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PubMed1995

Influence of ion channel modulation on in vitro interferon-gamma induced MHC class I and II expression on macrophages.

The in vitro effect of K+ channel blockers quinidine and verapamil, anion channel blocker SITS and K+ channel openers diazoxide, pinacidil, and BRL 38227 on interferon-gamma (IFN-gamma) induced MHC class I and II expression of Lewis rat peritoneal macrophages was investigated by cell ELISA assay. MHC class I expression was significantly enhanced by diazoxide at concentrations of 10(-5)M to 10(-6)M and by pinacidil and BRL 38227 at the concentration of 10(-6)M. MHC class II expression was enhanced by pinacidil and BRL 38227 at concentrations of 10(-5)M to 10(-6)M. The enhancing effect of pinacidil could be blocked by inhibitors of the protein kinases PKA and PKC suggesting that activation of both is required for optimum induction of MHC molecule expression. K+ and anion channel blockers were less active in modulation of MHC molecule expression. Verapamil had no influence, quinidine suppressed MHC class I expression at concentrations of 10(-4)M to 10(-5)M, and SITS suppressed MHC class I expression at the concentration of 10(-3)M. Since MHC class II expression is essential for efficient antigen presentation to T helper cells and MHC class I expression is required for target cell lysis by cytotoxic T cells, ion channel modulating drugs may be potential candidates for immunopharmacological intervention in inflammatory diseases.

Animals↗
PubMedDate not supplied

Ischemic and pharmacological induction of delayed cellular protection in iNOS gene-disrupted mice myocytes.

Inducible nitric oxide synthase (iNOS) has been implicated as a mediator in myocardial protection, but this property of iNOS is still conflicting. Therefore, the present study was designed to assess whether iNOS really contributes to the ischemically and pharmacologically induced delayed cellular protection (DCP) in mice myocytes. The following groups of cultured iNOS gene-knockout (iNOS-/-), and its respective wild-type (wt) mice myocytes subjected to simulated ischemia (SI) at 20 h were studied: (a) wt + SI: with ischemia alone; (b) iNOS-/- + SI: with ischemia alone; (c) iNOS-/- + heat shock (HS): iNOS-/- and HS; (d) iNOS-/- + sub-lethal simulated ischemia (SSI): iNOS-/- and SSI; (e) iNOS-/- + A1AR agonist 2-chloro-N6-cyclopentyladenosine (CCPA): iNOS-/- and 1 microM CCPA; (f) iNOS-/- + A1AR agonist (2S)-N6-[2-endo-norbomyl]adenosine (S-ENBA): iNOS-/- and 1 nM S-ENBA; (g) iNOS-/- + K(ATP) channel opener pinacidil (Pin): iNOS-/- and 0.05 microM Pin, and (h) iNOS-/- + mitochondrial K(ATP) channel opener diazoxide (Diazo): iNOS-/- and 100 microM Diazo. The release of LDH into the medium as well as the amount of LDH remaining in the cells was used as a marker of cellular injury and cell viability. The cellular resistance was acquired by iNOS-/- mice myocytes due to HS, SSI, CCPA, S-ENBA, pinacidil and diazoxide treatment, which was evidenced by reduction of LDH (U/L) release from 51.14 +/- 1.35 (iNOS-/-) to 42.20 +/- 1.01 (iNOS-/- + HS); 45.57 +/- 0.75 (iNOS-/- + SSI); 42.87 +/- 0.87 (iNOS-/- + CCPA); 43.21 +/- 0.70 (iNOS-/- + S-ENBA); 37.81 +/- 0.99 (iNOS-/- + Pin) and 36.79 +/- 0.68 (iNOS-/- + Diazo), p < 0.01. Our data suggest that heat shock (HS), sub-lethal simulated ischemia (SSI), A1 adenosine agonists CCPA, S-ENBA and K(ATP) channel openers pinacidil (membrane K(ATP) channel), diazoxide (mitochondrial K(ATP) channel) induce delayed cellular protection in mice myocytes against subsequent sustained simulated ischemia without the involvement of iNOS. Further, our data also suggest that pinacidil and diazoxide are more potent inducers of delayed cellular protection among others in iNOS-/- mice myocytes against sustained simulated ischemia.

Adrenergic Agonists↗
PubMed1993

Synergistic effects of glyburide and U-37883A, two structurally different vascular ATP-sensitive potassium channel antagonists.

