Delta-opioid receptor agonist SNC80 induces peripheral antinociception via activation of ATP-sensitive K+ channels

We investigated the effect of several K+ channel blockers on the antinociception induced by delta-opioid receptor agonist SNC80 using the paw pressure test, in which pain sensitivity is increased by an intraplantar injection (2 microg) of prostaglandin E2 (PGE2). Administration of SNC80 (20, 40 and 80 microg/paw) caused a decrease in the hyperalgesia induced by PGE2, in a dose-dependent manner. The possibility of higher dose of SNC80 (80 microg) causing a central or systemic effect was excluded since administration of the drug into the contralateral paw did not elicit antinociception in the right paw. Specific blockers of ATP-sensitive K+ channels, glibenclamide (20, 40 and 80 microg/paw) and tolbutamide (40, 80 and 160 microg/paw), antagonized the peripheral antinociception induced by SNC80 (80 microg). On the other hand, charybdotoxin (2 microg/paw), a large-conductance blocker of Ca(2+)-activated K+ channels, and dequalinium (50 microg/paw), a small conductance selective blocker of Ca(2+)-activated K+ channels, did not modify the effect of SNC80. This effect also remained unaffected by intraplantar administration of the voltage-dependent K+ channel blockers tetraethylammonium (30 microg/paw) and 4-aminopyridine (10 microg/paw), and of a non-specific K+ channel blocker, cesium (500 microg/paw). This study provides evidence that the peripheral antinociceptive effect of SNC80 result from the activation of ATP-sensitive K+ channels, and the other K+ channels are not involved.     

Role of ATP-sensitive K+ channels in antinociception induced by R-PIA,an adenosine A1 receptor agonist

The influence of several K⁺ channel-acting drugs on antinociception induced by the adenosine A₁ receptor agonist (–)-N⁶-(2-phenylisopropyl)-adenosine (R-PIA) was evaluated with a tail flick test in mice. The subcutaneous administration of R-PIA (0.5–8 mg/kg) induced a dose-dependent antinociceptive effect. The ATP-sensitive K⁺ (K_ATP) channel blocker gliquidone (2–8 g/mouse, i.c.v.) produced a dose-dependent displacement to the right of the R-PIA dose-response line, whereas the K_ATP channel opener cromakalim (32 g/mouse, i.c.v.) shifted it to the left. Several K_ATP channel blockers dose-dependently antagonized the antinociceptive effect of R-PIA, the order of potency being gliquidone > glipizide > glibenclamide (i.e., the same order of potency shown by these drugs in blocking K_ATP channels in neurons). In contrast, the K⁺ channel blockers 4-aminopyridine and tetraethylammonium did not antagonize the effect of R-PIA. These data suggest that antinociception produced by adenosine A₁ receptor agonists is mediated by the opening of ATP-sensitive K⁺ channels. The present results, together with those of previous studies, further support a role for K⁺ channel opening in the antinociceptive effect of agonists of receptors coupled to G_i/G_o proteins. Correspondence to: José M. Baeyens at the above address     

Involvement of ATP-sensitive K(+) channels in the peripheral antinociceptive effect induced by dipyrone

We evaluated the effect of several K(+) channel blockers on the peripheral antinociception induced by dipyrone using the rat paw pressure test, in which sensitivity is increased by intraplantar injection (2 micro g) of prostaglandin E(2). Dipyrone administered locally into the right hindpaw (50, 100 and 200 micro g) elicited a dose-dependent antinociceptive effect which was demonstrated to be local, since only higher doses produced an effect when injected in the contralateral paw. The specific blockers of ATP-sensitive K(+) channels glibenclamide (40, 80 and 160 micro g/paw) and tolbutamide (80, 160 and 320 micro g/paw) antagonized the peripheral antinociception induced by dipyrone (200 micro g/paw). Charybdotoxin (2 micro g/ paw), a blocker of large conductance Ca(2+)-activated K(+) channels, and dequalinium (50 micro g/paw), a selective blocker of small conductance Ca(2+)-activated K(+) channels, did not modify the effect of dipyrone. This effect was also unaffected neither by intraplantar administration of non-specific voltage-dependent K(+) channel blockers tetraethylammonium (1700 micro g) and 4-aminopyridine (100 micro g) nor cesium (500 micro g), a non-specific K(+) channel blocker. These results suggest that the peripheral antinociceptive effect of dipyrone may result from activation of ATP-sensitive K(+) channels, while other K(+) channels appear not to be involved in the process.     

