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PubMed1991

Characterization of binding of the ATP-sensitive potassium channel ligand, [3H]glyburide, to neuronal and muscle preparations.

Binding of the hypoglycemic sulfonylurea, [3H]glyburide, to crude membrane fractions from brain, heart and smooth (intestinal) muscle was saturable, linear with protein concentration and reversible. Saturation analysis revealed high affinity sites (KH values, 7 x 10(-11) M, 5 x 10(-11) M and 6 x 10(-11) M), with Bmax-H values 209, 36 and 23 fmol/mg protein in the brain, heart and smooth muscle, respectively. High affinity [3H]glyburide binding was pharmacologically specific, insensitive to a variety of receptor-active ligands, but sensitive to a series of sulfonylureas, and good, essentially 1:1, correlations were obtained between binding affinities and literature-derived pharmacologic activities. The K+ channel activators, cromakalim, nicorandil, pinacidil and minoxidil were not effective as inhibitors of [3H]glyburide binding. However, diazoxide was a modestly effective inhibitor. Putative low affinity sites (KL values, 3 x 10(-7) M, 1 x 10(-7) M and 2 x 10(-9) M) with Bmax-L values 4956, 336 and 53 fmol/mg protein in brain, heart and smooth muscle, respectively, were identified. Their significance remains to be established. Except for ATP gamma S, the ability of nucleotide triphosphates to inhibit high affinity [3H] glyburide binding was dependent on the presence of Mg++. ADP, in the presence of Mg++, inhibited binding with an IC50 value of 6.3 x 10(-4) M. Nucleotide monophosphates did not inhibit [3H] glyburide binding in the presence or absence of Mg++, whereas in the presence of Mg++, nucleotide triphosphates were equally potent inhibitors of binding. The rank order potency for nucleotide diphosphate inhibition of binding, in the presence of Mg++, is ADP greater than GDP greater than IDP = UDP. In the absence of Mg++, [3H]glyburide binding shows a biphasic response to ADP, and the inhibition of binding by ADP was prevented by ATP. It is suggested that this biphasic response is the result of a second nucleotide binding site.

Adenosine Triphosphate↗
PubMed1990

Alterations by glyburide of effects of BRL 34915 and P 1060 on contraction, 86Rb efflux and the maxi-K+ channel in rat portal vein.

Effects of the K+ channel blocking agent, glyburide, on the actions of two K+ channel openers, BRL 34915 (cromakalim) and P 1060 (Leo), a potent pinacidil derivative (N-(t-butyl)-N"-cyano-N'-3-pyridyl-guanidine), were ascertained. Tension responses and 86Rb fluxes in rat portal vein strips and single channel electrophysiological recordings in enzymatically dissociated rat portal vein cells were obtained. Glyburide (0.3 microM) increased spontaneous contractile activity and caused concentration-dependent shifts in the relaxation responses to BRL 34915 and P 1060. Increases in 86Rb efflux were obtained only at much higher concentrations of BRL 34915 or P 1060, and these increases were blocked only at higher concentrations of glyburide (5.0 microM). BRL 34915 and P 1060 specifically increase the open-state probability of the Ca+(+)-activated K+ (maxi-K+) channel, and these actions are blocked by glyburide and also by charybdotoxin. Changes in single channel activity and contractile responsiveness occur at similar concentrations of agonists and antagonists. Thus, the membrane channel in rat portal vein affected by glyburide, BRL 34915 and P 1060 appears to be the Ca+(+)-activated maxi-K+ channel (that does not show ATP dependence under the conditions of these experiments). Concentrations of agonists and antagonists effective on maxi-K+ channel activity correspond to those affecting contractile responsiveness and are lower than those eliciting changes in 86Rb flux.

Animals↗
PubMedDate not supplied

[Potassium channel activators: from pharmacology to therapeutics].