Glyburide, a sulfonylurea, and U-37883A, a guanidine (4-Morpholinecarboximidine-N-1-Adamantyl-N' cyclohexylhydrochloride), have been previously characterized as antagonists of the vascular ATP-sensitive K+ channels (KATP). In this report, the in vitro interaction between these two chemically distinct KATP antagonists was investigated using isolated rabbit mesenteric artery. The KATP antagonism was functionally studied as the inhibition of vasodilation produced by various KATP openers as follows: pinacidil (1 microM), minoxidil sulfate (5 microM), cromakalim (0.5 microM) and RP-49356 (1 microM). Glyburide alone produced inhibition in the concentration range of 50 to 500 nM with the glyburide IC50 ranging from 72 to 148 nM. U-37883A alone produced inhibition in the concentration range of 0.5 to 5 microM, with the U-37883A IC50 ranging from 0.78 to 1.4 microM. In the presence of a threshold U-37883A concentration of 0.5 microM, the glyburide inhibition dose-response curve against pinacidil was significantly shifted to the left and the glyburide IC50 was lowered from 72 to 3.9 nM, representing an 18-fold decrease. Similarly, in the presence of a threshold glyburide concentration of 50 nM, the U-37883A inhibition dose-response curve against pinacidil was significantly shifted to the left and the U-37883A IC50 was lowered from 780 to 96 nM, representing an eightfold decrease. Thus, glyburide and U-37883A potentiated each other's effects as KATP blockers. This synergistic interaction between glyburide and U-37883A was observed independently of the pinacidil, cromakalim or minoxidil sulfate used to produce vasodilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Adamantane↗
PubMed1998

Shortening of action potential duration is not prerequisite for cardiac protection by ischemic preconditioning or a KATP channel opener.

Our purpose was to determine whether amelioration of myocardial contractile dysfunction by an ATP-sensitive potassium (KATP) channel opener or ischemic preconditioning is mediated by shortening of action potential duration during the early period of ischemia. Extracellular potassium concentration ([K+]e), monophasic action potential duration (MAPD) and thickening fraction were measured during ischemia and reperfusion of the left anterior descending coronary artery in anesthetized dogs. Control dogs were subjected to a 10-min occlusion (test occlusion) followed by a 120-min reperfusion. The five dogs which made up the pinacidil group, received 0.03 mg/kg as an i.v. bolus and then were infused at a rate of 0.04 mg/kg/h for 20 min prior to the test occlusion. In the preconditioning group, six dogs were subjected to a 5-min occlusion and a 10-min reperfusion prior to the test occlusion and reperfusion. Both pinacidil and preconditioning improved regional contraction during reperfusion after the test occlusion. In the control group, MAPD shortened and [K+]e increased during ischemia. Preconditioning abolished MAPD shortening and blunted the rise of [K+]e during ischemia. Pinacidil did not affect either the shortening of MAPD or [K+]e elevation during ischemia. These results suggest that the shortening of MAPD is not a prerequisite for amelioration of contractile dysfunction by a KATP channel opener or ischemic preconditioning.

Action Potentials↗
PubMed1998

The role of adenosine and ATP-sensitive potassium channels in the protection afforded by ischemic preconditioning against the post-ischemic endothelial dysfunction in guinea-pig hearts.

The role of adenosine and ATP-sensitive potassium channels (KATP) in the mechanism of ischemic preconditioning (IPC)-induced protection against the post-ischemic endothelial dysfunction was studied. Langendorff-perfused guinea-pig hearts were subjected either to 40 min of global ischemia and 40 min reperfusion or were preconditioned prior to the ischemia/reperfusion with three cycles of either 5 min ischemia/5 min reperfusion (IPC) or 5 min infusion/5 min wash-out of adenosine, adenosine A1 receptor agonist, N6-cyclohexyladenosine (CHA) or KATP opener, pinacidil. The magnitude of coronary flow reduction caused by NO-synthase inhibitor, Nomega-nitro-l-arginine methyl ester (l-NAME), served as an index of a basal endothelium-dependent vasodilator tone. Coronary overflows produced by a bolus of acetylcholine (ACh) and sodium nitroprusside (SNP) were used as measures of agonist-induced endothelium-dependent and endothelium-independent vascular function, respectively. The coronary flow, LVDP, ACh response and l-NAME response were reduced by 8, 32, 41 and 54%, respectively, while SNP response was not changed in the hearts subjected to ischemia/reperfusion. ACh response was fully restored, l-NAME response was partially restored, and SNP response was not affected in the hearts subjected to IPC. The post-ischemic recoveries of coronary flow and LVDP were not improved by IPC. The protective effect of IPC on the ACh response was mimicked by adenosine, CHA, and pinacidil. The protective effect of IPC, CHA and pinacidil was abolished by KATP antagonist, glibenclamide. The IPC protection was affected neither by a non-specific adenosine antagonist, 8-p-sulfophenyltheophylline, nor by a specific adenosine A1 receptor antagonist, 8-cyclopentyl-1, 3-dipropylxanthine (DPCPX). Our data indicate that: (1) IPC affords endothelial protection in the mechanism that involves activation of KATP, but not adenosine A1 receptors; (2) exogenous adenosine and A1 receptor agonist afford the protection, which might be of a potential clinical significance; (3) the endothelial dysfunction is not involved in the mechanism of myocardial stunning in guinea-pig hearts.