Study of the involvement of K+ channels in the peripheral antinociception of the kappa-opioid receptor agonist bremazocine

The involvement of the nitric oxide (NO)/cyclic GMP pathway in the molecular mechanisms of antinociceptive drugs like morphine has been previously shown by our group. Additionally, it is known that the desensitisation of nociceptors by K(+) channel opening should be the final target for several analgesic drugs including nitric oxide donors and exogenous micro-opioid receptor agonists. In our previous study, we demonstrated that bremazocine, a kappa-opioid receptor agonist, induces peripheral antinociception by activating nitric oxide/cyclic GMP pathway. In the current study, we assessed whether bremazocine is capable to activate K(+) channels eliciting antinociception. Bremazocine (20, 40 and 50 microg) dose-dependently reversed the hyperalgesia induced in the rat paw by local injection of carrageenan (250 microg) or prostaglandin E(2) (2 microg), measured by the paw pressure test. Using the selective kappa-opioid receptor antagonist nor-binaltorphimine (Nor-BNI, 200 microg/paw), it was confirmed that bremazocine (50 microg/paw) acts specifically on the kappa-opioid receptors present at peripheral sites. Prior treatment with the ATP-sensitive K(+) channel blockers glibenclamide (40, 80 and 160 microg) and tolbutamide (40, 80 and 160 microg) did not antagonise the antinociceptive effect of bremazocine (50 microg). The same results were obtained when we used prostaglandin E(2) (2 microg) as the hyperalgesic stimulus. The supposed participation of other types of K(+) channels was tested using the Ca(2+)-activated K(+) channel blockers dequalinium (12.5, 25 and 50 microg) and charybdotoxin (0.5, 1 and 2 microg) and different types of the non-selective K(+) channel blockers tetraethylammonium (25, 50 and 100 microg) and 4-aminopyridine (10, 25 and 50 microg). None of the K(+) channel blockers reversed the antinociceptive effect of bremazocine. On the basis of these results, we suggest that K(+) channels are not involved in the peripheral antinociceptive effect of bremazocine, although this opioid receptor agonist induces nitric oxide/cGMP pathway activation.     

Role of 4-aminopyridine-sensitive potassium channels in peripheral antinociception

Previous studies has report the modulation of K+ channels play key roles in the induction of peripheral antinociception induced by many types of drugs. However, the possible participation of 4-aminopyridine-sensitive K+ channels to local antinociception induced by tramadol, a mu opioid receptor agonist, and lidocaine, a local anaesthetic, has been less studied. In this study, we therefore investigated this by using thermal plantar test. Tramadol or lidocaine administered intraplantarly into the hind paw elicited an antinociceptive effect. 4-aminopyridine caused an increase in the antinociception produced by lidocaine. However, tramadol induced antinociception remained unaffected by intraplantar administration of 4-aminopyridine. These results suggest that 4-aminopyridine-sensitive K+ channels may play an important role in the thermal peripheral antinociception produced by lidocaine, but not tramadol.     

