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At least 757 records · Page 42Linked to original sources
PubMed1993

Enhancement of depolarization-induced contractions after endothelium denudation is not related to an impaired production of nitric oxide or prostacyclin in the rabbit basilar artery.

Enhancement of the extracellular potassium ion (K+) concentration combined with endothelial injury have been suggested to occur during cerebral ischaemia-reperfusion and vasospasm after subarachnoid hemorrhage. The effect of potassium (K+) depolarization was therefore investigated in isolated segments of the rabbit basilar artery with and without an intact endothelial cell layer. Addition of potassium chloride to the organ bath induced a concentration-dependent contraction. Endothelial denudation of the artery resulted in an unstable baseline tension and a leftward shift of the K+ concentration-response curve. The K+ concentration eliciting half maximum contraction decreased from 26 mmol l-1 in the presence to 12 mmol l-1 in the absence of an intact endothelium. Nimodipine (3 x 10(-7) mol l-1) or exposure to a calcium-free medium abolished the spontaneous as well as K(+)-induced contractions. N omega-nitro-L-arginine (10(-4) mol l-1), indomethacin (3 x 10(-6) mol l-1) and glibenclamide (10(-5) mol l-1) did not affect the contractile response to K+ in intact arteries. However, N omega-nitro-L-arginine increased the baseline tension, and this effect could not be reproduced with N omega-nitro-D-arginine. Pinacidil (10(-6) mol l-1) abolished the spontaneous contractile activity in endothelium-denuded arteries and reduce the K+ sensitivity to the same level as in intact arteries. Tetraethylammonium (3 mmol l-1) and ouabain (10(-5) mol l-1) increased the basal tension and shifted the K+ concentration-response curve to the left.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1997

Sulphonylurea receptor 2B and Kir6.1 form a sulphonylurea-sensitive but ATP-insensitive K+ channel.

1. We analysed the K+ channel composed of the sulphonylurea receptor 2B (SUR2B) and an inwardly rectifying K+ channel subunit Kir6.1 coexpressed in a mammalian cell line, HEK293T, with the patch clamp technique. 2. In the cell-attached configuration, K+ channel openers (pinacidil and nicorandil) activated approximately 33 pS K+ channels (approximately 145 mM external K+), which were inhibited by the sulphonylurea glibenclamide. 3. Although SUR2B forms an ATP-sensitive K+ channel with Kir6.2, whose amino acid sequence is approximately 70% homologous with that of Kir6.1, the K+ channel composed of SUR2B and Kir6.1 surprisingly did not spontaneously open on patch excision in the absence of intracellular ATP. 4. In inside-out patches, uridine diphosphate and guanosine diphosphate induced channel activity, which was inhibited by glibenclamide but not ATP. Intracellular ATP on its own activated the channels. K+ channel openers and intracellular nucleotides synergistically activated the channel. 5. Therefore, the K+ channel composed of SUR2B and Kir6.1 is not a classical ATP-sensitive K+ channel but closely resembles the nucleotide diphosphate-dependent K+ channel in vascular smooth muscle cells.

ATP-Binding Cassette Transporters↗
PubMed2002

Smooth muscle membrane potential modulates endothelium-dependent relaxation of rat basilar artery via myo-endothelial gap junctions.

The release of endothelium-derived relaxing factors, such as nitric oxide (NO), is dependent on an increase in intracellular calcium levels ([Ca(2+)](i)) within endothelial cells. Endothelial cell membrane potential plays a critical role in the regulation of [Ca(2+)](i) in that calcium influx from the extracellular space is dependent on membrane hyperpolarization. In this study, the effect of inhibition of vascular smooth muscle delayed rectifier K(+) (K(DR)) channels by 4-aminopyridine (4-AP) on endothelium-dependent relaxation of rat basilar artery to acetylcholine (ACh) was assessed. ACh-evoked endothelium-dependent relaxations were inhibited by N-(Omega)-nitro-L-arginine (L-NNA) or 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ), confirming a role for NO and guanylyl cyclase. 4-AP (300 microM) also suppressed ACh-induced relaxation, with the maximal response reduced from approximately 92 to approximately 33 % (n = 11; P < 0.01). However, relaxations in response to exogenous NO, applied in the form of authentic NO, sodium nitroprusside or diethylamineNONOate (DEANONOate), were not affected by 4-AP treatment (n = 3-11). These data are not consistent with the view that 4-AP-sensitive K(DR) channels are mediators of vascular hyperpolarization and relaxation in response to endothelium-derived NO. Inhibition of ACh-evoked relaxation by 4-AP was reversed by pinacidil (0.5-1 microM; n = 5) or 18beta-glycyrrhetinic acid (18betaGA; 5 microM; n = 5), indicating that depolarization and electrical coupling of the smooth muscle to the endothelium were involved. 4-AP caused depolarization of both endothelial and vascular smooth muscle cells of isolated segments of basilar artery (mean change 11 +/- 1 and 9 +/- 2 mV, respectively; n = 15). Significantly, 18betaGA almost completely prevented the depolarization of endothelial cells (n = 6), but not smooth muscle cells (n = 6) by 4-AP. ACh-induced hyperpolarization of endothelium and smooth muscle cells was also reduced by 4-AP, but this inhibition was not observed in the combined presence of 4-AP and 18betaGA. These data indicate that 4-AP can induce an indirect inhibition of endothelium-dependent relaxation in the rat basilar artery by electrical coupling of smooth muscle membrane depolarization to the endothelium via myo-endothelial gap junctions.