Acetylcholine↗
PubMed1990

Effects of potassium channel openers on single potassium channels in mouse skeletal muscle.

The patch-clamp technique was used to study the effects of the potassium channel openers cromakalim, pinacidil, RP 49356 and diazoxide on single potassium channels in mouse skeletal muscle. In excised patches in the inside-out configuration, one type of potassium channel, the ATP-sensitive potassium channel, could be activated by internally applied RP 49356 even in the absence of internal ATP. At a concentration of 0.4 and 0.8 mmol/l, RP 49356 increased the open-probability of the channels by a factor of 2.7 and 17.4 respectively. The stimulating effect of cromakalim (0.2-0.8 mmol/l) and pinacidil (0.4 mmol/l) depended on the presence of ATP (0.1 mmol/l) at the cytoplasmic side of the patch membrane. The two drugs were able to restore the open-probability of the channels blocked by internal ATP (0.1 mmol/l) to 50-90% of its value in ATP-free solution. No channel reactivation could be observed at a higher ATP concentration (1 mmol/l). Diazoxide (0.4 mmol/l) had almost no effect. None of these channel openers could stimulate the other prominent type of potassium channel in skeletal muscle, the large-conductance Ca2(+)-activated potassium channel. The results show that cromakalim, pinacidil and RP 49356 are specific openers of ATP-sensitive potassium channels in skeletal muscle. It is suggested that the drugs displace the channel blocker ATP and that RP 49356 in addition recruits inactive channels.

Adenosine Triphosphate↗
PubMed1993

Single-channel properties and regulation of pinacidil/glibenclamide-sensitive K+ channels in follicular cells from Xenopus oocyte.

Follicular oocytes from Xenopus laevis contain K+ channels that are activated by members of the recently recognized class of vasorelaxants that includes the pinacidil derivative P1060. These channels are blocked by antidiabetic sulphonylureas such as glibenclamide. Opening of the glibenclamide-sensitive K+ channels with P1060 promotes follicular oocyte maturation. Whole-cell and single-channel patch-clamp configurations were used to monitor K+ channel activity in isolated follicular cells. In the presence of micromolar concentrations of intracellular Mg2+ATP, P1060 activated a whole-cell K+ current that was blocked by glibenclamide. The P1060 response was depressed by millimolar concentrations of intracellular ATP and ATP[gamma S]. Single-channel recordings identified two different types of K+ channel. These channels differed in their unitary conductances (19 pS and 150 pS), in their sensitivities to internal Ca2+, to charybdotoxin and to pinacidil and glibenclamide. Only the Ca(2+)-independent K+ channel (19 pS) was activated by the pinacidil derivative and blocked by glibenclamide. Opening of the 19-pS glibenclamide-sensitive K+ channel by P1060 critically required the presence of a low concentration of Mg2+ATP in the intracellular medium. The 19-pS K+ channel was opened by increasing intracellular cAMP. Similar effects were obtained by intracellular application of the catalytic subunit of protein kinase A in the presence of micromolar concentrations of Mg2+ATP. Both acetylcholine and the phorbol ester phorbol 12-myristate 13-acetate blocked the 19-pS K+ channel after it was activated by P1060.

Acetylcholine↗
PubMed2002

Effects of K(ATP) channel modulators on acetylcholine release from guinea-pig isolated atria and small intestine.

