Ionotropic mechanisms involved in postsynaptic inhibition by the endothelins of ganglionic transmission in dog cardiac sympathetic ganglia.
We investigated the effects of endothelin-1 and endothelin-3 (ET-1, ET-3) on the ganglionic transmission of cardiac sympathetic ganglia in vivo by the direct administration of agents to the ganglia through the right subclavian artery while monitoring the heart rate (HR) as an indicator of the ganglionic function in spinal dogs. The positive chronotropic responses to dimethylphenylpiperazinium (DMPP) and McN-A-343 administered to the ganglia were similarly inhibited by ET-1 (0.05-0.2 microg) and ET-3 (0.5-2 microg), but ET-1 was approximately 10 times more potent than ET-3. The inhibition induced by ETs was antagonized by endothelin ETA receptor antagonist BQ-123 (20 microg). This inhibition was unaffected by pretreatment with indomethacin given intravenously (i.v.), ruling out the possible involvement of endogenous prostaglandins production. The voltage-sensitive Ca2+ channel antagonist nifedipine had no effect on inhibition. However, the inhibition was antagonized by pretreatment with the low conductance Ca2+-activated potassium channel antagonists, such as apamin (20 microg intraarterially, i.a.), scyllatoxin (10 mug i.a.) and D-tubocurarine (0.6 mg i.a.). On the other hand, the voltage-sensitive K+ channel antagonist 4-aminopyridine (4-AP), ATP-dependent K+ channel antagonist, glibenclamide, and high-conductance Ca2+-activated K+ channel antagonists iberiotoxin and charybdotoxin failed to affect the inhibition by ETs. The results suggest that ETs inhibit the nicotinic and muscarinic ganglionic transmission through the ETA receptor-operated low-conductance Ca2+-activated potassium channel at postganglionic sites.
Tsutsumi
S
S
Department of Pharmacology, School of Medicine, Fukuoka University, Japan.
Kushiku
K
K
Kuwahara
T
T
Tokunaga
R
R
Furukawa
T
T
D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride / Q000494:pharmacology; D000818:Animals; D002118:Calcium / Q000378:metabolism; D004246:Dimethylphenylpiperazinium Iodide / Q000494:pharmacology; D004285:Dogs; D016232:Endothelins / Q000494:pharmacology*; D005260:Female; D005728:Ganglia, Sympathetic / Q000187:drug effects* / Q000502:physiology; D006339:Heart Rate / Q000187:drug effects*; D007213:Indomethacin / Q000494:pharmacology; D008297:Male; D009543:Nifedipine / Q000494:pharmacology; D010456:Peptides, Cyclic / Q000494:pharmacology; D015221:Potassium Channels / Q000187:drug effects; D009435:Synaptic Transmission / Q000187:drug effects*
D016232:Endothelins; D010456:Peptides, Cyclic; D015221:Potassium Channels; D004246:Dimethylphenylpiperazinium Iodide; D008455:(4-(m-Chlorophenylcarbamoyloxy)-2-butynyl)trimethylammonium Chloride; D009543:Nifedipine; C072247:cyclo(Trp-Asp-Pro-Val-Leu); D002118:Calcium; D007213:Indomethacin