4-Aminopyridine↗
PubMed2003

Modulation of slow waves by hyperpolarization with potassium channel openers in antral smooth muscle of the guinea-pig stomach.

Modulation of spontaneous electrical activities (slow waves, pacemaker potentials and follower potentials) in response to hyperpolarization produced by the ATP-sensitive K+ channel openers (KCOs) pinacidil or nicorandil was investigated in smooth muscle tissues of the guinea-pig stomach antrum. With hyperpolarization, the amplitude of slow waves and follower potentials was reduced and that of pacemaker potentials was increased, with a minor modulation of their frequency. The attenuation of slow waves was associated with an inhibition of the 1st component and abolition of the 2nd component. All these actions of KCOs were antagonized by glibenclamide. An increase in the extracellular K+ concentration prevented the KCO-induced hyperpolarization with partial restoration of slow waves, suggesting that the inhibition was produced mainly by a decrease in membrane resistance. Exposure of tissues to KCOs for a long period of time (> 20 min) resulted in the reappearance of slow waves displaying both 1st and 2nd components. The 2nd component of the slow wave, which displayed a slower recovery, was inhibited again by 5-hydroxydecanoic acid, an inhibitor of mitochondrial ATP-sensitive K+ channels. Noradrenaline hyperpolarized the membrane by activating apamin-sensitive K+ channels and increased the amplitude and frequency of slow waves through activation of alpha 1-adrenoceptors, actions different from those of KCOs. Thus, inhibition of slow waves by KCOs may be primarily related to the decrease in amplitude of a passive electrotonic component, possibly due to a reduction of the input resistance. The hyperpolarization shifted the threshold potential for generation of the 2nd component of slow waves to negative levels, presumably due to modulation of mitochondrial functions.

ATP-Binding Cassette Transporters↗
PubMed1999

Stoichiometry of potassium channel opener action.

Potassium channel openers (KCOs; e.g., P1075, pinacidil) exert their effects on excitable cells by opening ATP-sensitive potassium channels. These channels are heteromultimers composed with a 4:4 stoichiometry of an inwardly rectifying K(+) channel subunit plus a regulatory subunit comprising the receptor sites for hypoglycemic sulfonylureas and KCOs (a sulfonylurea receptor). To elucidate stoichiometry of KCO action, we analyzed P1075 sensitivity of channels coassembled from sulfonylurea receptor isoforms with high or low P1075 affinity. Concentration activation curves for cDNA ratios of 1:1 or 1:10 resembled those for channel opening resulting from interaction with a single site, whereas models for activation requiring occupation of two, three, or four sites were incongruous. We conclude KCO-induced channel activation to be mediated by interaction with a single binding site per tetradimeric complex.

ATP-Binding Cassette Transporters↗
PubMed1989

Hyperpolarizing vasodilators activate ATP-sensitive K+ channels in arterial smooth muscle.

