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Titolo:
RELAXANT EFFECTS OF NKH477, A NEW WATER-SOLUBLE FORSKOLIN DERIVATIVE,ON GUINEA-PIG TRACHEAL SMOOTH-MUSCLE - THE ROLE OF CA2-ACTIVATED K+ CHANNELS()
Autore:
SATAKE K; TAKAGI K; KODAMA I; HONJO H; TOYAMA J; SHIBATA S;
Indirizzi:
NAGOYA UNIV,SCH MED,DEPT INTERNAL MED 2 NAGOYA AICHI 466 JAPAN NAGOYA UNIV,SCH MED,DEPT INTERNAL MED 2 NAGOYA AICHI 466 JAPAN ENVIRONM MED RES INST,DEPT CIRCULAT NAGOYA AICHI 46401 JAPAN ENVIRONM MED RES INST,DEPT HUMORAL REGULAT NAGOYA AICHI 46401 JAPAN UNIV HAWAII,SCH MED,DEPT PHARMACOL HONOLULU HI 96822
Titolo Testata:
British Journal of Pharmacology
fascicolo: 4, volume: 123, anno: 1998,
pagine: 753 - 761
SICI:
0007-1188(1998)123:4<753:REONAN>2.0.ZU;2-U
Fonte:
ISI
Lingua:
ENG
Soggetto:
ACTIVATED POTASSIUM CHANNELS; BETA-ADRENOCEPTOR AGONISTS; CYCLIC-AMP; SODIUM-NITROPRUSSIDE; MECHANICAL-ACTIVITY; CHARYBDOTOXIN; PHOSPHORYLATION; SULFONYLUREAS; INHIBITION; POTENT;
Keywords:
AIRWAY SMOOTH MUSCLE; NKH477; HISTAMINE; IBERIOTOXIN; CA2+-ACTIVATED K+ CHANNELS; VOLTAGE-DEPENDENT CA2+ CHANNELS;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Science Citation Index Expanded
Citazioni:
36
Recensione:
Indirizzi per estratti:
Citazione:
K. Satake et al., "RELAXANT EFFECTS OF NKH477, A NEW WATER-SOLUBLE FORSKOLIN DERIVATIVE,ON GUINEA-PIG TRACHEAL SMOOTH-MUSCLE - THE ROLE OF CA2-ACTIVATED K+ CHANNELS()", British Journal of Pharmacology, 123(4), 1998, pp. 753-761

Abstract

1 Mechanisms underlying the bronchorelaxant action of NKH477, a newlydeveloped water-soluble forskolin derivative, were investigated in guinea-pig isolated tracheal smooth muscle. 2 In muscles precontracted with 3 mu M histamine, NKH477 (1 nM - 1 mu M) caused a concentration-dependent decrease of isometric tension, resulting in a complete relaxation at 300 nM. The EC50 for the relaxation was 32.6+/-4.3 nM (n=6). 3 In the presence of 30 or 90 nM iberiotoxin (IbTX), a selective blockerof the large-conductance Ca2+-activated K+ (BKCa) channel, the relaxing action of NKH477 on the histamine-induced contraction was inhibited, giving rise to a parallel shift of the concentration-response curves; the EC50 of NKH477 was increased to 131.4+/-20.4 nM at 30 nM IbTX (n=4), and 125.3+/-12.2 nM at 90 nM IbTX (n=4). 4 Pretreatment of muscles with 30 mM tetraethylammonium (TEA) caused a similar rightward shiftof the concentration-response curve to NKH477 with an increase of theEC50 to 139.8+/-18.4 nM (n=5). In contrast, the relaxing action of NKH477 was unaffected by 10 mu M glibenclamide, an ATP-sensitive K+ channel blocker, or by 100 nM apamin, a blocker of small conductance Ca2+-activated K+ channels. 5 In muscles pretreated with 1 mu M nifedipine,a blocker of the voltage-dependent Ca2+ channel (VDC), 30-90 nM IbTX did not affect the relaxant effects of NKH477 on the histamine-inducedcontraction. 6 In muscles precontracted by a K+-rich (40 mM) solution, NKH477 caused only minimal relaxation (19.8+/-1.7%, n=4) even at thehighest concentration (1 mu M). 7 In experiments to measure the ratioof fura-2 fluorescence signals (R-340/380) as an index of the intracellular Ca2+ concentration ([Ca2+](i)), the application of 100 nM NKH477 or 200 nM isoprenaline to the preparation precontracted by 3 mu M histamine resulted in a decrease in [Ca2+](i) in association with a decrease in tension. The reduction of [Ca2+](i) and tension by NKH477 was 47.0+/-5.6% and 62.8+/-7.0%, respectively (n=5), and that with isoprenaline 60.6+/-7.4% and 67.4+/-6.4%, respectively (n=5). These effects of NKH477 and isoprenaline on [Ca2+](i) and tension were inhibited by 30 nM IbTX. The inhibitory action of IbTX was abolished in the presenceof 1 mu M nifedipine. 8 These results suggest that the bronchorelaxant action of NKH477 may result, at least in part, from activation of BKCa channels, which may cause a hyperpolarization of smooth muscle cellmembranes and a secondary decrease in Ca2+ influx through VDCs, leading to a decrease in [Ca2+](i).

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Documento generato il 05/12/20 alle ore 01:52:39