. The pA2 values of sertraline and glimepiride reversal of pinacidil-induced relaxation were 5.5 and 6.2 respectively. These studies suggest the involvement of K+ channels in hypoglyceimic effects of sertraline.

Animals↗
PubMed1995

The effect of intracavernous injection of potassium channel openers in monkeys and dogs.

Cavernous smooth muscle relaxation is effected through a complex biochemical pathway; therefore, a defect in any step of this pathway may result in erectile dysfunction. Administration of pharmacologic agents which cause relaxation of the cavernous smooth muscle through a different mechanism may serve as an effective therapeutic alternative for impotent patients. To test this hypothesis two potassium channel openers, pinacidil and cromakalim, were used to initiate and maintain cavernous smooth muscle relaxation. The drugs were given as intracavernous injections in two animal models. In 10 dogs pinacidil and cromakalim produced full erection. With pinacidil (10(-2) M), the mean intracavernous pressure increased from a baseline pressure of 32.6 +/- 3.43 cm H2O to a peak intracavernous pressure of 131.8 +/- 12.01 cm H2O, and remained elevated for a period of 17.8 +/- 9.4 min. With cromakalim (10(-2) M) intracavernous pressure rose from a baseline pressure of 32 +/- 2.55 cm H2O to a peak intracavernous pressure of 140 +/- 3.39 cm H2O, for a period of 19.4 +/- 0.89 min. Additionally, in 5 primates injected with cromakalim (10(-2) M) intracavernous pressure rose from 24 +/- 3.81 to 131.2 +/- 7.56 cm H2O, for 27.0 +/- 4.79 min. It is concluded that both pinacidil and cromakalim can initiate and maintain erection in dogs and that cromakalim produces a similar erectile response in monkeys. Further study of the local and systemic effects of chronic injection is needed to determine whether this class of pharmacologic agents can provide therapy for impotent patients.

Animals↗
PubMed1994

Pharmacology and structure-activity relationships for KATP modulators: tissue-selective KATP openers.

KATP openers are recognized as having a therapeutic potential for the treatment of various cardiovascular and noncardiovascular diseases. However, the first-generation agents open KATP in a variety of tissues that limit their potential clinical utility. This review describes our studies aimed at the identification of a common pharmacophore among structurally diverse KATP openers and the discovery of tissue-selective agents that may offer advantages over the first-generation agents for the treatment of cardiovascular diseases. Compounds (e.g., BMS-182264) combining the structural features of KATP openers cromakalim and pinacidil, show smooth-muscle relaxing and antihypertensive activities comparable to their predecessors, indicating cromakalim and pinacidil may express their biologic effects through similar structural requirements. The hypothesis about common features is further supported by radioligand-binding studies showing cromakalim, pinacidil, and the combination compound BMS-182264 bind to a similar receptor site in rat aortic smooth-muscle cells. Regardless of having a pharmacologic profile similar to cromakalim and pinacidil in vascular smooth muscle, BMS-182264 had no effect on action potential duration in guinea pig papillary muscle, indicating smooth-muscle selectivity for BMS-182264. We demonstrate that no correlation exists between anti-ischemic and smooth-muscle relaxing potencies for a variety of structurally different KATP openers. Efforts to find KATP openers selective for the ischemic myocardium led to the identification of BMS-180448 which, despite having similar anti-ischemic potency to cromakalim, was significantly less active as a smooth-muscle relaxant. This compound was shown to be efficacious as an anti-ischemic agent in vivo without affecting hemodynamic variables, a potential liability of first-generation compounds.(ABSTRACT TRUNCATED AT 250 WORDS)

Action Potentials↗
PubMed1993

Antifibrillatory effects of ibutilide in the rabbit isolated heart: mediation via ATP-dependent potassium channels.

This study determined if ibutilide, a drug with class III activity, exhibited antifibrillatory effects in an isolated heart model of ventricular fibrillation (VF). Langendorff-perfused hearts were randomized among six groups. Group I (n = 9) served as the vehicle-treated control group. Groups II (n = 6), III (n = 10) and IV (n = 9) were pretreated with ibutilide 0.1; 1.0 or 3.0 microM, respectively. Ten minutes after perfusion in the presence of vehicle or ibutilide, hearts were perfused with the ATP-dependent potassium channel opener, pinacidil (1.25 microM) and subjected to a 12-min hypoxic period followed by 40 min of reoxygenation, or until the onset of VF. Groups V and VI were used to investigate electrophysiological effects of ibutilide (n = 12), as well as its chemical defibrillatory activity (n = 9), respectively. Additional experiments involved isometric tension recordings from canine atrial pectinate muscle exposed to increasing concentrations of pinacidil (3-300 microM) in the presence of ibutilide (3-30 microM). Ibutilide decreased the incidence of VF in a concentration-dependent manner; eight of nine control hearts developed VF vs. two of nine hearts (P = .018 chi 2) treated with 3.0 microM ibutilide. In atrial pectinate tissue, ibutilide attenuated the negative inotropic effect of pinacidil. An unexpected finding was the ability of ibutilide to achieve chemical defibrillation when added to the perfusion medium after the electrical induction of ventricular fibrillation in the isolated heart. The antifibrillatory effect of ibutilide may result from inhibition of the ATP-dependent potassium channel made susceptible to opening by pinacidil during hypoxia.