Potassium channels activators (PCA) are drugs which open or prolong the open state duration of potassium channels. Hence they promote potassium efflux, hyperpolarize the cell membrane, thus preventing intracellular penetration of calcium through the voltage-dependent calcium channels. The resulting decrease in intracellular free calcium concentration induces relaxant effects in smooth muscle cells (vessels, bronchi, bladder, etc.) which are the rationale for the present and future therapeutic indications of PCA, namely hypertension, asthma, etc. In animals, PCA produce vasodilating, hypotensive and antihypertensive effects, accompanied by tachycardia and stimulation of the renin-angiotensin system. The regional vasodilator profile of PCA is heterogeneous and their hypotensive properties are antagonized only by glibenclamide, an antagonist of ATP-dependent potassium channels. In patients, only pinacidil, minoxidil and diazoxide are presently used as antihypertensive drugs.

Antihypertensive Agents↗
PubMed1988

K+-channel opening as a mechanism for relaxing airways smooth muscle.

The properties and physiological roles of K+-channels in the plasmalemma of airways smooth muscle are currently being clarified by the use of techniques such as patch-clamp recording. K+-channel activity plays an important role in determining both the resting membrane potential and the electrical excitability of the airways smooth muscle cell. Established bronchodilators such as agonists at beta-adrenoceptors and methylxanthines may provide K+-channel opening but this is not crucial for their relaxant action. The actions of other smooth muscle relaxants such as BRL 34915 and pinacidil (Fig.) may more closely depend on their ability to open K+-channels and such agents are currently being examined to determine whether they protect against bronchoconstrictor challenge in vivo or have beneficial effects in asthma.

Animals↗
PubMed1995

KR-30450, a newly synthesized benzopyran derivative, activates the cardiac ATP-sensitive K+ channel.

KR-30450 (2-(2"(1",3"-dioxolone)-2-methyl-4-(2'-oxo-1'-pyrrollidinyl) -6- nitro-2H-1-benzopyren) is a newly synthesized benzopyran derivative. We examined the effect of KR-30450 on the action potential duration of isolated rat papillary muscle and on the ATP-sensitive K+ channel (KATP) activity in single rat ventricular myocytes with 3 M KCl-filled conventional microelectrode and patch clamp techniques. KR-30450 (10(-7) approximately 10(-5) M) reduced the action potential duration in a concentration-dependent manner and this was inhibited by 3 microM glibenclamide, suggesting that KATP was involved. In cell-attached patches, KR-30450 (10(-5) M) in the pipette activated the KATP which was closed by 3 microM glibenclamide. In inside-out patches, the effects of KR-30450 on KATP activity were examined before and after run-down of the channel. Before run-down, KR-30450 increased the KATP activity only in the presence of ATP and shifted the [ATP]i-KATP activity relationship to the right. After run-down, KR-30450 did not affect the KATP activity either in the presence or absence of 3 mM UDP, but increased the UDP-induced KATP activity in the presence of 1 mM ATP-gamma-S. From these results, we conclude that KR-30450 antagonizes the inhibitory effect of ATP on the KATP in a competitive manner. These effects of KR-30450 are similar to those of ER-001533 and HOE-234, but different from those of pinacidil and lemakalim.

Action Potentials↗
PubMed1995

K-channel opening activity of dihydropyridine ZM244085: effect on 86Rb efflux and 3H-P1075 binding in urinary bladder smooth muscle.