ATP-sensitive K+ channels in the kidney

ATP-sensitive K⁺ channels (K_ATP channels) form a link between the metabolic state of the cell and the permeability of the cell membrane for K⁺ which, in turn, is a major determinant of cell membrane potential. K_ATP channels are found in many different cell types. Their regulation by ATP and other nucleotides and their modulation by other cellular factors such as pH and kinase activity varies widely and is fine-tuned for the function that these channels have to fulfill. In most excitable tissues they are closed and open when cell metabolism is impaired; thereby the cell is clamped in the resting state which saves ATP and helps to preserve the structural integrity of the cell. There are, however, notable exceptions from this rule; in pancreatic -cells, certain neurons and some vascular beds, these channels are open during the normal functioning of the cell.In the renal tubular system, K_ATP channels are found in the proximal tubule, the thick ascending limb of Henle's loop and the cortical collecting duct. Under physiological conditions, these channels have a high open probability and play an important role in the reabsorption of electrolytes and solutes as well as in K⁺ homeostasis. The physiological role of their nucleotide sensitivity is not entirely clear; one consequence is the coupling of channel activity to the activity of the Na-K-ATPase (pump-leak coupling), resulting in coordinated vectorial transport. In ischemia, however, the reduced ATP/ADP ratio would increase the open probability of the K_ATP channels independently from pump activity; this is particularly dangerous in the proximal tubule, where 60 to 70% of the glomerular ultrafiltrate is reabsorbed.The pharmacology of K_ATP channels is well developed including the sulphonylureas as standard blockers and the structurally heterogeneous family of channel openers. Blockers and openers, exemplified by glibenclamide and levcromakalim, show a wide spectrum of affinities towards the different types of K_ATP channels. Recent cloning efforts have solved the mystery about the structure of the channel: the K_ATP channels in the pancreatic -cell and in the principal cell of the renal cortical collecting duct are heteromultimers, composed of an inwardly rectifying K⁺ channel and sulphonylurea binding subunit(s) with unknown stoichiometry. The proteins making up the K_ATP channel in these two cell types are different (though homologous), explaining the physiological and pharmacological differences between these channel subtypes.     

The peripheral antinociceptive effect induced by morphine is associated with ATP-sensitive K(+) channels

The effect of several K(+) channel blockers such as glibenclamide, tolbutamide, charybdotoxin (ChTX), apamin, tetraethylammonium (TEA), 4-aminopyridine (4-AP) and cesium on the peripheral antinociceptive effect of morphine was evaluated by the paw pressure test in Wistar rats. The intraplantar administration of a carrageenan suspension (250 microg) resulted in an acute inflammatory response and a decreased threshold to noxious pressure. Morphine administered locally into the paw (25, 50, 100 and 200 microg) elicited a dose-dependent antinociceptive effect which was demonstrated to be mediated by a peripheral site up to the 100 microg dose. The selective blockers of ATP-sensitive K(+) channels glibenclamide (20, 40 and 80 microg paw(-1)) and tolbutamide (40, 80 and 160 microg paw(-1)) antagonized the peripheral antinociception induced by morphine (100 microg paw(-1)). This effect was unaffected by ChTX (0. 5, 1.0 and 2.0 microg paw(-1)), a large conductance Ca(2+)-activated K(+) channel blocker, or by apamin (2.5, 5.0 and 10.0 microg paw(-1)), a selective blocker of a small conductance Ca(2+)-activated K(+) channel. Intraplantar administration of the non-specific K(+) channel blockers TEA (160, 320 and 640 microg), 4-AP (10, 50 and 100 microg) and cesium (125, 250 and 500 microg) also did not modify the peripheral antinociceptive effect of morphine. These results suggest that the peripheral antinociceptive effect of morphine may result from activation of ATP-sensitive K(+) channels, which may cause a hyperpolarization of peripheral terminals of primary afferents, leading to a decrease in action potential generation. In contrast, large conductance Ca(2+)-activated K(+) channels, small conductance Ca(2+)-activated K(+) channels as well as voltage-dependent K(+) channels appear not to be involved in this transduction pathway. British Journal of Pharmacology (2000) 129, 110 - 114     

Possible participation of nitric oxide/cyclic guanosine monophosphate/protein kinase C/ATP-sensitive K(+) channels pathway in the systemic antinociception of flavokawin B

The possible mechanisms of action in the antinociceptive activity induced by systemic administration (intraperitoneal, i.p.) of flavokawin B (FKB) were analysed using chemical models of nociception in mice. It was demonstrated that i.p. administration of FKB to the mice at 0.3, 1.0, 3.0 and 10 mg/kg produced significant dose-related reduction in the number of abdominal constrictions. The antinociception induced by FKB in the acetic acid test was significantly attenuated by i.p. pre-treatment of mice with L-arginine, the substrate for nitric oxide synthase or glibenclamide, the ATP-sensitive K(+) channel inhibitor, but was enhanced by methylene blue, the non-specific guanylyl cyclase inhibitor. FKB also produced dose-dependent inhibition of licking response caused by intraplantar injection of phorbol 12-myristate 13-acetate, a protein kinase C activator (PKC). Together, these data indicate that the NO/cyclic guanosine monophosphate/PKC/ATP-sensitive K(+) channel pathway possibly participated in the antinociceptive action induced by FKB.     