The effects of K(ATP) channel blockers (glibenclamide, HMR 1883, HMR 1372) and openers (cromakalim, pinacidil, diazoxide) on the electrically-evoked (5 Hz) release of [(3)H]acetylcholine were studied in isolated guinea-pig atria and myenteric plexus-longitudinal muscle preparations which had been preincubated with [(3)H]choline. Atria: Cromakalim (0.3 microM and 1 microM), pinacidil (10 microM) and diazoxide (30 microM) significantly reduced the stimulation-evoked release of [(3)H]acetylcholine. The inhibition produced by cromakalim and pinacidil was prevented by 1 microM of either HMR 1883, HMR 1372 or glibenclamide. The blockers alone significantly increased the release at concentrations of 30 microM, whereas 1 microM and 10 microM had no effect. Myenteric plexus-longitudinal muscle preparation: The electrically-evoked release of [(3)H]acetylcholine was not affected by K(ATP) channel blockers or openers. In contrast, the contractions of the longitudinal muscle caused by electrical stimulation or by carbachol were strongly inhibited by 1 microM cromakalim which suggests that the relaxant effect of the K(ATP) channel openers is exclusively a direct effect on intestinal smooth muscle. The findings suggest that blockade of activated K(ATP) channels in vagal nerves of guinea-pig atria stimulates acetylcholine release, and that this effect may contribute to the antiarrhythmic actions of K(ATP) channel blockers. By contrast, release of acetylcholine from guinea-pig myenteric plexus is not modulated by K(ATP) channels which suggests heterogeneity of K(ATP) channel distribution in peripheral autonomic nerves.

Acetylcholine↗
PubMed2001

Modulation of K+-evoked [3H]-noradrenaline release from rat and human brain slices by gabapentin: involvement of KATP channels.

To elucidate the mechanism of action of the anticonvulsant gabapentin (GBP), we compared its effects on K+-evoked [3H]-noradrenaline ([3H]-NA) release from rat hippocampal and human neocortical slices with those of the KATP channel opener pinacidil and the Na+ channel blockers phenytoin, carbamazepine and lamotrigine. Rat hippocampal and human neocortical slices were loaded with [3H]-NA and superfused. [3H]-NA release was evoked by increasing the extracellular [K+] from 3 to 15 mM. GBP decreased [3H]-NA release from rat hippocampal with a pIC50 of 5.59 and a maximum inhibition of 44%. Concentration-dependent inhibition was also seen in human neocortical slices (39% inhibition with 100 microM GBP). These inhibitory effects were antagonized by the KATP channel antagonist glibenclamide, yielding a pA2 of 7.50 in the rat. The KATP channel opener pinacidil (10 microM), like GBP, decreased [3H]-NA release from rat hippocampal slices by 27% and this effect was also antagonized by glibenclamide. In human neocortical slices the inhibition by pinacidil (10 microM) was 31%. Although phenytoin (10 microM), carbamazepine (100 microM) and lamotrigine (10 microM) also decreased [3H]-NA release (by 25%, 57% and 22%, respectively), glibenclamide did not antagonize the effects of these classical Na+ channel blockers. These findings suggest that GBP inhibits K+-evoked [3H]-NA release through activation of KATP channels. To establish whether the KATP channels under investigation were located on noradrenergic nerve terminals or on other neuronal elements, the effects of GBP were compared in the absence and in the presence of tetrodotoxin (TTX 0.32 microM) throughout superfusion. Since the functional elimination of the perikarya of interneurons by TTX reduced the inhibitory effect of GBP, the KATP channels mediating the effect of GBP may be located on nerve terminals, probably on both noradrenergic and glutamatergic nerve endings.

Acetates↗
PubMed1993

Effects of KRN2391, a novel vasodilator, on pancreatic exocrine secretion in anesthetized dogs.

The effects of KRN2391, a newly synthesized vasodilator, on pancreatic exocrine secretion in anesthetized dogs were compared with those of Ki3315, pinacidil and nitroprusside. Graded doses of KRN2391 (0.03-3 mumol/kg) and nitroprusside (0.003-0.3 mumol/kg) injected i.a. produced dose-dependent increases in the secretion of pancreatic juice, with a high concentration of protein and low concentration of bicarbonate, but Ki3315 or pinacidil did not (up to 10 mumol/kg). KRN2391 and nitroprusside increased the cyclic GMP levels in pancreatic tissue together with the increase in pancreatic secretion. Methylene blue decreased pancreatic secretion and cyclic GMP levels stimulated by KRN2391 and nitroprusside, but glibenclamide did not. KRN2391, Ki3315, pinacidil and nitroprusside caused vasodilator actions. These results suggest that KRN2391 has direct secretory properties on pancreatic exocrine glands of the dog and its nitro moiety has an important role in the stimulation of pancreatic secretion, but the K+ channel opening action or increasing of blood flow rate does not participate in the secretion.