Zeneca ZM244085, 9-(3 cyanophenyl)hexahydro-1,8 acridinedione, is a novel dihydropyridine (DHP) which relaxes KCl precontracted urinary bladder smooth muscle in vitro. The effect of ZM244085 on low and high KCl induced contractions, 86Rb efflux and [3H]-P1075 binding in guinea pig bladder strips was investigated to characterize the K-channel opening properties of this compound. Since ZM244085 is a dihydropyridine its effect on DHP binding sites on Ca2+ channels was also investigated. ZM244085 was found to be more potent in relaxing detrusor strips precontracted with 15 mM KCl than strips precontracted with 80 mM KCl (Li et al., 1995). This functional profile of ZM244085 is similar to that exhibited by typical K-channel openers (PCO). In addition, inhibition of ZM244085 induced relaxation of detrusor strips by glibenclamide suggests that ZM244085 opens ATP sensitive K-channel (KATP) in urinary bladder (Li et al., 1995). Since the glibenclamide sensitive smooth muscle relaxation activity of ZM244085 could still be an indirect effect of this compound on KATP channels we carried out 86Rb efflux studies and [3H]-P1075 binding studies to further confirm these findings. The 86Rb efflux assay is a direct method for monitoring the movement of K+ ions across the cell membranes. Displacement of [3H]-P1075 binding to bladder membranes supports a direct action of the compound on the KATP channel. The present study demonstrates that ZM244085 in a concentration dependent manner increases the rate of 86Rb efflux from guinea pig bladder strips. This effect was inhibited by glibenclamide (30 microM), a known KATP channel blocker. In addition, interaction of ZM244085 with KATP channels was also confirmed in human bladder smooth muscle cells using a 42K efflux assay. Furthermore, we were able to demonstrate that ZM244085, structurally distinct PCO, inhibited the binding of 3H-P1075 to urinary bladder strips in a manner similar to other KATP openers such as cromakalim and pinacidil. Inhibition of 3H-P1075 binding by ZM244085 and other PCO's correlates well with increases in 86Rb efflux and bladder muscle relaxation studies. Finally, ZM244085 did not exhibit any significant affect on VSCC as evidenced by very weak inhibition of [3H]-PN200,110 binding to bladder membranes by ZM244085. It is concluded that Zeneca ZM244085 is a PCO which activates KATP channels in urinary bladder.

Acridines↗
PubMed1995

Regulation of a potassium conductance in rat midbrain dopamine neurons by intracellular adenosine triphosphate (ATP) and the sulfonylureas tolbutamide and glibenclamide.

The presence of adenosine triphosphate-regulated potassium channels (K-ATPs) in midbrain dopamine neurons is currently in dispute. This was investigated using whole-cell patch-clamp recordings from dopamine neurons in slices of midbrain from 9-12-d-old rats. Intracellular dialysis with Mg2+ ATP-free solutions resulted in a membrane hyperpolarization (14 +/- 6 mV), or outward current (102 +/- 27 pA) in voltage clamp, which developed over 14 +/- 1.6 min. These hyperpolarizations and outward currents were reversed by the K-ATP-blocking sulfonylureas tolbutamide (100 microM) and glibenclamide (3 microM). This sulfonylurea-sensitive outward current was associated with an increase in a nonrectifying (between -50 and -130 mV) conductance of approximately 2 nS, with a reversal potential of -100 mV (in 2.5 mM extracellular potassium), consistent with a potassium conductance increase. When the dialyzate contained Mg2+ATP (2 mM), no slowly developing hyperpolarization or outward current occurred, and tolbutamide (200 microM) and glibenclamide (10 microM) did not affect membrane potential or current. Additionally, the "potassium channel activators" (KCAs) lemakalim (200 microM) and pinacidil (50 microM) were also without effect on the membrane potential or holding current in these cells. The hyperpolarizations and outward currents caused by baclofen and quinpirole, agonists at GABAB and D2 receptors, respectively, were neither blocked by sulfonylureas nor occluded by the current resulting from depletion of intracellular ATP. Thus, these K-ATPs appear independent of the potassium channels coupled to GABAB and D2 receptors in these cells. This ATP-regulated potassium conductance may constitute a protective mechanism during anoxia or hypoglycemia, by restricting membrane depolarization of dopamine neurons when intracellular ATP levels fall.

Adenosine Triphosphate↗
PubMed1993

[Anti-angina activity of potassium-channel activators].