ATP-sensitive K+ channels of the cardiovascular system

ATP-sensitive K+ (KATP) channels are inhibited by intracellular ATP and activated by intracellular nucleoside diphosphates, and thus provide a link between cellular metabolism and excitability. They are widely distributed in various tissues including heart and vasculature, and thus may play essential regulatory roles in the cardiovascular system. Furthermore, KATP channels are the targets of two important classes of drugs, i.e., the antidiabetic sulfonylureas which block the channels, and a series of vasorelaxants called "K+ channel openers" which tend to maintain the channels in an open conformation. Recently, the molecular structure of KATP channels has been clarified in various tissues including cardiovascular system to be a complex of at least two subunits, i.e. SUR and Kir6.0. The KATP channels in heart and vascular smooth muscle now appear to be the complexes of SUR2A/Kir6.2 and SUR2B/Kir6.1, respectively. Further works are now in progress to understand the molecular mechanisms responsible for the control of KATP channel function by intracellular nucleotides and drugs.     

Inhibition of ATP-sensitive potassium channels by haloperidol

Chronic haloperidol treatment has been associated with an increased incidence of glucose intolerance and type-II diabetes mellitus. We studied the effects of haloperidol on native ATP-sensitive potassium (K(ATP)) channels in mouse pancreatic beta cells and on cloned Kir6.2/SUR1 channels expressed in HEK293 cells. The inhibitory effect of haloperidol on the K(ATP) channel was not mediated via the D2 receptor signaling pathway, as both D2 agonists and antagonists blocked the channel. K(ATP) currents were studied using the patch-clamp technique in whole-cell and outside-out patch configurations. Addition of haloperidol to the extracellular solution inhibited the K(ATP) conductance immediately, in a reversible and voltage-independent manner. Haloperidol did not block the channel when applied intracellularly in whole-cell recordings. Haloperidol blocked cloned Kir6.2/SUR1 and Kir6.2DeltaC36 K(ATP) channels expressed in HEK cells. This suggests that the drug interacts with the Kir6.2 subunit of the channel. The IC(50) for inhibition of the K(ATP) current by haloperidol was 1.6 microM in 2 mM extracellular K(+) concentration ([K(+)](o)) and increased to 23.9 microM in 150 mM [K(+)](o). The Hill coefficient was close to unity, suggesting that the binding of a single molecule of haloperidol is sufficient to close the channel. Haloperidol block of K(ATP) channels may contribute to the side effects of this drug when used therapeutically.     

Dibutyryl-cyclic GMP induces peripheral antinociception via activation of ATP-sensitive K(+) channels in the rat PGE2-induced hyperalgesic paw