Animals↗
PubMed1994

Regulation of ileal electrolyte transport by K+ channel activators.

Pinacidil (N"-cyano-N-4-pyridyl-N'-1,2,2-trimethylpropylguanidine monohydrate) and BRL 38227, a benzopyran derivative, two K+ channel activators, were found to decrease short-circuit current (ISC), a measure for ion movement across the intestinal tissue. This decrease in ISC was correlated with an increase in NaCl absorption. These results suggest the possibility of new forms of drug therapy for diarrheal diseases. The effects of pinacidil were compared to galanin which also increased NaCl absorption. Galanin increased potassium currents in whole-cell patch clamp studies. The effects of galanin and pinacidil on Isc were not additive suggesting a common pathway in their mechanism of action.

Animals↗
PubMed2005

Effect of the ATP-sensitive potassium channel opener ZM226600 on cystometric parameters in rats with ligature-intact, partial urethral obstruction.

The activity of a recent K(ATP) channel opener, the N-(4-Phenylsulfonylphenyl)-3,3,3-trifluoro-2-hydroxy-2-methylpropionamide (ZM226600) was investigated on a female rat model of overactive bladder with outlet obstruction. Both ZM226600 and pinacidil instilled into the bladder (10(-7) M, 30 min) or following systemic administration (10, 100 nmol/kg e.v.) almost completely abolished bladder overactivity and improved residual volume and frequency of micturition. However, pinacidil affected arterial pressure. Oxybutynin instilled into the bladder (10(-7), 10(-6), 10(-5) M, 30 min) decreased detrusor overactivity by about 16%, 25% and 46% respectively, but also blocked micturition reflexes at highest doses tested. Oxybutynin reduced detrusor overactivity by about 50% and 80%, after systemic administration (10, 100 nmol/kg e.v.), but also blocked micturition reflexes at the highest dose tested. In conclusion, ZM226600 is more active than oxybutynin in reducing bladder overactivity, and it is devoid of vascular side effects observed with pinacidil. Its short duration of action (about 1 h) is probably the main problem to solve, in order to consider this compound a valid alternative to antimuscarinics in the therapy of bladder overactivity.

Adenosine Triphosphate↗
PubMed2005

Doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.

To determine if doxapram stimulates the carotid body through the same mechanism as hypoxia, we compared the effects of doxapram and hypoxia on isolated-perfused carotid bodies in rabbits. Doxapram stimulated the carotid body in a dose-dependent manner. In Ca(2+)-free solution, neither doxapram nor hypoxia stimulated the carotid body. Although, doxapram had an additive effect on the carotid body chemosensory response to hypercapnia, a synergistic effect was not observed. Also, we investigated the various K(+) channel activators on the response to doxapram and hypoxia: pinacidil and levcromakalim as ATP-sensitive K(+) channel activators; NS-1619 as a Ca(2+)-sensitive K(+) channel activator; and halothane as a TASK-like background K(+) channel activator. The hypoxic response was partially reduced by halothane only, while pinacidil, levcromakalim and NS-1619 had no effect. Interestingly, the effect of doxapram was partially inhibited by NS-1619. Neither pinacidil nor levcromakalim affected the stimulatory effect of doxapram. We conclude that doxapram stimulates the carotid body via a different mechanism than hypoxic chemotransduction.

Anesthetics, Inhalation↗
PubMed1999

Modulation of norepinephrine release by ATP-dependent K(+)-channel activators and inhibitors in guinea-pig and human isolated right atrium.