Recently, a new class of drugs has been developed with unique properties with regard to cardiovascular pharmacology: K(+)-channel openers. The increased K+ efflux from smooth muscle cells induced by these drugs is accompanied by a reduced intracellular availability of free Ca++, which in turn induces vascular relaxation. This property is currently being exploited to achieve peripheral and coronary artery dilatation in patients with ischemic heart disease. Cromakalim, pinacidil, and nicorandil, are the most extensively investigated agents in this class. Nicorandil, in addition to its K(+)-channel opener property, also shows a nitrate-like activity on guanylate cyclase of vascular smooth muscle cells. Clinical trials demonstrate that chronic administration of nicorandil can significantly increase exercise tolerance in patients with coronary artery disease. In experimental studies, this drug has also shown protective effects against myocardial injury induced by ischemia and reperfusion, by mechanisms partly independent of its vasodilating properties. These results suggest that K(+)-channel openers may have a relevant place in the pharmacological treatment of patients with ischemic heart disease.

Angina Pectoris↗
PubMed1994

Functional receptors in Xenopus oocytes for U-37883A, a novel ATP-sensitive K+ channel blocker: comparison with rat insulinoma cells.

Follicle-enclosed Xenopus oocytes were used to describe the ATP-sensitive K+ (KATP) channel-blocking properties of U-37883A (4-morpholinecarboximidine-N-1-adamantyl-N'-cyclohexyl), in comparison with glibenclamide. In follicular oocytes, the KATP channel opener P1060 (30 microM), a pinacidil analog, activated a large outward K+ current that was blocked by glibenclamide (IC50 = 0.33 microM) and U-37883A (IC50 = 0.26 microM). P1060 activation was inhibited by both U-37883A and glibenclamide in a noncompetitive manner. U-37883A also blocked the KATP channel activation by cAMP (300 microM) and adenosine (10 microM). Single-channel studies on isolated follicular cells showed that U-37883A (10 microM) reduced the open probability of the KATP channel by 76%, without significantly modifying the single-channel current amplitude. Receptor binding studies with [3H]U-37883 in membranes from follicle-enclosed oocytes demonstrated a single class of low affinity binding sites, with a Kd of 450 nM and a Bmax of 17 pmol/mg of protein. Studies with analogs of U-37883A showed that U-52090A inhibited KATP current and displaced [3H]U-37883 from its binding site with similar potencies. In contrast, U-42069D neither inhibited KATP current nor competed with [3H]U-37883 binding. In RINm5F cells (an insulinoma cell line), U-37883A, unlike glibenclamide, failed to inhibit KATP current. Furthermore, there was no significant specific binding of [3H]U-37883 in RINm5F cell membranes, which displayed high levels of specific binding of [3H]glibenclamide. These data demonstrate the presence of a receptor for U-37883A-type guanidines that controls the activity of the endogenous KATP channels in follicle-enclosed oocytes. The available data collectively suggest that U-37883A is a more selective blocker of the follicular KATP channel, which is very similar to that in smooth muscle, than of the pancreatic beta cell KATP channel.

Adamantane↗
PubMedDate not supplied

Potassium channel openers induce mitochondrial matrix volume changes via activation of ATP-sensitive K+ channel.

Recently, using patch-clamp method, an ATP-sensitive potassium channel in rat liver mitochondrial inner membrane was identified. In this report we investigated the effects of different potassium channel openers on potassium ion permeability of rat liver mitochondria. For that purpose we employed light scattering technique, reflecting mitochondrial volume changes linked to solute transport. Among various potassium channel openers RP 66471, pinacidil, minoxidil sulfate and KRN 2391 were found to stimulate mitochondrial swelling with high efficiency. P1060, aprykalim and diazoxide had only a slight effect, while Ro 31-6930 and nicorandil were found ineffective. Activation by the K+ openers was abolished by the antidiabetic sulfonylurea, glibenclamide (the well known blocker of ATP-sensitive potassium channels). These findings may suggest that mitochondrial ATP-dependent K+ channel is involved in regulation of mitochondrial matrix volume.

Adenosine Triphosphate↗
PubMed1993

YM934, a novel K+ channel opener, activates ATP-sensitive K+ channels in cardiac myocytes.

