K+ Channel Blocker (k+ + channel_blocker)

Distribution by Scientific Domains


Selected Abstracts


Xanthine-analog, KMUP-2, enhances cyclic GMP and K+ channel activities in rabbit aorta and corpus cavernosum with associated penile erection

DRUG DEVELOPMENT RESEARCH, Issue 3 2002
Rong-Jyh Lin
Abstract The pharmacological properties of KMUP-2 were examined in isolated rabbit aorta and corpus cavernosum smooth muscle (CCSM). KMUP-2 caused relaxations that were attenuated by removed endothelium, high K+, and pretreatment with the soluble guanylate cyclase (sGC) inhibitors methylene blue (10 ,M) and ODQ (1 ,M), a NOS inhibitor, L-NAME (100 ,M), a K+ channel blocker TEA (10 mM), a KATP channel blocker glibenclamide (1 ,M), a voltage-dependent K+ channel blocker 4-AP (100 ,M), and the Ca2+ -dependent K+ channel blockers apamin (1 ,M) and charybdotoxin (ChTX, 0.1 ,M). The relaxant responses of KMUP-2 (0.01, 0.05, 0.1 ,M) together with a PDE inhibitor, IBMX (0.5 ,M), had additive effects on rabbit aorta and CCSM. Additionally, KMUP-2 (100 ,M) also affected cGMP metabolism, due to its inhibiting activity on PDE in human platelets. KMUP-2 (0.1,100 ,M) further induced an increase of intracellular cGMP levels in the primary cultured rabbit aortic and CCSM cells. These increases in cGMP content were abolished in the presence of methylene blue (100 ,M) and ODQ (10 ,M). Obviously, the relaxant effects of KMUP-2 on rabbit isolated tissues are more sensitive in CCSM than in aorta. Moreover, KMUP-2 also stimulated NO/sGC/cGMP pathway and subsequent elevation of cGMP by blockade of PDE and enhanced opening of K+ channels in rabbit aorta and CCSM. KMUP-2 (0.2, 0.4, 0.6 mg/kg), similar to KMUP-1 and sildenafil, caused increases of intracavernous pressure (ICP) and duration of tumescene (DT) in a dose-dependent manner. It is concluded that both the increases of cGMP and the opening activity of K+ channels play prominent roles in KMUP-2-induced aortic smooth muscle and CCSM relaxation and increases of ICP in rabbits. Drug Dev. Res. 55:162,172, 2002. 2002 Wiley-Liss, Inc. [source]


Excitatory actions of substance P in the rat lateral posterior nucleus

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 1 2010
Kush Paul
Abstract The lateral posterior nucleus (LP) receives inputs from both neocortex and superior colliculus (SC), and is involved with integration and processing of higher-level visual information. Relay neurons in LP contain tachykinin receptors and are innervated by substance P (SP)-containing SC neurons and by layer V neurons of the visual cortex. In this study, we investigated the actions of SP on LP relay neurons using whole-cell recording techniques. SP produced a graded depolarizing response in LP neurons along the rostro-caudal extent of the lateral subdivision of LP nuclei (LPl), with a significantly larger response in rostral LPl neurons compared with caudal LPl neurons. In rostral LPl, SP (5,2000 nm) depolarized nearly all relay neurons tested (> 98%) in a concentration-dependent manner. Voltage-clamp experiments revealed that SP produced an inward current associated with a decreased conductance. The inward current was mediated primarily by neurokinin receptor (NK)1 tachykinin receptors, although significantly smaller inward currents were produced by specific NK2 and NK3 receptor agonists. The selective NK1 receptor antagonist RP67580 attenuated the SP-mediated response by 71.5% and was significantly larger than the attenuation of the SP response obtained by NK2 and NK3 receptor antagonists, GR159897 and SB222200, respectively. The SP-mediated response showed voltage characteristics consistent with a K+ conductance, and was attenuated by Cs+, a K+ channel blocker. Our data suggest that SP may modulate visual information that is being processed and integrated in the LPl with inputs from collicular sources. [source]


Mechanisms of ATP action on motor nerve terminals at the frog neuromuscular junction

