NIP-121 and cromakalim, potassium channel openers, preferentially suppress prostanoid-induced contraction of the guinea-pig isolated trachea

Shikada, Ken-ichi; Yamamoto, Akira; Tanaka, Sakuya

doi:10.1016/0014-2999(91)90012-f

Cited by 12 publications

(12 citation statements)

References 17 publications

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“…However, in our calculation of the area under the frequency-response curve, cromakalim (0.3 ,uM) showed selective and significant inhibition against vagus nerve-evoked responses, a finding that is in agre ement with the study of McCaig and De Jonckheere (4). Our novel potassium channel opener NIP-121 was reported to be 5 times stronger than cromakalim in suppressing spontaneous tone in guinea pig trachea (2). In the present study, NIP-121 was about 10 times more potent than cromakalim.…”

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confidence: 52%

“…A higher concentra tion of hydrocortisone (300,uM) largely inhibited the vagus nerve-mediated response and had a small but sig nificant effect on the response to field stimulation. The novel potassium channel opener NIP-121 (7) and cro makalim, at concentrations that abolished spontaneous tone of the tracheal spiral preparation to a submaximal extent (2), preferentially suppressed the vagus nerve mediated response over the response induced by field stimulation. The potency of NIP-121 was about ten times that of cromakalim.…”

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confidence: 99%

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Effects of Anti-Asthma Drugs and Potassium Channel Openers on Neurally-Mediated Contraction of Isolated Guinea Pig Trachea

Yamamoto

Shikada

Tanaka

1992

Japanese Journal of Pharmacology

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ABSTRACT-Keywords: Anti-asthma drugs, Neurally-mediated contraction, Trachea (guinea pig)The airways are under the control of the autonomic nervous system. Abnormalities in autonomic regulation of the airway, such as an increase in cholinergic activ ity, may underlie bronchial hyperreactivity and contrib ute to the bronchoconstriction of asthma (1). 8-Adreno ceptor agonist and methylxanthines have been widely used to treat asthma, because of their airway smooth muscle relaxant activity. Glucocorticoid therapy has been also applied in the treatment of asthma, based on its anti-inflammatory activity. However, actual involve ment of these mechanisms in the treatment of asthma does not seem to be clear.The potassium channel openers posses not only vasorelaxing activity but also bronchodilation activity in isolated guinea pig trachea (2). Taylor et al. (3) re ported that cromakalim is an effective inhibitor of spon taneous tone in isolated human bronchioles. Recently, cromakalim was reported to modulate neurotransmis sion in the guinea pig trachea (4, 5), and its possible use in the treatment of asthma is now under investiga tion.In this study, we investigated the effects of iso proterenol, aminophylline, hydrocortisone and potas sium channel openers on the increase in intraluminal pressure (ILP) of isolated guinea pig trachea. The ILP was evoked by: 1) stimulation of the vagus nerve, 2) transmural field stimulation and 3) exogenously applied acetylcholine (ACh), and we compared the modes of action of these drugs. The methods of Blackman and McCaig (6) were modified and used. Briefly, male Hartley guinea pigs (250-400 g) were killed by a blow to the head, and the trachea was excised with the right vagus nerve. The preparation was cannulated at each end, set up horizon tally and maintained at 37°C in an 80-ml organ bath containing aerated modified Tyrode solution. The lu men of the trachea was filled with the Tyrode solution. The composition of the Tyrode solution was as follows: 137 mM NaCl, 2.7 mM KC1, 1.8 mM CaC12, LO MM MgC12, 20 mM NaHCO3, 0.32 mM NaH2PO4 and 11 mM dextrose. One end of the trachea was closed and the other end was attached to a pressure transducer (TP-400T, Nihon Kohden) to record ILP.The trachea was equilibrated for 50 min and the re sponse to 100 p.t M histamine was recorded and washed. Histamine increased ILP to 42 ± 2 mmHg (n = 7), and the responses of the following experiments were ex pressed as percentages of the histamine response. Fifty minutes after the washout of histamine, responses to vagus nerve and transmural field stimulation were obtained. The vagus nerve and transmural field stimula tion were delivered by an electronic stimulator (SEN

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confidence: 99%

Effects of Anti-Asthma Drugs and Potassium Channel Openers on Neurally-Mediated Contraction of Isolated Guinea Pig Trachea

Yamamoto

Shikada

Tanaka

1992

Japanese Journal of Pharmacology

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“…NIP-121, a potassium channel opener ' Author for correspondence. (Masuda et al, 1991), has potent bronchodilator activity in the guinea-pig isolated trachea (Shikada et al, 1991). We reported recently that NIP-121, as well as cromakalim, inhibited neurally-mediated contraction (Yamamoto et al, 1992) and epithelium-dependent potentiation of sodium nitroprusside-induced relaxation in the guinea-pig isolated trachea .…”

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confidence: 99%

Influence of epithelium on the inhibition of melittin‐induced contraction of guinea‐pig isolated trachea by the potassium channel opener NIP‐121