2-(3,4-Dihydro-2,2-dimethyl-6-nitro-2H-1,4-benzoxazin-4-yl)pyridin e N-oxide (YM934) is a newly synthesized benzoxazin. The effects of YM934 on ATP-sensitive K+ (KATP) channels in guinea pig cardiac ventricular myocytes and in an insulin-secreting cell line, HIT T15 beta-cells, were examined using the gigaohm-seal patch-clamp techniques. Under the whole-cell clamp condition, YM934 induced in ventricular myocytes a time-independent, glibenclamide-sensitive K+ current in a concentration-dependent fashion (EC50 = approximately 3 microM). On formation of inside-out patches in ATP-free solution, the KATP channel current abruptly appeared and then ran down. YM934 was applied to inside-out patches before, during and after channel "run-down." Because nucleoside diphosphates, such as uridine diphosphate (UDP), can induce channel openings after complete run-down, the effects of YM934 on the UDP-induced channel openings were also examined. Before run-down, YM934 enhanced KATP channel activity by decreasing the sensitivity of channels to intracellular ATP. YM934 also enhanced the partially run-down channel, even in the absence of ATP. After run-down, YM934 had no effect but could enhance the UDP-induced KATP channel openings. These effects of YM934 on cardiac KATP channels were similar to those of pinacidil and lemakalim. In HIT T15 beta-cells, 100 microM YM934 was ineffective in both cell-attached and inside-out patch configurations, suggesting the tissue-specific nature of the action of this novel K+ channel opener.

Adenosine Triphosphate↗
PubMed1993

Binding of the K+ channel opener [3H]P1075 in rat isolated aorta: relationship to functional effects of openers and blockers.

P1075 [N-cyano-N'-(1,1-dimethylpropyl)-N"-3-pyridylguanidine], an analogue of the K+ channel opener pinacidil, was shown to be a K+ channel opener in rat aorta, based on (i) its ability to stimulate 86Rb+ efflux, (ii) its ability to relax contractions in response to noradrenaline under normal conditions (5 mM KCl) but not under depolarized conditions (55 mM KCl), and (iii) the sensitivity of these effects to inhibition by the sulfonylurea glibenclamide. In these assays, P1075 was approximately 20 times more potent than cromakalim. Using a tritiated derivative, [3H] P1075, specific binding could not be detected in microsomal preparations from various tissues. However, in rat aortic strips specific binding of [3H]P1075 has been observed and was reduced by lowering the temperature or by decreasing intracellular ATP levels via metabolic inhibition. Specific [3H]P1075 binding was influenced neither by depolarization (55 mM KCl) nor by lowering the pH from 7.4 to 6.0. Binding was inhibited by representatives from all major families of K+ channel openers, with potencies that correlated well with the potencies obtained in 86Rb+ efflux and relaxation studies. However, stimulation of 86Rb+ efflux occurred at 40 times higher concentrations than did binding (and vasorelaxation). Of the various inhibitors of the K+ channel openers tested, only the sulfonylureas inhibited [3H] P1075 binding with the same rank order of potencies as that required for inhibition of P1075-induced 86Rb+ efflux, although at higher concentrations. The results show that binding of [3H] P1075 is independent of membrane potential but decreases concomitantly with the intracellular ATP level. The excellent correlation between the potencies of the openers and sulfonylurea blockers in binding assays and functional studies suggests that the 'drug receptor' labeled by [3H]P1075 in rat isolated aorta is of functional relevance. However, the fact that binding of the openers occurred at concentrations considerably lower than those required for K+ channel opening and that binding of the sulfonylureas was only reflected at concentrations higher than those needed to block the channel requires complex models to link binding and effect, possibly involving two agonist binding sites coupled by negative cooperativity.