Vasodilators are used clinically for the treatment of hypertension and heart failure. The effects of some vasodilators seem to be mediated by membrane hyperpolarization. The molecular basis of this hyperpolarization has been investigated by examining the properties of single K+ channels in arterial smooth muscle cells. The presence of adenosine triphosphate (ATP)-sensitive K+ channels in these cells was demonstrated at the single channel level. These channels were opened by the hyperpolarizing vasodilator cromakalim and inhibited by the ATP-sensitive K+ channel blocker glibenclamide. Furthermore, in arterial rings the vasorelaxing actions of the drugs diazoxide, cromakalim, and pinacidil and the hyperpolarizing actions of vasoactive intestinal polypeptide and acetylcholine were blocked by inhibitors of the ATP-sensitive K+ channels, suggesting that all these agents may act through a common pathway in smooth muscle by opening ATP-sensitive K+ channels.

Acetylcholine↗
PubMed1993

ATP-sensitive K+ channels in rat aorta and brain microvascular endothelial cells.

The endothelium plays an important role in the modulation of vascular tone and blood cell activation. Extensive work has demonstrated that the release of endothelium-derived relaxing factor (EDRF) from the endothelium is evoked by a number of physical and chemical stimuli requiring Ca2+. Because endothelial cells do not express voltage-dependent Ca2+ channels, Ca2+ influxes following receptor activation may be facilitated by cell hyperpolarizations mediated by the activation of K+ conductances. There has been recent interest in the role of ATP-sensitive K+ channels (KATP) suggesting that KATP may play a role in the regulation of blood flow. We have investigated the electrophysiological properties of an ATP-sensitive K+ conductance in whole cell and membrane patches from rat aorta and brain microvascular endothelial cells. Whole cell as well as single-channel currents were increased by either intracellular dialysis of ATP or application of glucose-free/NaCN (2 mM) solutions. Both currents were reversibly blocked by glibenclamide (1-100 microM). The KATP channel opener pinacidil (30 microM) caused activation of an outward current in the presence of physiological intracellular ATP concentrations. In inside-out patches, 10 microM-1 mM ATP invariably caused a dramatic decrease in channel activity. We conclude that both rat aorta and brain microvascular endothelial cells express KATP channels. KATP may play a role in the regulation of endothelial cell resting potential during impaired energy supply and therefore modulate EDRF release and thus cerebral blood flow.

Adenosine Triphosphate↗
PubMed2000

Pharmacology and modulation of K(ATP) channels by protein kinase C and phosphatases in gallbladder smooth muscle.

ATP-sensitive K(+) (K(ATP)) channels exhibit pharmacological diversity, which is critical for the development of novel therapeutic agents. We have characterized K(ATP) channels in gallbladder smooth muscle to determine how their pharmacological properties compare to K(ATP) channels in other types of smooth muscle. K(ATP) currents were measured in myocytes isolated from gallbladder and mesenteric artery. The potencies of pinacidil, diazoxide, and glibenclamide were similar in gallbladder and vascular smooth muscle, suggesting that the regions of the channel conferring sensitivity to these agents are conserved among smooth muscle types. Activators of protein kinase C (PKC), however, were less effective at inhibiting K(ATP) currents in myocytes from gallbladder than mesenteric artery. The phosphatase inhibitor okadaic acid increased the efficacy of PKC activators and revealed ongoing basal activation of K(ATP) channels by protein kinase A in gallbladder. These results suggest that phosphatases and basal kinase activity play an important role in controlling K(ATP) channel activity.

Adenosine Triphosphate↗
PubMed1999

Cholesterol inhibits spontaneous action potentials and calcium currents in guinea pig gallbladder smooth muscle.

Elevated cholesterol decreases agonist-induced contractility and enhances stone formation in the gallbladder. The current study was conducted to determine if and how the electrical properties and ionic conductances of gallbladder smooth muscle are altered by elevated cholesterol. Cholesterol was delivered as a complex with cyclodextrin, and effects were evaluated with intracellular recordings from intact gallbladder and whole cell patch-clamp recordings from isolated cells. Cholesterol significantly attenuated the spontaneous action potentials of intact tissue. Furthermore, calcium-dependent action potentials and calcium currents were reduced in the intact tissue and in isolated cells, respectively. However, neither membrane potential hyperpolarizations induced by the ATP-sensitive potassium channel opener, pinacidil, nor voltage-activated outward potassium currents were affected by cholesterol. Hyperpolarizations elicited by calcitonin gene-related peptide were reduced by cholesterol enrichment, indicating potential changes in receptor ligand binding and/or second messenger interactions. These data indicate that excess cholesterol can contribute to gallbladder stasis by affecting calcium channel activity, whereas potassium channels remained unaffected. In addition, cholesterol enrichment may also modulate receptor ligand behavior and/or second messenger interactions.