Shikada

Tanaka

1993

British J Pharmacology

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We have investigated the effect of the potassium channel opener, NIP‐121, on contraction elicited by melittin (a phospholipase A2 activator) in epithelium‐intact and epithelium‐denuded trachea isolated from guinea‐pigs. The effects of NIP‐121 were compared with those of isoprenaline, aminophylline and hydrocortisone. In the presence of the cyclo‐oxygenase inhibitor, indomethacin (5 μm), melittin (3 μg ml−1) caused time‐dependent contraction. The melittin‐induced contractile response was significantly augmented by removal of the epithelium and was concentration‐dependently and completely inhibited by the phospholipase A2 (PLA2) inhibitor, p‐bromophenacyl bromide (BPB 10–100 μm), and the lipoxygenase inhibitor, phenidone (10–300 μm). Similar inhibition of the melittin response by BPB (10 μm) and phenidone (10 μm) was observed in the epithelium‐denuded trachea. Concentration‐dependent inhibition of the melittin response was induced by preincubation with NIP‐121 (0.03 and 0.1 μm), isoprenaline (0.001 and 0.01 μm), aminophylline (30 and 100 μm) and hydrocortisone (100 and 300 μm). The effect of NIP‐121 was abolished by glibenclamide (1 μm). The inhibitory effect of NIP‐121 on the melittin response was greatly reduced by removing the epithelium while that of the isoprenaline, aminophylline or hydrocortisone was not changed. The inhibition of the melittin response by these drugs was similar to their inhibition of the contraction elicited by a low concentration (3 nm) of leukotriene D4 (LTD4) in the epithelium‐intact trachea. Inhibition of the LTD4 response by NIP‐121 was not observed in the epithelium‐denuded trachea. However, higher concentrations of NIP‐121 (0.3 and 1 μm) did inhibit LTD4‐induced contractions of epithelium‐denuded trachea. These findings suggest that melittin causes epithelium‐dependent contraction of the guinea‐pig isolated trachea which is mediated by products of lipoxygenase activity. NIP‐121 may inhibit the melittin response by activating glibenclamide‐sensitive potassium channels, which appear to be epithelium‐dependent (an indirect effect of NIP‐121 apart from its direct effect on the airway smooth muscle) while isoprenaline, aminophylline and hydrocortisone act directly to relax the trachealis smooth muscle.

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“…Similar findings have been reported for cromakalim (1-7). The smooth muscle relaxation and negative inotropic effect of NIP-121 have been reported to be about 10 times more potent than those of cromakalim in rat aorta (11, 13 -15), guinea pig trachea (16) and heart (19), respectively.…”

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“…NIP-121, (+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-piperidine-1-yl)-6H-pyrano [2, 3 f ] benz-2,1, 3-oxadiazole, has also been reported to produce arterial (11)(12)(13)(14)(15) or tracheal (16,17) smooth muscle relaxation, to lower blood pressure (18), and also to shorten action potential duration (19). The effects were thought to be associated with an increase in the 86Rb+ efflux that passes through potassium channels and is competitively inhibited by glibenclamide, an ATP-sensitive potassium channel blocker (11,(13)(14)(15).…”

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Comparative Study of Vasodilator Effects of the Potassium Channel Openers NIP-121 and Levcromakalim in Dogs and Rats

Yamashita

Masuda

Kawamura

et al. 1995

Japanese Journal of Pharmacology

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ABSTRACT-The effects of potassium channel openers NIP-121 ((+)-7,8-dihydro-6,6-dimethyl-7-hydroxy-8-(2-oxo-piperidine-1-yl)-6H-pyrano[2,3 f]benz-2,1,3-oxadiazole) and levcromakalim were examined in vitro and in vivo. In isolated canine vascular beds, NIP-121 (3 x 10-9 to 10' M) and levcromakalim (3 x 10-8 to 10-6 M) produced a concentration-dependent reduction in the vasoconstrictor responses to U46619. The effects were antagonized by glibenclamide, an ATP-sensitive potassium channel blocker. The maximal relaxation was more than 70% of the maximal vasodilation induced by papaverine (10-'M), except in the basilar artery. These compounds had very potent effects on the coronary and cranial mesenteric arteries and saphenous vein. In the coronary perfused rat heart, both compounds (10-' M) also increased coronary perfusion flow. The effects were also inhibited by glibenclamide (10-6 M). In anesthetized dogs, NIP-121 (1 to 10 t€g/kg (3.2 to 32 nmol/kg), i.v.) and levcromakalim (3 to 30 tag/kg (10.5 to 105 nmol/kg), i.v.) dosedependently increased coronary and renal blood flow. NIP-121 and levcromakalim at higher doses produced the greatest increase in coronary blood flow among the blood vessels examined, in spite of the hypotensive effect. In conclusion, NIP-121 and levcromakalim were similarly selective vasodilators on the canine isolated coronary and cranial mesenteric arteries and saphenous vein, and they selectively increased coronary blood flow in vivo. With respect to increasing the coronary blood flow, NIP-121 had a fourfold greater potency than levcromakalim. This effect might be related to the glibenclamide-sensitive potassium channels.

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NIP-121 and cromakalim, potassium channel openers, preferentially suppress prostanoid-induced contraction of the guinea-pig isolated trachea

Cited by 12 publications

References 17 publications

Effects of Anti-Asthma Drugs and Potassium Channel Openers on Neurally-Mediated Contraction of Isolated Guinea Pig Trachea

Effects of Anti-Asthma Drugs and Potassium Channel Openers on Neurally-Mediated Contraction of Isolated Guinea Pig Trachea

Influence of epithelium on the inhibition of melittin‐induced contraction of guinea‐pig isolated trachea by the potassium channel opener NIP‐121

Comparative Study of Vasodilator Effects of the Potassium Channel Openers NIP-121 and Levcromakalim in Dogs and Rats

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