1. Using the rat paw pressure test, in which increased sensitivity is induced by intraplantar injection of prostaglandin E2, we studied the action of several K(+) channel blockers in order to determine what types of K(+) channels could be involved in the peripheral antinociception induced by dibutyrylguanosine 3 : 5'-cyclic monophosphate (DbcGMP), a membrane permeable analogue of cyclic GMP. 2. DbcGMP elicited a dose-dependent (50, 75, 100 and 200 microg paw(-1)) peripheral antinociceptive effect. The effect of the 100 microg dose of DbcGMP was considered to be local since only a higher dose (300 microg paw(-1)) produced antinociception in the contralateral paw. 3. The antinociceptive effect of DbcGMP (100 microg paw(-1)) was dose-dependently antagonized by intraplantar administration of the sulphonylureas tolbutamide (20, 40 and 160 microg) and glibenclamide (40, 80 and 160 microg), selective blockers of ATP-sensitive K(+) channels. 4. Charybdotoxin (2 microg paw(-1)), a selective blocker of high conductance Ca(2+)-activated K(+) channels, and apamin (10 microg paw(-1)), a selective blocker of low conductance Ca(2+)-activated K(+) channels, did not modify the peripheral antinociception induced by DbcGMP. 5. Tetraethylammonium (2 mg paw(-1)), 4-aminopyridine (200 microg paw(-1)) and cesium (800 paw(-1)), non-selective voltage-gated potassium channel blockers, also had no effect. 6. Based on this experimental evidence, we conclude that the activation of ATP-sensitive K(+) channels could be the mechanism by which DbcGMP induces peripheral antinociception, and that Ca(2+)-activated K(+) channels and voltage-dependent K(+) channels appear not to be involved in the process.     

Activation of central ATP-sensitive potassium channels produces the antinociception and spinal noradrenaline turnover-enhancing effect in mice

ICV cromakalim, a K⁺ channel opener, produced antinociception. This effect was completely antagonized by ICV glibenclamide, a selective adenosine triphosphate-sensitive K⁺ channel (K_ATP channel) blocker. Furthermore, direct opening of central K_ATP channels by ICV cromakalim increased the spinal noradrenaline (NA) turnover. On the other hand, the antinociception induced by ICV morphine ( opioid agonist), but not ICV U-50,488H ( opioid agonist) was markedly potentiated by cromakalim. These findings suggest that the opening of central K_ATP channels may elicit the antinociceptive effect and activate the descending NAergic pathway, and central K_ATP channels play an important role as a modulator of the antinociception induced by agonists but not agonists.     

Role of potassium channels in the antinociception induced by agonists of alpha2-adrenoceptors

1. The effect of the administration of pertussis toxin (PTX) as well as modulators of different subtypes of K+ channels on the antinociception induced by clonidine and guanabenz was evaluated in the mouse hot plate test. 2. Pretreatment with pertussis toxin (0.25 microg per mouse i.c.v.) 7 days before the hot-plate test, prevented the antinociception induced by both clonidine (0.08-0.2 mg kg(-1), s.c.) and guanabenz (0.1-0.5 mg kg(-1), s.c.). 3. The administration of the K(ATP) channel openers minoxidil (10 microg per mouse, i.c.v.), pinacidil (25 microg per mouse, i.c.v.) and diazoxide (100 mg kg(-1), p.o.) potentiated the antinociception produced by clonidine and guanabenz whereas the K(ATP) channel blocker gliquidone (6 microg per mouse, i.c.v.) prevented the alpha2 adrenoceptor agonist-induced analgesia. 4. Pretreatment with an antisense oligonucleotide (aODN) to mKv1.1, a voltage-gated K+ channel, at the dose of 2.0 nmol per single i.c.v. injection, prevented the antinociception induced by both clonidine and guanabenz in comparison with degenerate oligonucleotide (dODN)-treated mice. 5. The administration of the Ca2+-gated K+ channel blocker apamin (0.5-2.0 ng per mouse, i.c.v.) never modified clonidine and guanabenz analgesia. 6. At the highest effective doses, none of the drugs used modified animals' gross behaviour nor impaired motor coordination, as revealed by the rota-rod test. 7. The present data demonstrate that both K(ATP) and mKv1.1 K+ channels represent an important step in the transduction mechanism underlying central antinociception induced by activation of alpha2 adrenoceptors.     

