Role of Ca2+-dependent potassium channels in in vitro anandamide-mediated mesenteric vasorelaxation in rats with biliary cirrhosis.
OBJECTIVE
Anandamide can activate potassium (K(+)) channels to induce an endothelium-dependent vasorelaxation in normal rat mesenteric arteries. Cannabinoids contribute partly to the splanchnic vasodilation in cirrhosis. This study investigated the roles of vascular K(+) channels in anandamide-induced mesenteric vasorelaxation in isolated rat cirrhotic vessels.


METHODS
The effects of the pretreatment of AM251, a specific CB(1) receptor antagonist, were assessed on the vascular reactivity to phenylephrine (PE), potassium chloride (KCl), acetylcholine (ACh) and sodium nitroprusside (SNP). Additionally, cannabinoid (CB(1) and CB(2)) receptors' protein expression and the effects of different K(+) channel blockers on vascular reactivity to anandamide were also studied.


RESULTS
Cirrhotic mesenteric arteries showed an overexpression of CB(1) receptor associated with hyporeactivity to PE and KCl, and hyper-response to ACh, SNP and anandamide. Pretreatment with AM251 significantly improved the hyporeactivity to KCl and ameliorated the hyper-response to ACh in cirrhotic vessels. Increased relaxation response to anandamide was suppressed by combinations of vascular Ca(2+)-dependent K(+) channel blockers (including apamin+charybdotoxin+iberiotoxin or apamin+TRAM-34+iberiotoxin) (TRAM-34, 1-[(2-chlorophenyl)diphenylmethyl]-1H-pyrazole).


CONCLUSIONS
In cirrhotic mesenteric arteries, vascular CB(1) receptor and anandamide contribute to the in vitro hyporeactivity to KCl. In addition, hyper-response to ACh may probably act through the modulation of vascular Ca(2+)-dependent K(+) channels.
Yang
Ying-Ying
YY
Institute of Clinical Medicine, National Yang-Ming University School of Medicine, Taipei, Taiwan.
Lin
Han-Chieh
HC
Huang
Yi-Tsau
YT
Lee
Tzung-Yan
TY
Hou
Ming-Chih
MC
Wang
Ying-Wen
YW
Lee
Fa-Yauh
FY
Lee
Shou-Dong
SD
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001030:Apamin / Q000494:pharmacology; D001095:Arachidonic Acids / Q000378:metabolism*; D063385:Cannabinoid Receptor Modulators / Q000378:metabolism*; D018999:Charybdotoxin / Q000494:pharmacology; D003135:Common Bile Duct / Q000601:surgery; D004305:Dose-Response Relationship, Drug; D063388:Endocannabinoids; D005905:Glyburide / Q000494:pharmacology; D008026:Ligation; D008105:Liver Cirrhosis, Biliary / Q000378:metabolism* / Q000503:physiopathology; D008106:Liver Cirrhosis, Experimental / Q000378:metabolism* / Q000503:physiopathology; D008297:Male; D017538:Mesenteric Artery, Superior / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D009599:Nitroprusside / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D053284:Polyunsaturated Alkamides / Q000378:metabolism*; D011188:Potassium / Q000378:metabolism*; D026902:Potassium Channel Blockers / Q000494:pharmacology; D024681:Potassium Channels, Calcium-Activated / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011189:Potassium Chloride / Q000494:pharmacology; D011720:Pyrazoles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D043884:Receptor, Cannabinoid, CB1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D043885:Receptor, Cannabinoid, CB2 / Q000378:metabolism; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects; D014665:Vasodilator Agents / Q000494:pharmacology
D001095:Arachidonic Acids; D063385:Cannabinoid Receptor Modulators; D063388:Endocannabinoids; D010455:Peptides; D010880:Piperidines; D053284:Polyunsaturated Alkamides; D026902:Potassium Channel Blockers; D024681:Potassium Channels, Calcium-Activated; D011720:Pyrazoles; D043884:Receptor, Cannabinoid, CB1; D043885:Receptor, Cannabinoid, CB2; C411671:TRAM 34; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; D018999:Charybdotoxin; D009599:Nitroprusside; D010656:Phenylephrine; D001030:Apamin; C103505:AM 251; D011189:Potassium Chloride; C064719:iberiotoxin; D000109:Acetylcholine; D011188:Potassium; D005905:Glyburide; C078814:anandamide