OBJECTIVE: The aim of this study was to show, whether ATP sensitive K+ channels (KATP channels), are involved in the modulation of norepinephrine (NE) release from the sympathetic nerves innervating the guinea-pig and human right atrium. METHODS: The resting and stimulation-evoked release of [3H]norepinephrine ([3H]NE) was measured from the isolated guinea-pig and human right atrium and the effect of activators and inhibitors of ATP sensitive K+ channels was studied. RESULTS: Cromakalim (30-300 microM), a KATP channel-agonist decreased concentration-dependently the stimulation-evoked release of NE from the guinea-pig atrium, an effect, antagonized by glibenclamide, a KATP channel-antagonist (30 microM). Diazoxide (30-300 microM), another activator of the KATP channels reduced the resting release of NE, and also attenuated the evoked release at a single concentration (100 microM), and this latter action was also counteracted by glibenclamide (30 microM). Pinacidil, increased dose-dependently the resting and stimulation-evoked release of NE in a glibenclamide-sensitive manner and reversed the inhibitory effect of cromakalim (100 microM), suggesting that it acts as an antagonist. Glibenclamide (30-300 microM), by itself enhanced the stimulation-evoked release of [3H]NE, and also increased the resting release of NE. On the other hand, 5-hydroxydecanoate, an ischemia-selective inhibitor of cardiac KATP channels did not change NE release. Adenosine, (30-300 microM), an A1-receptor agonist, clonidine (3 microM), an alpha 2-adrenoceptor agonist and oxotremorine, a muscarinic receptor agonist (30 microM) all reduced the evoked release of [3H]NE, but these effects were not modified by glibenclamide (300 microM), indicating that neuronal adenosine (A1), adrenergic (alpha 2) and muscarinic (M3) receptors do not act on KATP channels. In the human right atrium, cromakalim, and diazoxide did not affect significantly the release of [3H]NE. However, glibenclamide (30-300 microM) and pinacidil (30-300 microM) enhanced dose-dependently the evoked-release of NE, and pinacidil also augmented the resting release. CONCLUSIONS: Our results indicate that sympathetic nerve endings of the human and guinea-pig atrium are endowed with ATP-sensitive K+ channels. These channels responded to agonists and antagonists under the experimental conditions applied and they could modulate the release of NE thereby affecting the autonomic control of cardiac function under various physiological and pathophysiological conditions.

Adenosine↗
PubMed2001

Dimethylsulfoxide and ethanol, commonly used diluents, prevent dilation of pial arterioles by openers of K(ATP) ion channels.

Ethanol and dimethylsulfoxide are commonly used as diluents for water-insoluble drugs. Both are antioxidants. An earlier study of cats presented pharmacological evidence indicating that oxidants could open the K(ATP) ion channel in cerebral surface arterioles [pial arterioles] and that antioxidants including dimethylsulfoxide and L-cysteine prevented opening of these channels. Ethanol was not tested. The present study extends the older observations to a second species, the rat, and examines ethanol as well as dimethylsulfoxide and L-cysteine. A microscope and image splitter were used to measure arteriolar diameters under a closed cranial window in pentobarbital-anesthetized, paralyzed rats. Drugs were topically applied. Dose-dependent dilations produced by two well-established openers of the K(ATP) ion channel were inhibited in dose-dependent manner by ethanol at doses from 0.01% to 0.075%. Above this dose, the effect disappeared. Dilation by sodium nitroprusside was not affected. Dimethylsulfoxide and L-cysteine inhibited dilation produced by pinacidil. Dimethylsulfoxide inhibited pinacidil in a dose-dependent manner at doses from 0.01% to 0.2%. L-Cysteine inhibited pinacidil. Since all the inhibitory drugs have antioxidant properties, their effect may be a reflection of that property as suggested in an earlier paper. Ethanol and dimethylsulfoxide inhibited in doses frequently present when these agents are used as solvents. When investigators use these solvents to dissolve water-insoluble, topically applied drugs, we suggest that they first test the possibility that their observations are being made under conditions in which opening of the K(ATP) ion channel is inhibited.

Animals↗
PubMed1999

Comparison of the vascular relaxant effects of ATP-dependent K+ channel openers on aorta and pulmonary artery isolated from spontaneously hypertensive and Wistar-Kyoto rats.