Adenosine Triphosphate↗
PubMed1995

Characterization of and modulation by a beta-subunit of a human maxi KCa channel cloned from myometrium.

cDNAs encoding functional maxi KCa channel alpha-subunits (hslo) were cloned from human myometrium. Northern blot analysis revealed a high abundance of mRNA in human uterine smooth muscle. Calcium- and voltage-activated K+ currents were recorded from Xenopus laevis oocytes injected with hslo cRNA and compared with currents after reconstitution of oocyte membranes expressing cloned maxi KCa channels. The expressed channels displayed characteristics of native maxi KCa channels, including large conductance (280 pS in symmetrical 110 mM K+), calcium sensitivity, kinetics and pharmacology. Currents were activated by niflumic acid; blocked by tetraethylammonium, charybdotoxin and iberiotoxin; and were insensitive to lemakalim, pinacidil, apamin and 4-aminopyridine. Coexpression with the beta-subunit, cloned from bovine trachea smooth muscle, dramatically increased the apparent calcium sensitivity as evident from a leftward shift of the voltage-activation curves. Half maximal activation (V1/2), measured in 10 microM Ca2+, was 12 +/- 18 mV (+/- SD, n = 62) for the alpha-subunit alone and -87 +/- 10 mV (+/- SD, n = 39) in presence of the beta-subunit.

Animals↗
PubMed1997

Hyperpolarized cardioplegic arrest with nicorandil: advantages over other potassium channel openers.

BACKGROUND: Our laboratory has demonstrated that the potassium channel openers (PCOs) aprikalim and pinacidil are effective cardioplegic agents but exhibit toxicity at high doses. In this study, the effectiveness of another PCO, nicorandil, was investigated for several reasons. The chemical structure of nicorandil is distinct from other PCOs, in part because of a nitrate moiety, which may confer additional cardioprotection. Moreover, nicorandil has been approved for human use and has not been shown to exhibit significant toxicity in clinical trials. METHODS AND RESULTS: Using a blood-perfused, parabiotic, isolated rabbit heart model, 45 hearts underwent 30 minutes of global normothermic ischemia after infusion of 50 mL of cardioplegia, followed by 30 minutes of reperfusion. Cardioplegia consisted of Krebs-Henseleit solution either alone (control) or with nicorandil (100 micromol/L, 300 micromol/L, or 1 mmol/L), 20 mmol/L KCl, or nicorandil (100 micromol/L) plus glibenclamide (10 micromol/L), a potassium channel blocker. Over a wide range of volumes, left ventricular systolic function and diastolic compliance were measured at baseline and after reperfusion. The percentage of recovery of developed pressure (mean+/-SEM) for control, glibenclamide plus nicorandil, 100 micromol/L nicorandil, 1 mmol/L nicorandil, and 20 mmol/L KCl was 44.1+/-3.4%, 44.9+/-2.9%, 61.1+/-4.7%, 58.4+/-3.0%, and 63.2+/-1.5%, respectively. Postreperfusion end-diastolic pressures were significantly increased in control, 300 micromol/L nicorandil, and nicorandil plus glibenclamide groups. CONCLUSIONS: Nicorandil (100 micromol/L and 1 mmol/L) significantly improved functional recovery compared with control and was as effective as KCl cardioplegia. The protective effect of nicorandil was eliminated by glibenclamide, indicating that nicorandil is cardioprotective primarily through its capability as a PCO. In contrast to other PCOs, nicorandil produced mechanical arrest as quickly as KCl and did not show toxicity.

Animals↗
PubMed1997

Pharmacological characterization of novel cyanoguanidines as vascular KATP channel blockers.