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2005
S. Grishin
Abstract We have shown previously that ATP inhibits transmitter release at the neuromuscular junction through the action on metabotropic P2Y receptors coupled to specific second messenger cascades. In the present study we recorded K+ or Ca2+ currents in motor nerve endings or blocked K+ or Ca2+ channels in order to explore the nature of downstream presynaptic effectors. Endplate currents were presynaptically depressed by ATP. Blockers of Ca2+ -activated K+ -channels, such as iberiotoxin, apamin or tetraethylammonium, did not change the depressant action of ATP. By contrast, K+ channel blocker 4-aminopyridine (4-AP) and raised extracellular Ca2+ attenuated the effect of ATP. However, these effects of 4-AP and high Ca2+ were reversed by Mg2+, suggesting Ca2+ -dependence of the ATP action. Ba2+ promoted the depressant action of ATP as did glibenclamide, a blocker of ATP-sensitive K+ channels, or mild depolarization produced by 7.5 mm K+. None of the K+ channel blockers affected the depressant action of adenosine. Focal recording revealed that neither ATP nor adenosine affected the fast K+ currents of the motor nerve endings. However, unlike adenosine, ATP or UTP, an agonist of P2Y receptors, reversibly reduced the presynaptic Ca2+ -current. This effect was abolished by suramin, an antagonist of P2 receptors. Depressant effect of ATP on the endplate and Ca2+ -currents was mimicked by arachidonate, which precluded the action of ATP. ATP reduced acetylcholine release triggered by ionomycin or sucrose, suggesting inhibition of release machinery. Thus, the presynaptic depressant action of ATP is mediated by inhibition of Ca2+ channels and by mechanism acting downstream of Ca2+ entry. [source]


Morphine, opioids, and the feline pulmonary vascular bed

ACTA ANAESTHESIOLOGICA SCANDINAVICA, Issue 7 2008
A. D. KAYE
Background: Opioid-induced vasodepressor responses have been reported in a variety of species and laboratory models. The aim of this study was to ascertain the relative potencies of different clinically relevant opioids compared with traditional vasodepressor agents in the feline pulmonary vascular bed. A second aim was to study the effects of morphine and to identify the receptors involved in the mediation or the modulation of these effects. Methods: This was a prospective vehicle-controlled study involving an intact chest preparation of adult mongrel cats. The effects of various opioids, morphine, fentanyl, remifentanil, sufentanil, and meperidine were compared with other vasodepressor agents. Additionally, the effects of l - N5 -(1-iminoethyl) ornithine hydrochloride (l -NIO) (nitric oxide synthase inhibitor), nimesulide [selective cyclooxygenase (COX)-2 inhibitor], glibenclamide (ATP-sensitive K+ channel blocker), naloxone (non-selective opioid receptor antagonist), and diphenhydramine (histamine H1 -receptor antagonist) were investigated on pulmonary arterial responses to morphine and other selected agonists in the feline pulmonary vascular bed. The systemic pressure and lobar arterial perfusion pressure were continuously monitored, electronically averaged, and recorded. Results: In the cat pulmonary vascular bed of the isolated left lower lobe, morphine, remifentanil, fentanyl, sufentanil, and meperidine induced a dose-dependent moderate vasodepressor response and it appeared that sufentanil was the most potent on a nanomolar basis. The effects of morphine were not significantly altered after administration of l -NIO, nimesulide, and glibenclamide. However, the vascular responses to morphine were significantly attenuated following administration of naloxone and diphenhydramine. Conclusion: The results of the present study suggest that sufentanil appears to have slightly more potency and morphine the least of the five opioid agonists studied on a nanomolar basis. Morphine-induced vasodilatory responses appeared to be mediated or modulated by both opioid receptor and histamine-receptor-sensitive pathways. [source]


Excitatory purinergic neurotransmission in smooth muscle of guniea-pig taenia caeci