Dexamethasone improves vascular hyporeactivity induced by LPS in vivo by modulating ATP-sensitive potassium channels activity

(1) Septic shock represents an important risk factor for patients critically ill. This pathology has been largely demonstrated to be a result of a myriad of events. Glucocorticoids represent the main pharmacological therapy used in this pathology. (2) Previously we showed that ATP-sensitive potassium (KATP) channels are involved in delayed vascular hyporeactivity in rats (24 h after Escherichia coli lipopolysaccharide (LPS) injection). In LPS-treated rats, we observed a significant hyporeactivity to phenylephrine (PE) that was reverted by glybenclamide (GLB), and a significant increase in cromakalim (CRK)-induced hypotension. (3) We evaluated the effect of dexamethasone (DEX 8 mg kg-1 i.p.) whether on hyporeactivity to PE or on hyperreactivity to CRK administration, in vivo, in a model of LPS (8 x 106 U kg-1 i.p.)-induced endotoxemia in urethane-anaesthetised rats. (4) DEX treatment significantly reduced, in a time-dependent manner, the increased hypotensive effect induced by CRK in LPS-treated rats. This effect was significantly (P<0.05) reverted by the glucocorticoid receptor antagonist RU38486 (6.6 mg kg-1 i.p.). (5) GLB-induced hypertension (40 mg kg-1 i.p.), in LPS-treated rats, was significantly inhibited by DEX if administered at the same time of LPS. (6) Simultaneous administration of DEX and LPS to rats completely abolished the hyporeactivity to PE observed after 24 h from LPS injection. (7) In conclusion, our results suggest that the beneficial effect of DEX in endotoxemia could be ascribed, at least in part, to its ability to interfere with KATP channel activation induced by LPS. This interaction may explain the improvement of vascular reactivity to PE, mediated by DEX, in LPS-treated rats, highlighting a new pharmacological activity to the well-known anti-inflammatory properties of glucocorticoids.     

Cardiovascular effects of the aqueous extract from Caesalpinia ferrea: involvement of ATP-sensitive potassium channels

Caesalpinia ferrea is a plant very used in the folk medicine for treatment of several diseases, such as diabetes. This study investigated the cardiovascular effects of the aqueous extract from stem bark of C. ferrea (AECF). In non-anesthetized rats, AECF (10, 20, 40, 60 and 80 mg/kg; i.v.) induced hypotension (-9+/-1;-12+/-1;-14+/-1; -20+/-3 and -51+/-6%; respectively) and tachycardia (6+/-1; 8+/-1; 12+/-2; 14+/-2 and 26+/-3%; respectively). Hypotension was not affected after atropine or L-NAME. Furthermore, AECF (40 mg/kg) induced atrioventricular block and extrasystoles, which was not affected after atropine. In intact rings of the rat mesenteric artery, AECF (0.001-30 mg/ml, n=6) induced relaxations of phenylephrine tonus (Emax=110+/-4%), which was not changed after the removal of endothelium (Emax=113+/-9%). In rings without endothelium pre-contracted with KCl 80 mM, phenylephrine plus KCl 20 mM or phenylephrine plus glibenclamide, the curve to AECF was significantly attenuated (Emax=24+/-4%, 70+/-5% and 62+/-7%, respectively, n=6), but was not affected in the presence of tetraethylammonium or 4-aminopyridine (Emax=125+/-15% and 114+/-7%, respectively, n=6). These results demonstrate that AECF induces hypotension associated to tachycardia; however, in dose of 40 mg/kg, AECF induces transient bradyarrhythmias. Furthermore, AECF induces vasodilatation in rat mesenteric artery which appears to be mediated by ATP-sensitive K+ channel openings.     

Antiallodynic effect of etidronate, a bisphosphonate, in rats with adjuvant-induced arthritis: involvement of ATP-sensitive K+ channels