3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethy↗
PubMed2005

Initiation of remote microvascular preconditioning requires K(ATP) channel activity.

The purpose of this study was to investigate vascular preconditioning of individual microvascular networks. Prior work shows that exposure of downstream arterioles to specific agonists preconditions upstream arterioles so that they exhibit an altered local vasoactive response [remote microvascular preconditioning (RMP)]. We hypothesized that mitochondrial ATP-sensitive K+ (K(ATP)) channels were involved in stimulation of RMP. Arteriolar diameter (approximately 15 microm) was observed approximately 1,000 microm upstream of the remote exposure site in the cheek pouch of pentobarbital sodium-anesthetized (70 mg/kg) male hamsters (n = 104); all agonists were applied via micropipette. RMP was initiated by application of pinacidil (Pin), diazoxide (DZ), sodium nitroprusside (SNP), or bradykinin (BK) to the downstream vessel. After 15 min, RMP was apparent at the upstream observation site from testing of local vasoactive responses to L-arginine. Pin, DZ, SNP, and BK each stimulated RMP. To evaluate a specific role for mitochondrial K(ATP) channels in this response, 5-hydroxydecanoate was applied (via a 2nd pipette) during downstream stimulation with agonist. 5-Hydroxydecanoate blocked RMP initiated by Pin, DZ, or SNP, suggesting that mitochondrial K(ATP) channels are involved before SNP signal transduction. To verify this, we applied N(omega)-nitro-L-arginine during DZ or SNP stimulation. RMP was blocked during SNP, but not during DZ, stimulation. Thus stimulation of the RMP response requires mitochondrial K(ATP) channel activity after stimulation by nitric oxide donors.

ATP-Binding Cassette Transporters↗
PubMed2002

Hypoxic vasorelaxation inhibition by organ culture correlates with loss of Kv channels but not Ca(2+) channels.

We (Thorne GD, Shimizu S, and Paul RJ. Am J Physiol Cell Physiol 281: C24-C32, 2001) have recently shown that organ culture for 24 h specifically inhibits relaxation to acute hypoxia (95% N(2)-5% CO(2)) in the porcine coronary artery. Here we show similar results in the porcine carotid artery and the rat and mouse aorta. In the coronary artery, part of the inability to relax to hypoxia after organ culture is associated with a concomitant loss in ability to reduce intracellular Ca(2+) concentration ([Ca(2+)](i)) during hypoxia (Thorne GD, Shimizu S, and Paul RJ. Am J Physiol Cell Physiol 281: C24-C32, 2001). To elucidate the mechanisms responsible for the loss of relaxation to hypoxia, we investigated changes in K(+) and Ca(2+) channel activity and gene expression that play key roles in [Ca(2+)](i) regulation in vascular smooth muscle (VSM). Reduced mRNA expression of O(2)-sensitive K(+) channels (Kv1.5 and Kv2.1) was shown by reverse transcriptase-polymerase chain reaction in the rat aorta. In contrast, no change in other expressed voltage-gated K(+) channels (Kv1.2 and Kv1.3) or Ca(2+) channel subtypes was found. Modified K(+) channel expression is supported by functional evidence indicating a reduced response to general K(+) channel activation, by pinacidil, and to specific voltage-dependent K(+) (Kv) channel blockade by 4-aminopyridine. In conclusion, organ culture decreases expression of specific Kv channels. These changes are consistent with altered mechanisms of VSM contractility that may be involved in Ca(2+)-dependent pathways of hypoxia-induced vasodilation.

Animals↗
PubMed2002

Ketamine abolishes ischemic preconditioning through inhibition of K(ATP) channels in rabbit hearts.

Although ketamine inhibits ATP-sensitive K (K(ATP)) channels in rat ventricular myocytes and abolishes the cardioprotective effect of ischemic preconditioning in isolated rat hearts and in rabbits in in vivo, no studies to date specifically address the precise mechanism of this prevention of ischemic preconditioning by ketamine. This study investigated the mechanism of the blockade of ischemic preconditioning by ketamine in rabbit ventricular myocytes using patch-clamp techniques and in rabbit heart slices model for simulated ischemia and preconditioning. In cell-attached and inside-out patches, ketamine inhibited sarcolemmal K(ATP) channel activities in a concentration-dependent manner. Ketamine decreased the burst duration and increased the interburst duration without a change in the single-channel conductance. In the heart slice model of preconditioning, heart slices preconditioned with a single 5-min anoxia, pinacidil, or diazoxide, followed by 15-min reoxygenation, were protected against subsequent 30-min anoxia and 1-h reoxygenation, and the cardioprotection was blocked by the concomitant presence of ketamine. These data are consistent with the notion that inhibition of sarcolemmal or mitochondrial K(ATP) channels may contribute, at least in part, to the mechanism of the blockade of ischemic preconditioning by ketamine.