The vasorelaxant actions of adenosine 5'-triphosphate (ATP)-dependent K+ channel openers and sodium nitroprusside in isolated thoracic aorta and pulmonary artery of spontaneously hypertensive rats (SHR) and normotensive Wistar-Kyoto (WKY) rats (14-18 weeks old) were investigated. Cumulative addition of sodium nitroprusside and different ATP-dependent K+ channel openers (pinacidil, cromakalim, nicorandil, 2-(2"(1",3"-dioxolone)-2-methyl-4-(2'-oxo-1'-pyrrolidinyl)-6-nitro -2H-1-benzopyren (KR-30450) and aprikalim) to these preparations caused a concentration-dependent relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. The relative order of relaxation potency, estimated by comparing the IC50, was sodium nitroprusside > KR-30450 > aprikalim > or = cromakalim > pinacidil > nicorandil in pulmonary artery and aorta from both strains. At high concentrations (> or =1 microM), cromakalim, aprikalim and KR-30450 produced a greater percentage relaxation in SHR aorta than in WKY aorta. However, there was no apparent difference between SHR and WKY in the relaxation response to all drugs tested on the pulmonary artery. The effects of cromakalim, aprikalim, pinacidil and KR-30450 observed in aorta and pulmonary artery were significantly attenuated by 3 microM glibenclamide. 6-Anilino-5,8-quinolinequinone (LY 83583, 1 microM), a soluble guanylate cyclase inhibitor, abolished the vasorelaxant effects of nicorandil and sodium nitroprusside. In conclusion, sodium nitroprusside and ATP-dependent K+ channel openers cause relaxation of noradrenaline-pre-contracted aorta and pulmonary artery from both strains. However, all the drugs tested failed to cause selective relaxation of the pulmonary artery relative to the thoracic aorta.

Adenosine Triphosphate↗
PubMed1997

Channel activators regulate ATP-sensitive potassium channel (KIR6.1) expression in chick cardiomyocytes.

ATP-sensitive potassium channels (K(ATP)) are widely expressed and yet little is known about the mechanisms regulating their expression. Here we report that expression of chick heart Kir6.1 is regulated by channel activators. Activation of K(ATP) with either ATP depletion or pinacidil, up-regulated Kir6.1 mRNA 1.8- to 2.4-fold in cultured ventricular myocytes as measured by competitive PCR. Pinacidil treatment also increased Kir6.1 protein as detected using an antibody to Kir6.1. Glibenclamide, a K(ATP) inhibitor, completely blocked the pinacidil-induced increase in Kir6.1 levels. It appears that Kir6.1 is up-regulated by an unknown signal transduction pathway initiated by K(ATP) opening.

Adenosine Triphosphate↗
PubMed2001

Altered effects of potassium channel modulation in the coronary circulation in experimental hypercholesterolemia.

OBJECTIVE: To evaluate the role of potassium channels in the regulation of coronary hemodynamics in experimental hypercholesterolemia. BACKGROUND: Potassium (K(+)) channels play an important role in coronary vasoregulation. It has previously been demonstrated that experimental hypercholesterolemia is associated with altered coronary vasomotion; however, the role of K(+) channels in modulating coronary blood flow in this pathophysiologic state has not been evaluated. METHODS AND RESULTS: Pinacidil (group 1, n=5) at 2 microg/kg per min, glibenclamide (group 2, n=5), or N-monomethyl-L-arginine (LNMMA) (group 3, n=4) at 50 microg/kg per min were infused into the left anterior descending artery of pigs prior to and following 10 weeks of 2% cholesterol diet. After 10 weeks of cholesterol feeding, intracoronary pinacidil resulted in a significant increase in coronary blood flow (CBF) and coronary artery diameter (CAD) compared to the normolipidemic state (111+/-10 versus 59+/-12%, and 6+/-1.1 versus 2.7+/-1.0%, respectively, P<0.05 for both comparisons), whereas intracoronary glibenclamide resulted in a significant decrease in CBF and CAD compared to the normolipidemic state (-17+/-5 versus 5+/-6%, and -0.8+/-1.4 versus 3.6+/-1.6%, respectively, P<0.05 for both comparisons). The effect of intracoronary LNMMA on CBF and CAD was significantly attenuated after 10 weeks of cholesterol feeding as compared to the normolipidemic state (-47+/-5.4 versus -0.8+/-6.8%, and -19.4+/-5.7 versus -2.3+/-3.3%, respectively, P<0.05 for both comparisons). Furthermore, pretreatment with intracoronary LNMMA did not alter the CBF response to pinacidil in normal pigs (group 4, n=4) (57.4+/-19 versus 59+/-12%, P=NS). CONCLUSIONS: The current study demonstrates an enhanced effect of coronary K(+) channel modulation and confirms the attenuated basal NO activity previously reported in experimental hypercholesterolemia. Acute withdrawal of basal NO activity alone, however, does not explain the enhanced effect of coronary K(+) channel modulation. These findings underscore the importance of the K(+) channel pathway in the regulation of coronary vasomotor tone in pathophysiologic states.

Adenosine Triphosphatases↗