Adenosine Triphosphate↗
PubMed1994

K+ channel openers relax longitudinal muscle of guinea pig ileum.

The plexus-free longitudinal muscle was used to investigate the muscle-relaxing effects of the known K+ channel openers, cromakalim, pinacidil and nicorandil, and compared with other known muscle relaxants, calcitonin gene-related peptide (CGRP) and isoprenaline. The three K+ channel openers all decreased basal tension and inhibited the tonic tension evoked by 30 mM KCl, 0.5 microM histamine or 0.1 microM oxotremorine in a dose-dependent manner. The order of potency is cromakalim > pinacidil > nicorandil in KCl or oxotremorine-precontracted muscle strip and nicorandil > cromakalim > pinacidil in histamine-precontracted muscle strip. Inhibition by cromakalim was completely reversed by glibenclamide, a blocker of ATP-sensitive K+ channels, while inhibition by nicorandil or pinacidil was only partially antagonized. The tonic tension evoked by KCl, histamine or oxotremorine was relaxed by CGRP or isoprenaline. Inhibition by neither of these compounds was relieved by glibenclamide. These results suggest that while ATP-sensitive K+ channels may be present in the longitudinal muscle cells, they may not be involved in the actions of CGRP or isoprenaline on the longitudinal muscle.

Animals↗
PubMed1998

Effects of K+ channel openers on relaxations to nitric oxide and endothelium-derived hyperpolarizing factor in rat mesenteric artery.

Relaxation of methoxamine-precontracted, endothelium-intact, rat mesenteric artery in the presence of NG-nitro-L-arginine methyl ester (L-NAME; 100 microM) and indomethacin (10 microM) is attributed to endothelium-derived hyperpolarizing factor (EDHF). The potency of carbachol in the presence (but not the absence) of L-NAME was reduced by levcromakalim and pinacidil, activators of ATP-sensitive K+ channels (KATP). EDHF-mediated relaxation to Ca2+ ionophore A23187 was unaffected by these compounds but was inhibited by verapamil at the level of the smooth muscle. Levcromakalim and pinacidil had the same effects at both reduced and standard levels of tone. Glibenclamide (10 microM), a KATP blocker, alone did not affect carbachol relaxations but abolished both relaxation to levcromakalim and pinacidil and their inhibitory action on EDHF released by carbachol. Levcromakalim inhibited the endothelium-dependent hyperpolarization of mesenteric arteries to carbachol but not to A23187. Thus, levcromakalim or pinacidil inhibit EDHF, but not nitric oxide, release by carbachol through an action on the endothelium.

Animals↗
PubMed2003

Functional involvement of sulphonylurea receptor (SUR) type 1 and 2B in the activity of pig urethral ATP-sensitive K+ channels.

(1) We have investigated the possible roles of sulphonylurea receptor (SUR) type 1 and 2B in the activity of pig urethral ATP-sensitive K(+) channels (K(ATP) channels) by use of patch-clamp and reverse transcriptase-polymerase chain reaction (RT-PCR) techniques. (2) In voltage-clamp experiments, not only diazoxide, a SUR1 and weak SUR2B activator, but also pinacidil, a selective SUR2 activator, caused an inward current at a holding potential of -50 mV in symmetrical 140 mM K(+) conditions. (3) Gliclazide (</=1 micro M), a selective SUR1 blocker, inhibited the 10 micro M pinacidil-induced currents (K(i)=177 micro M) and the 500 micro M diazoxide-induced currents (high-affinity site, K(i1)=5 nM; low-affinity site, K(i2)=108 micro M) at -50 mV. (4) Application of tolbutamide (</=100 micro M) reversibly caused an inhibition of the 500 micro M diazoxide-induced current at -50 mV. (5) MCC-134, a SUR type-specific K(ATP) channel regulator (1-100 micro M), produced a concentration-dependent inward K(+) current, which was suppressed by the application of glibenclamide at -50 mV. The amplitude of the MCC-134 (100 micro M)-induced current was approximately 50% of that of the 100 micro M pinacidil-induced currents. (6) Using cell-attached configuration, MCC-134 activated a glibenclamide-sensitive K(ATP) channel which was also activated by pinacidil. (7) RT-PCR analysis demonstrated the presence of SUR1 and SUR2B transcripts in pig urethra. 8 These results indicate that both SUR1 and SUR2B subunits play a functional role in regulating the activity of pig urethral K(ATP) channels and that SUR1 contributes less than 25% to total K(ATP) currents.

ATP-Binding Cassette Transporters↗
PubMed2005

Preconditioning by isoflurane induces lasting sensitization of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium channel by a protein kinase C-delta-mediated mechanism.