Animals↗
PubMed1991

Hyperpolarization of arterial smooth muscle induced by endothelial humoral substances.

A sandwich preparation was obtained by placing a segment of the endothelium-free guinea pig coronary artery over the intact carotid artery with the objective being to determine whether the endothelium-dependent hyperpolarization by acetylcholine chloride (ACh) is mediated by a humoral factor. ACh hyperpolarized the sandwiched coronary smooth muscle membrane, the amplitude being larger than that of the carotid artery and smaller than that of the intact coronary artery. When spontaneously active smooth muscles (stomach antrum or portal vein) were used as the donor tissue, no electrical signal was transducted to the overlying coronary smooth muscles. In the sandwiched coronary artery, the ACh-induced hyperpolarization was not inhibited by ouabain, indomethacin, or nitroarginine. Pinacidil hyperpolarized the coronary smooth muscle membrane; the responses were inhibited by glybenclamide but not by tetraethylammonium chloride (TEA). The ACh-induced hyperpolarization was inhibited by TEA but not by glybenclamide. These results suggest that the ACh-induced hyperpolarization is mediated by an endothelium-derived humoral substance (endothelium-derived hyperpolarizing factor). Possible contribution of Ca-dependent K channels, but not ATP-sensitive K channels, to the endothelium-derived hyperpolarizing factor-induced hyperpolarization was considered.

Acetylcholine↗
PubMed1992

Glibenclamide decreases basal coronary blood flow in anesthetized dogs.

The effects of ATP-sensitive K+ channel blockade on coronary blood flow were studied in 13 anesthetized open-chest dogs. A specific ATP-sensitive K+ channel blocker, glibenclamide, was infused into the left circumflex coronary artery (LCx). Coronary blood flow of LCx and systolic segment shortening at the LCx area were measured. Intracoronary infusion of glibenclamide (0.5, 5, and 50 micrograms.kg-1.min-1) decreased coronary blood flow dose dependently. Glibenclamide at the dose of 50 micrograms.kg-1.min-1 decreased LCx coronary blood flow by 55 +/- 4% (P less than 0.01), which was accompanied by a decrease in percentage segment shortening at the LCx area (P less than 0.01) and ST elevation. When coronary blood flow was maintained at the baseline level by simultaneous infusion of sodium nitroprusside (1-3 micrograms/min ic) or pinacidil (0.3-0.6 mg/min ic), glibenclamide did not alter percentage segment shortening or produced ST elevation. The latter results suggest that glibenclamide decreased coronary blood flow, which secondarily induced myocardial ischemia and dysfunction. Our results suggest that ATP-sensitive K+ channels of coronary arteries are involved in maintaining the level of resting coronary blood flow under physiological conditions in anesthetized dogs.

Animals↗
PubMed1993

Arteriolar tone is determined by activity of ATP-sensitive potassium channels.

The role of ATP-sensitive potassium channels (KATP) in determining resting arteriolar tone and vasodilator reactivity was assessed in superfused, hamster microcirculatory beds studied via intravital microscopy. Under resting conditions, the selective KATP blocker, glibenclamide, produced concentration-dependent vasoconstriction in both the cheek pouch and the cremaster muscle. Concentration-related constriction of cheek pouch arterioles was also observed with tetrapentylammonium, although this agent appeared to have toxic effects on the microcirculation. Glibenclamide (2 microM) abolished arteriolar vasodilation to cromakalim and pinacidil over a concentration range (10 nM-1 microM) in which these agents are selective KATP agonists and also significantly inhibited adenosine-, carbacyclin-, and isoproterenol-induced vasodilation. In contrast, responses to other vasodilators were not significantly affected [methacholine, forskolin, and dibutyryl adenosine 3',5'-cyclic monophosphate (cAMP)] or only slightly depressed (sodium nitroprusside). Thus the activity of KATP determines, in part, resting arteriolar tone in the hamster. Furthermore, vasodilators like adenosine, beta-adrenergic agonists, and prostacyclin appear to act through these ion channels by a mechanism that may not involve cAMP.