THE JOURNAL OF PHYSIOLOGY, Issue 3 2005
Yong Zhang
Non-adrenergic, non-cholinergic (NANC) inhibitory neurotransmission has been an area of intense interest in gut motor physiology, whereas excitatory NANC neurotransmission has received less attention. In order to further explore excitatory NANC neurotransmission, we performed conventional intracellular recordings from guinea-pig taenia caeci smooth muscle. Tissue was perfused with oxygenated Krebs solution at 35C and nerve responses evoked by either oral or aboral nerve stimulation (NS) (4 square wave pulses, 0.3 ms duration, 20 Hz). Electrical activity was characterized by slow waves upon which one to three action potentials were superimposed. Oral NS evoked an inhibitory junction potential (IJP) at either the valley or peak of the slow wave. Application of nifedipine (1 ,m) abolished slow waves and action potentials, but membrane potential flunctuations (1,3 mV) and IJPs remained unaffected. Concomitant application of apamin (300 nm), a small-conductance Ca2+ -activated K+ channel blocker, converted the IJP to an EJP that was followed by slow IJP. Further administration of NG -nitro- l -arginine methyl ester (l -NAME, 200 ,m), a nitric oxide synthase inhibitor, abolished the slow IJP without affecting the EJP, implying that the slow IJP is due to nitrergic innervation. The EJP was abolished by tetrodotoxin (1 ,m), but was not significantly affected by atropine (3 ,m) and guanethidine (3 ,m) or hexamethonium (500 ,m). Substance P (SP, 1 ,m) desensitization caused slight attenuation of the EJP, but the EJP was abolished by desensitization with ,,,-methylene ATP (50 ,m), a P2 purinoceptor agonist that is more potent than ATP at the P2X receptor subtype, suramin (100 ,m), a non-selective P2 purinoceptor antagonist, and pyridoxal-phosphate-6-azophenyl-2,,4,-disulphonic acid (PPADS, 100 ,m), a selective P2X purinoceptor antagonist. In contrast, the EJP was unaffected by MRS-2179 (2 ,m), a selective P2Y1 receptor antagonist. Aboral NS evoked an apamin- and l -NAME-sensitive IJP, but virtually no NANC EJP. These data suggest the presence of polarized excitatory purinergic neurotransmission in guinea-pig taenia caeci, which appears to be mediated by P2X purinoceptors, most likely the P2X1 subtype. [source]


The Effect of Korean Red Ginseng Extract on the Relaxation Response in Isolated Rabbit Vaginal Tissue and Its Mechanism

THE JOURNAL OF SEXUAL MEDICINE, Issue 9 2008
Sun-Ouck Kim MD
ABSTRACT Introduction., Ginseng is an herbal medicine with a variety of biological activities. Aim., The purpose of this study was to investigate the effect of Korean red ginseng (KRG) extract on the relaxation response in isolated rabbit vaginal tissue and its mechanism as a potential therapeutic agent for female sexual dysfunction. Method., Strips of rabbit vagina were mounted in organ chambers to measure isometric tension. After the strips were precontracted with phenylephrine, the contractile responses to KRG extract (1,20 mg/mL), nitric oxide inhibitor (N[omega]-nitro-L-arginine methyl ester [L-NAME]), an inhibitor of soluble guanylate cyclase (methylene blue), an inhibitor of Ca2+ -activated K+ channels (tetraethylammonium [TEA]), and an adenosine triphosphate (ATP)-sensitive K+ channel blocker (glybenclamide) were examined. Main Outcome Measures., The relaxation of the vaginal tissue strip was assessed after treating KRG extract or other chemicals. Results., KRG (1,20 mg/mL) extract relaxed the vaginal tissue strip in a dose-dependent manner up to 85%. The relaxation effect was significantly inhibited by L-NAME (30 M) and methylene blue (30 M) (P < 0.05). In addition, KRG inhibited the contraction induced by depolarization with 10, 20, and 40 mM KCl. The KRG-induced relaxation effect was significantly inhibited by TEA (300 M) (P < 0.05), and not by glybenclamide (30 M). Conclusions., These data show that KRG extract has a relaxing effect on rabbit vaginal smooth muscle tissue. These effects might be mediated partly through the NO pathway and hyperpolarization via Ca2+ -activated K+ channels. Kim S-O, Kim MK, Lee H-S, Park JK, and Park K. The effect of Korean red ginseng extract on the relaxation response in isolated rabbit vaginal tissue and its mechanism. J Sex Med 2008;5:2079,2084. [source]


Deoxycholic acid inhibits pacemaker currents by activating ATP-dependent K+ channels through prostaglandin E2 in interstitial cells of Cajal from the murine small intestine

BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2005
Jae Yeoul Jun
1We investigated the role of deoxycholic acid in pacemaker currents using whole-cell patch-clamp techniques at 30C in cultured interstitial cells of Cajal (ICC) from murine small intestine. 2The treatment of ICC with deoxycholic acid resulted in a decrease in the frequency and amplitude of pacemaker currents and increases in resting outward currents. Also, under current clamping, deoxycholic acid produced the hyperpolarization of membrane potential and decreased the amplitude of the pacemaker potentials. 3These observed effects of deoxycholic acid on pacemaker currents and pacemaker potentials were completely suppressed by glibenclamide, an ATP-sensitive K+ channel blocker. 4NS-398, a specific cyclooxygenase-2 (COX-2) inhibitor, significantly inhibited the deoxycholic acid-induced effects. The treatment with prostaglandin E2 (PGE2) led to a decrease in the amplitude and frequency of pacemaker currents and to an increase in resting outward currents, and these observed effects of PGE2 were blocked by glibenclamide. 5We next examined the role of deoxycholic acid in the production of PGE2 in ICC, and found that deoxycholic acid increased PGE2 production through the induction of COX-2 enzyme activity and its gene expression. 6The results suggest that deoxycholic acid inhibits the pacemaker currents of ICC by activating ATP-sensitive K+ channels through the production of PGE2. British Journal of Pharmacology (2005) 144, 242,251. doi:10.1038/sj.bjp.0706074 [source]