BACKGROUND: Cardioprotective effects of volatile anesthetics in anesthetic-induced preconditioning involve activation of the cardiac sarcolemmal adenosine triphosphate-sensitive potassium (sarcKATP) channels. This study addressed the memory phase of anesthetic preconditioning by investigating whether brief exposure to isoflurane produces lasting sensitization of the sarcKATP channel and whether protein kinase C mediates this effect. METHODS: Whole cell sarcKATP channel current (IKATP) was monitored from single isolated rat ventricular cardiomyocytes. Pinacidil was used to open the channel, and the magnitude of activated IKATP was an indicator of channel's ability to open. Involvement of protein kinase C was investigated using chelerythrine and isoform-specific peptide inhibitors and activators of protein kinase C-delta and protein kinase C-epsilon. RESULTS: The mean density of IKATP elicited by pinacidil (5 microm) in anesthetic-free conditions was 3.8 +/- 3.7 pA/pF (n = 11). After 10 min of exposure to isoflurane (0.56 mm) and 10 or 30 min of anesthetic washout, pinacidil-elicited IKATP was increased to 15.6 +/- 11.3 pA/pF (n = 12; P < 0.05) and 11.8 +/- 3.9 pA/pF (n = 6; P < 0.05), respectively. In the presence of chelerythrine (5 microm), isoflurane did not potentiate channel opening, and IKATP was 6.6 +/- 4.6 pA/pF (n = 11). Application of protein kinase C-delta peptide inhibitor also abolished isoflurane-induced sensitization of sarcKATP channel, and IKATP was 7.7 +/- 5.4 pA/pF (n = 12). In contrast, protein kinase C-epsilon peptide inhibitor did not affect channel sensitization, and pinacidil-elicited current was 14.8 +/- 9.6 pA/pF (n = 12). Interestingly, when both protein kinase C-delta and protein kinase C-epsilon activators were applied instead of isoflurane, they sensitized the channel to the same extent as isoflurane (18.9 +/- 7.2 pA/pF, n = 11, and 18.6 +/- 11.1 pA/pF, n = 10, respectively). CONCLUSION: Isoflurane induces prolonged sensitization of the sarcKATP channel to opening that persists even after anesthetic withdrawal. Our results indicate that protein kinase C-delta, rather than protein kinase C-epsilon, is a likely mediator of isoflurane effects, although both protein kinase C-delta and protein kinase C-epsilon can modulate the channel function.

Adenosine Triphosphate↗
PubMed1999

EDHF-mediated relaxation is impaired in fructose-fed rats.

Insulin resistance (IR) is associated with endothelial dysfunction. A defect in endothelium-dependent relaxation via outward potassium conductance has been observed in mesenteric arteries from IR rats. The purpose of this study was to assess whether this defect in endothelium-dependent relaxation was due to impaired endothelium-derived hyperpolarizing factor (EDHF) and to determine which specific potassium channel(s) are involved in relaxation. This was accomplished by using specific potassium channel inhibitors in the presence of nitric oxide synthase and cyclooxygenase inhibition. In addition, we sought to assess the function of smooth muscle cell adenosine triphosphate (ATP)-dependent potassium (K(ATP)) channels. Sprague-Dawley rats were randomized to control or IR. To determine EDHF-mediated relaxation, acetylcholine (ACh)-induced (10(-9)-10(-5) M) relaxation was measured (in vitro) in mesenteric arteries in the presence of indomethacin (10(-5) M) and N-nitro-L-arginine (L-NNA) (10(-4) M). Subsequently the combination of charybdotoxin (CTX) (0.1 microM) and apamin (0.5 microM) or glibenclamide (Glib) (10 microM) was added to the bath to inhibit KCa or K(ATP), respectively. In separate experiments, relaxation to pinacidil (10(-13)-10(-5) M), a K(ATP) activator, was assessed in vessels with intact endothelium, endothelium denuded, or with L-NNA. Maximal relaxation to ACh in the presence of L-NNA and indomethacin was 68+/-6% for control and 12+/-3% for IR (p<0.01). The addition of CTX + apamin almost abolished EDHF-mediated relaxation in control (Emax, 8+/-5% vs. 68+/-6%; p<0.01), whereas Glib had little affect. Neither CTX + apamin nor Glib had any affect on IR. Additionally, IR arteries were less sensitive to pinacidil than were controls (EC50, 1.5+/-0.9 microM vs. 5x10(-4)+/-3x10(-4) microM, respectively; p<0.01). Endothelial removal or L-NNA pretreatment of control arteries decreased the response to pinacidil similar to IR, whereas IR vessels were unaffected. EDHF-mediated relaxation is impaired in IR arteries. In addition, the K(Ca) channel appears to be imperative for activity of EDHF in rat small mesenteric arteries. Moreover, activation of K(ATP) channels by pinacidil is impaired in IR, and this appears to be a result of endothelial dysfunction.

Animals↗