Abstract
We previously reported that endothelin (ET) 3 inhibited presynaptically the dog stellate ganglionic transmission. Here, we report the investigation of the possible involvement of nitric oxide pathway in the endothelin-induced inhibition of the ganglionic transmission. The amount of acetylcholine released by preganglionic stimulation for 10 min was concentration-dependently inhibited after exposure to ET-3 (10−9–10−6 M) or IRL-1620, endothelin ETB receptor agonist (10−8–10−5M). The inhibition was antagonized by pretreatment with a nonselective endothelin receptors antagonist (bosentan) and an ETBreceptor antagonist (BQ-788) or a neuronal nitric oxide synthase inhibitor, 3-bromo-7-nitroindazole, but was not inhibited by a selective ETA receptor antagonist, BQ-123. The reduction induced by ET-3 was also antagonized by treatment with a selective inhibitor of soluble guanylyl cyclase, 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one. In addition, similar reductions were also mimicked by exposure to cGMP analog, 8-bromoguanosine-3,5-cyclic monophosphate and nitric oxide donor, S-nitroso-N-acetylpenicillamine. Exposure to ET-3 or IRL-1620 for a 30-min period increased the levels of total nitric oxide (NO), nitrite plus nitrate NOxconcentration in the incubation medium, with the increase in NOx also being antagonized by BQ-788 at the same concentration. The ET-3-induced increase in NOx was antagonized by treatment with the same concentration of 3-bromo-7-nitroindazole or a selective inhibitor of receptor-mediated Ca2+ entry, 1-[b-[3-(4-methoxyphenyl) propoxy]-4-methoxyphenethyl]-1H-imidazole (10−5 M), and with a calmodulin antagonist,N-(6-aminohexyl)-5-chloro-1-naphthalenesulfonamide. These results indicate that ETB receptor activation inhibits the sympathetic ganglionic transmission via reducing acetylcholine release from presynaptic nerve terminals, although this inhibition also seems to involve the ETB receptor-operated Ca2+-calmodulin-dependent activation of endogenous nitric oxide production.
Footnotes
-
Send reprint requests to: Kazushi Kushiku Ph.D., Department of Pharmacology, School of Medicine, Fukuoka University, 45-1, 7-chome Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan. E-mail:kkushiku{at}fukuoka-u.ac.jp
- Abbreviations:
- ET
- endothelin
- NO
- nitric oxide
- NOS
- NO synthase
- nNOS
- neuronal NOS
- IPHC
- isopropylhomocholine chloride
- SNAP
- S-nitroso-N-acetylpenicillamine
- ODQ
- 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one
- 8-bromo-cGMP
- 8-bromoguanosine-3,5-cyclic monophosphate
- Received January 19, 1999.
- Accepted May 24, 1999.
- The American Society for Pharmacology and Experimental Therapeutics
JPET articles become freely available 12 months after publication, and remain freely available for 5 years.Non-open access articles that fall outside this five year window are available only to institutional subscribers and current ASPET members, or through the article purchase feature at the bottom of the page.
|