Purinergic activation of a leak potassium current in freshly dissociated myocytes from mouse thoracic aorta

ACTA PHYSIOLOGICA, Issue 2 2009
S. Hayoz
Abstract Aim:, Exogenous ATP elicits a delayed calcium-independent K+ current on freshly isolated mouse thoracic aorta myocytes. We investigated the receptor, the intracellular pathway and the nature of this current. Methods:, The patch-clamp technique was used to record ATP-elicited delayed K+ current in freshly dissociated myocytes. Results:, ATP-elicited delayed K+ current was not inhibited by a ,cocktail' of K+ channel blockers (4-AP, TEA, apamin, charybdotoxin, glibenclamide). The amplitude of the delayed K+ current decreased after the reduction of extracellular pH from 7.4 to 6.5. These two characteristics suggest that this current could be carried by the TASK subfamily of ,twin-pore potassium channels' (K2P). Purinergic agonists including dATP, but not ADP, activated the delayed K+ current, indicating that P2Y11 is the likely receptor involved in its activation. The PKC activator phorbol ester 12,13-didecanoate stimulated this current. In addition, the PKC inhibitor G 6850 partially inhibited it. Real-time quantitative PCR showed that the genes encoding TASK-1 and TASK-2 are expressed. Conclusion:, Our results indicate that blocker cocktail-insensitive delayed K+ current in freshly dissociated aortic myocytes is probably carried by the TASK subfamily of twin-pore channels. [source]


Mechanisms of ATP action on motor nerve terminals at the frog neuromuscular junction

EUROPEAN JOURNAL OF NEUROSCIENCE, Issue 5 2005
S. Grishin
Abstract We have shown previously that ATP inhibits transmitter release at the neuromuscular junction through the action on metabotropic P2Y receptors coupled to specific second messenger cascades. In the present study we recorded K+ or Ca2+ currents in motor nerve endings or blocked K+ or Ca2+ channels in order to explore the nature of downstream presynaptic effectors. Endplate currents were presynaptically depressed by ATP. Blockers of Ca2+ -activated K+ -channels, such as iberiotoxin, apamin or tetraethylammonium, did not change the depressant action of ATP. By contrast, K+ channel blocker 4-aminopyridine (4-AP) and raised extracellular Ca2+ attenuated the effect of ATP. However, these effects of 4-AP and high Ca2+ were reversed by Mg2+, suggesting Ca2+ -dependence of the ATP action. Ba2+ promoted the depressant action of ATP as did glibenclamide, a blocker of ATP-sensitive K+ channels, or mild depolarization produced by 7.5 mm K+. None of the K+ channel blockers affected the depressant action of adenosine. Focal recording revealed that neither ATP nor adenosine affected the fast K+ currents of the motor nerve endings. However, unlike adenosine, ATP or UTP, an agonist of P2Y receptors, reversibly reduced the presynaptic Ca2+ -current. This effect was abolished by suramin, an antagonist of P2 receptors. Depressant effect of ATP on the endplate and Ca2+ -currents was mimicked by arachidonate, which precluded the action of ATP. ATP reduced acetylcholine release triggered by ionomycin or sucrose, suggesting inhibition of release machinery. Thus, the presynaptic depressant action of ATP is mediated by inhibition of Ca2+ channels and by mechanism acting downstream of Ca2+ entry. [source]


Recombinant human serotonin 5A receptors stably expressed in C6 glioma cells couple to multiple signal transduction pathways