KATP blockers derived from cyanoguanidine KATP opener (P1075) chemistry were characterized in isolated rabbit mesenteric artery and evaluated functionally by their ability to antagonize maximal relaxation induced by pinacidil (1 microM) of norepinephrine (5 microM) contraction. PNU-89692, PNU-97025E and PNU-99963 were identified as KATP blockers with IC50 values of 860, 83 and 18 nM, respectively. Studies with selected chiral compounds demonstrated that the (R)-enantiomers were more potent as KATP blockers than the (S)-enantiomers. Further studies demonstrated that PNU-99963 (1) inhibited relaxations by other KATP openers, such as cromakalim (0.5 microM) and minoxidil sulfate (5 microM); (2) was more potent than the other known vascular KATP blockers (glyburide and PNU-37883A); and (3) acted as a KATP blocker in isolated rat aorta as well as dog coronary artery. PNU-99963 actions were selective because PNU-99963 (100 nM) was without any inhibitory effect on relaxations induced by forskolin (0.5 microM), nitroglycerin (1 microM), D600 (25 or 500 nM) or 15 mM K+-induced relaxations of NE contractions in K+-free PSS. The discovery of KATP blockers and openers from the same chemical series is a first for the K+ channel field. The close structural similarity between P1075 (KATP opener) and PNU-99963 (KATP blocker), stereospecificity of action and potency and selectivity all suggest that these molecules may prove to be valuable tools in understanding the structure and function of the KATP channel complex in vascular smooth muscle.

Adenosine Triphosphate↗
PubMed1998

Sulfonylureas inhibit cytokine-induced eosinophil survival and activation.

Eosinophils play a key role in the pathogenesis of asthma and other allergic inflammatory diseases. We have previously shown that treatment of eosinophils with lidocaine preferentially inhibits IL-5-induced survival. This inhibition cannot be overcome by increasing concentrations of IL-5 and is not due to the blocking of Na+ channels by lidocaine. Here we report that one class of K+ channel blockers, the sulfonylureas, inhibits eosinophil survival in a manner similar to lidocaine. The sulfonylurea glyburide inhibits eosinophil survival even at high concentrations of IL-5. In contrast, increasing concentrations of IL-3 or granulocyte-macrophage CSF overcome glyburide inhibition. Glyburide also blocks cytokine-induced eosinophil superoxide production. Similar results were seen with the sulfonylureas tolbutamide and glipizide. Interestingly, the effects of glyburide are not antagonized by the ATP-sensitive K+ channel openers cromakalim, pinacidil, or diazoxide. Although Scatchard analysis of [3H]glyburide binding to eosinophil membranes indicated that the high affinity sulfonylurea receptor (SUR1) is not present on eosinophils, human eosinophils do express mRNA homologous to the sulfonylurea receptor family, in keeping with the presence of a sulfonylurea receptor. Finally, coculture of eosinophils with combinations of glyburide, lidocaine, and dexamethasone resulted in synergistic inhibition of cytokine-mediated eosinophil survival and superoxide production. These results have intriguing clinical implications for the treatment of eosinophil-associated diseases.

ATP-Binding Cassette Transporters↗
PubMed2002

Activation of adenosine triphosphate-sensitive potassium channels confers protection against rotenone-induced cell death: therapeutic implications for Parkinson's disease.

It is anticipated that further understanding of the protective mechanism induced by ischemic preconditioning will improve prognosis for patients of ischemic injury. It is not known whether preconditioning exerts beneficial actions in neurodegenerative diseases, in which ischemic injury plays a causative role. Here we show that transient activation of ATP-sensitive potassium channels, a trigger in ischemic preconditioning signaling, confers protection in PC12 cells and SH-SY5Y cells against neurotoxic effect of rotenone and MPTP, mitochondrial complex I inhibitors that have been implicated in the pathogenesis of Parkinson's disease. The degree of protection is in proportion to the bouts of exposure to an ATP-sensitive potassium channel opener, a feature reminiscent of ischemic tolerance in vivo. Protection is sensitive to a protein synthesis inhibitor, indicating the involvement of de novo protein synthesis in the protective processes. Pretreatment of PC12 cells with preconditioning stimuli FeSO(4) or xanthine/xanthine oxidase also confers protection against rotenone-induced cell death. Our results demonstrate for the first time the protective role of ATP-sensitive potassium channels in a dopaminergic neuronal cell line against rotenone-induced neurotoxicity and conceptually support the view that ischemic preconditioning-derived therapeutic strategies may have potential and feasibility in therapy for Parkinson's disease.

Adenosine Triphosphate↗