The role of inducible nitric oxide synthase (iNOS) in cerebral edema and neurological deficit following traumatic brain injury (TBI) is not yet clear-cut. Therefore, the aim of this study was to investigate the effect of three different iNOS inhibitors on cerebral edema and functional outcome after TBI. First, the time courses of blood--brain barrier (BBB) breakdown, cerebral edema, and neurological deficit were studied in a rat model of fluid percussion-induced TBI. The permeability of BBB to Evans blue was increased from 1 h to 24 h after TBI. Consistently, a significant increase in brain water content (BWC) was observed at 6 and 24 h post-TBI. A deficit in sensorimotor neurological functions was also observed from 6 h to 7 days with a maximum 24 h after TBI. Second, a single dose of aminoguanidine (AG; 100 mg/kg, i.p.), L-N-iminoethyl-lysine (L-NIL; 20 mg/kg, i.p.), or N-[3-(aminomethyl)benzyl]acetamide (1400W; 20 mg/kg, s.c.) was administered at 6 h post-TBI. Treatment with AG reduced by 71% the increase in BWC evaluated at 24 h, while L-NIL and 1400W had no effect. In contrast, the three iNOS inhibitors reduced the neurological deficit from 30% to 40%. Third, 1400W (20 mg/kg, s.c.) was administered at 5 min, 8 and 16 h post-TBI. Although this treatment paradigm had no effect on cerebral edema evaluated at 24 h, it significantly reduced the neurological deficit and iNOS activity. In conclusion, iNOS contributes to post-TBI neurological deficit but not to cerebral edema. The beneficial effect of iNOS inhibitors is not due to their anti-edematous effect, and the reduction of cerebral edema by AG is unlikely related to iNOS inhibition. The 6 h therapeutic window of iNOS inhibitors could allow their use in the treatment of functional deficit at the acute phase of TBI.     

Activation of ATP-sensitive K+ channels by ADP and K+ channel openers: homology model of sulfonylurea receptor carboxyl-termini

The multispecific organic anion transporters have been indicated to be involved in the transmembrane transport of various anionic substances. The kidney and liver possess the distinct organic anion transport pathways for the elimination of potentially toxic anionic drugs and metabolites. In the kidney, proximal tubular cells actively excrete organic anions of both endogenous and exogenous origin. We have isolated the renal multispecific organic anion transporter, OAT1 (organic anion transporter 1), from the rat kidney. OAT1 is a 551-amino acid residue protein with 12 putative membrane spanning domains. OAT1 mediates sodium-independent, anion exchange for a variety of organic anions including p-aminohippurate, cyclic nucleotides, prostanoides, dicarboxylates, and anionic drugs including beta-lactams, non-steroidal antiinflammatory drugs, diuretics and antiviral drugs. So far, three other isoforms have been identified. OATs comprise a new family of multispecific organic anion transporter, i.e., the OAT family. OATs show weak structural similarity to organic cation transporters (OCTs) and OCTN/carnitine transporters. All of the members of the OAT family are commonly expressed in the kidney, suggesting its significance in the renal organic anion excretion. In addition, OAT members appear to be responsible for the distribution/elimination of water soluble anionic drugs into/from the liver, brain and fetus.     

线粒体ATP敏感性钾通道不参与异丙酚预处理的心肌保护

目的　观察异丙酚预处理对心肌缺血再灌注损伤的保护机制是否通过开放线粒体ATP敏感性K通道 (KATP)。方法　非循环式Langendorff离体心脏灌注模型 ,灌注 1h ,常温下行全心缺血 2 5min ,恢复再灌注 30min。通过Maclab仪记录左室舒张末压 (LVEDP)、左室发展压 (LVDP)、左室压上升和下降最大速率 (±dp/dtmax)。测恢复再灌注末心肌组织MDA含量。结果　恢复再灌注 30min末 ,对照组(Con)、异丙酚预处理组 (PP)、5 HD +PP和 5 HD组心肌组织的MDA含量分别为 (113 7± 2 0 9)、(89 4± 13 7)、(91 9± 14 4 )和 (114 8± 19 7)nmol·10 0mg-1。PP组和 5 HD+PP组的心肌MDA含量都明显低于Con组和 5 HD组 (P<0 0 5 ) ;PP组和 5 HD +PP组两组间的MDA差异无显著性 (P >0 0 5 )。恢复再灌注 30min末 ,Con组、PP组、5 HD+PP组和 5 HD组的LVEDP值分别为基础值的 5 1、3 2、3 6和 5 3倍。PP组和 5 HD +PP组LVEDP值的上升幅度均明显低于Con组和 5 HD组 (P <0 0 5 ) ,而 5 HD +PP组和PP组之间差异无显著性 (P >0 0 5 )。结论　异丙酚预处理的心肌保护不是通过开放线粒体ATP敏感性K通道 ,其心肌保护作用和线粒体KATP无关