JOURNAL OF NEUROCHEMISTRY, Issue 2 2003
Mami Noda
Abstract Human serotonin 5A (5-HT5A) receptors were stably expressed in undifferentiated C6 glioma. In 5-HT5A receptors-expressing cells, accumulation of cAMP by forskolin was inhibited by 5-HT as reported previously. Pertussis toxin-sensitive inhibition of ADP-ribosyl cyclase was also observed, indicating a decrease of cyclic ADP ribose, a potential intracellular second messenger mediating ryanodine-sensitive Ca2+ mobilization. On the other hand, 5-HT-induced outward currents were observed using the patch-clamp technique in whole-cell configuration. The 5-HT-induced outward current was observed in 84% of the patched 5-HT5A receptor-expressing cells and was concentration-dependent. The 5-HT-induced current was inhibited when intracellular K+ was replaced with Cs+ but was not significantly inhibited by typical K+ channel blockers. The 5-HT-induced current was significantly attenuated by 1,2-bis(2-aminophenoxy)ethane- N,N,N,,N,-tetraacetic acid (BAPTA) in the patch pipette. Depleting intracellular Ca2+ stores by application of caffeine or thapsigargin also blocked the 5-HT-induced current. Blocking G protein, the inositol triphosphate (IP3) receptor, or pretreatment with pertussis toxin, all inhibited the 5-HT-induced current. IP3 showed a transient increase after application of 5-HT in 5-HT5A receptor-expressing cells. It was concluded that in addition to the inhibition of cAMP accumulation and ADP-ribosyl cyclase activity, 5-HT5A receptors regulate intracellular Ca2+ mobilization which is probably a result of the IP3-sensitive Ca2+ store. These multiple signal transduction systems may induce complex changes in the serotonergic system in brain function. [source]


Mechanisms involved in the antinociceptive effect caused by diphenyl diselenide in the formalin test

JOURNAL OF PHARMACY AND PHARMACOLOGY: AN INTERNATI ONAL JOURNAL OF PHARMACEUTICAL SCIENCE, Issue 12 2008
Lucielli Savegnago
This study investigated the mechanisms involved in the antinociceptive action induced by diphenyl diselenide ((PhSe)2) in the formalin test. Mice were pre-treated with (PhSe)2 by the oral route (0.1,100 mg kg,1), 30 min before formalin injection. To address some of the mechanisms by which (PhSe)2 inhibits formalin-induced nociception mice were treated with different drugs. The antinociceptive effect of (PhSe)2 was shown in the first and second phases of the formalin test. The antinociceptive effect caused by (PhSe)2 (10 mg kg,1, p.o.) was prevented by intrathecal injection of K+ channel blockers such as apamin and charybdotoxin (small- and large-conductance Ca2+ -activated K+ channel inhibitors, respectively) and tetraethylammonium (TEA, a non-selective voltage-dependent K+ channel inhibitor), but not glib-enclamide (an ATP-sensitive K+ channel inhibitor). The antinociceptive action caused by (PhSe)2 (10 mg kg,1, p.o.) was also blocked by a nitric oxide (NO) synthase inhibitor (N, -nitro- l -arginine, L-NOARG) and the soluble guanylate cyclase inhibitors 1H -[1,2,4]oxadiazolo[4,3- a]quinoxalin-1-one (ODQ) and methylene blue. These results suggest the participation of NO/cyclic GMP/Ca2+ and K+ channel pathways in the antinociceptive effect caused by (PhSe)2. [source]


Antagonism of calcium currents and neurotransmitter release by barium ions at frog motor nerve endings

BRITISH JOURNAL OF PHARMACOLOGY, Issue 2 2000
Eugene M Silinsky
The effects of Ba2+ (0.1,2 mM) on the component of the perineural voltage change associated with nerve terminal calcium currents (prejunctional Ca2+ currents) were compared with the effects of this ion to antagonize calcium-dependent acetylcholine (ACh) release. These experiments were made on isolated neuromuscular junctions of the frog. In the presence of sufficient concentrations of K+ channel blockers to eliminate measurable prejunctional K+ currents, low concentrations of Ba2+ selectively antagonized prejunctional Ca2+ currents in normal Ca2+ solutions. Higher concentrations of Ba2+ also substantially reduced the Na+ component of the perineural waveform. Ba2+ inhibited the prolonged prejunctional Ca2+ currents that developed in the presence of higher concentrations of K+ channel blockers. Simultaneous measurements of the prejunctional Ca2+ currents and the electrophysiological correlates of ACh release (i.e. end-plate potentials, EPPs) were made under conditions of modest K+ channel blockade. Under these conditions, Ba2+ generally produced simultaneous decreases in both Ca2+ currents and EPP amplitudes. In some instances, a prolongation of prejunctional Ca2+ currents and a transient increase in EPP amplitudes preceded the decreases in both electrophysiological events. These results suggest that Ba2+ ions can antagonize the entry of calcium into motor nerve endings and this effect is likely to be responsible for the inhibitory effects of Ba2+ on evoked ACh release. British Journal of Pharmacology (2000) 129, 360,366; doi:10.1038/sj.bjp.0703036 [source]