Abstract
The relaxing effects of the nitric oxide (NO) donors 1,2,3,4-oxatriazolium,3-(3-chloro-2-methylphenyl-5-[[(4-methoxyphenyl)sulfonyl]amino]-,hydroxide inner salt (GEA 3268) 1,2,3,4-oxatriazolium,3-(3-chloro-2-methyphenyl-5-[methysulfonyl)amino]-hydroxide inner salt (GEA 5145), 3-morpholinosydnonimine (SIN-1) and S-nitroso- N -acetylpenicillamine (SNAP) were inhibitedin vitro by iberiotoxin (IbTX) and charybdotoxin (ChTX), the two selective inhibitors of Ca++-activated K+channels (KCa) in guinea pig trachea. When studied in cumulative concentrations in metacholine constriction, the relaxing effects of the NO donors were inhibited by at least 70% in the presence of the toxins, with the exception of SIN-1 in the presence of ChTX. The inhibitory effect of ChTX was less marked than that of IbTX. This suggests that the relaxing effects of the structurally different NO donors are mediated through KCa channels and that IbTX is more potent than ChTX. A selective inhibitor of soluble guanylate cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one (ODQ), significantly inhibited the relaxing effects of GEA 3268 and GEA 5145 on metacholine and KCl constriction and almost totally inhibited the relaxing effects of SIN-1 and SNAP. The inhibitor of the delayed rectifier K+ channel current 4-aminopyridine did not influence the relaxations of the NO donors, and under the experimental conditions of this study, the ATP-sensitive K+ channel inhibitor glibenclamide had no effect. In conclusion, the relaxing effects of the structurally different NO-releasing compounds are mediated via KCa channels. However, the significance of some other possible mechanisms unrelated to K+ channels cannot be excluded.
Footnotes
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Send reprint requests to: Prof. Heikki Vapaatalo, M.D., Institute of Biomedicine, Department of Pharmacology and Toxicology, P.O. Box 8, FIN-00014 University of Helsinki, Finland.
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↵1 Grants from the Emil Aaltonen Foundation, Tampere, Finland; Ida Montin Foundation, Helsinki, Finland; the Leiras Research Foundation, Turku, Finland.
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↵2 Grants from the GEA company, A/S GEA Pharmaceutisk Fabrik, Hvidrove, Denmark; the Pharmacological Research Foundation, Finland and TEKES, Finland.
- Abbreviations:
- ANOVA/MANOVA
- analysis of variance
- 4-AP
- 4-aminopyridine
- [ATP]i
- cellular ATP concentration
- KATP channels
- ATP-sensitive K+ channels
- ChTX
- charybdotoxin
- DMSO
- dimethylsulfoxide
- GEA 3268
- 1,2,3,4-oxatriazolium, 3-(3-chloro-2-methylphenyl)-5-[[(4-methoxyphenyl)sulfonyl]amino]—hydroxide inner salt
- GEA 5145
- 1,2,3,4-oxatriazolium, 3-(3-chloro-2-methylphenyl)-5-[(methylsulfonyl)amino]—hydroxide inner salt
- IbTX
- iberiotoxin, KCa channels, Ca++-activated K+ channels
- KV
- delayed rectifier channels
- NO
- nitric oxide
- ODQ
- 1H-[1,2,4]oxadiazolo[4,3-a]quinozalin-1-one
- sGC
- soluble guanylate cyclase
- SIN-1
- 3-morpholinosydnonimine
- SNAP
- S-nitroso-N-acetylpenicillamine
- Received August 27, 1997.
- Accepted March 10, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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