Adenosine Triphosphate↗
PubMed1994

Regulation of ATP-sensitive K+ channels by ATP and nucleotide diphosphate in rabbit portal vein.

The modulation of ATP-sensitive K+ (KATP)-channel activity was investigated by recording single-channel currents in isolated smooth muscle cells from rabbit portal vein. K(+)-channel openers (KCOs; pinacidil, lemakalim, and nicorandil) induced burstlike openings of single KATP channels in the cell-attached configuration. After patch excision, KATP channels showed "run-down" phenomenon in the presence of KCOs, but subsequent application of Mg-ATP (1 mM) restored KATP-channel activity. Removal of Mg-ATP resulted in transient augmentation of KATP currents, which eventually decayed out. Nucleotide diphosphates (NDPs; GDP, ADP, UDP, IDP, and CDP) also induced channel reopening in the presence of KCOs, which was markedly enhanced by addition of Mg2+ in millimolar concentrations at the internal side of the membrane. The dose-response relation between ATP and the UDP-induced KATP-channel activity was shifted to the right in the presence of Mg2+ (2 mM). These results suggest that intracellular ATP, NDPs, and Mg2+ regulate the channel state of KATP channels (operative and inoperative states) and that KCOs open KATP channels only in the operative state.

Adenosine Diphosphate↗
PubMed1995

Modulation of adrenergic coronary vasoconstriction via ATP-sensitive potassium channel.

We examined humoral and/or locally produced vasoactive factors involved in modulating sympathetic coronary vasoconstriction via the ATP-sensitive K (KATP) channel in 42 anesthetized dogs. Glibenclamide (30 micrograms.kg-1.min-1 ic or 0.6 mg.kg-1.min-1 left atrial injection) augmented coronary vascular resistance (CVR) at baseline and during cardiac sympathetic nerve stimulation (2-20 Hz), with a greater increase seen in the subepicardial region than in the subendocardial region both during beta-adrenergic receptor blockade and alpha- and beta-receptor blockade [P < 0.05 and P < 0.05 (n = 6 and 18 dogs), analysis of variance]. In contrast, pinacidil (10 micrograms.kg-1.min-1; n = 8 dogs) suppressed CVR. Glibenclamide enhanced CVR response to locally administered norepinephrine of 0.001-0.1 microgram.kg-1.min-1 (P < 0.05, analysis of covariance; n = 5 dogs) but did not enhance norepinephrine or neuropeptide Y overflow (n = 18 dogs). CVR was not modified by calcitonin gene-related peptide (CGRP) antagonist [CGRP-(8-37)], 8-phenyltheophylline, or N omega-nitro-L-arginine (n = 11 dogs). Thus sympathetic coronary vasoconstriction is modified by coronary vascular KATP channels with a transmural difference. However, CGRP, adenosine, and endothelial nitric oxide production are not involved in the modulation.

Adenosine↗
PubMed1996

Nonspecific inhibition of adenosine-activated K+ current by glibenclamide in guinea pig atrial myocytes.

The ATP-sensitive K+ (KATP) channel blocker glibenclamide was reported to inhibit the K+ current activated by adenosine. This study investigated whether the inhibition by glibenclamide of the adenosine-induced current is due to a specific blockade of KATP channels in guinea pig atrial myocytes. In the absence of adenosine, the basal background current was an inward rectifier K+ current (IK1). Glibenclamide at concentrations of 10, 30, and 100 microM reduced the basal background K+ current by 15 +/- 6, 43 +/- 10, and 63 +/- 11%, respectively. In the presence of adenosine (10 microM), glibenclamide (30 microM) decreased the adenosine-induced K+ current by 39 +/- 3%. A similar inhibitory effect of glibenclamide on the outward K+ currents activated by either the muscarinic agonist carbachol or the nonhydrolyzable GTP analogue guanosine 5'-[gamma-thio]triphosphate was observed. A low concentration (1 microM) of glibenclamide did not significantly attenuate the current elicited by adenosine, although it completely abolished the outward K+ current activated by pinacidil, a KATP channel opener. Thus we conclude that the inhibition of adenosine-induced K+ current by glibenclamide at high concentrations (> 1 microM) is not due to a specific blockade of KATP channels, but rather, resulted from a blockade of IK1.

Action Potentials↗