Carbon monoxide-mediated activation of large-conductance calcium-activated potassium channels contributes to mesenteric vasodilatation in cirrhotic rats.
Large-conductance calcium-activated potassium channels (BK(Ca)s) are important regulators of arterial tone and represent a mediator of the endogenous vasodilator carbon monoxide (CO). Because an up-regulation of the heme oxygenase (HO)/CO system has been associated with mesenteric vasodilatation of cirrhosis, we analyzed the interactions of BK(Ca) and of HO/CO in the endothelium-dependent dilatation of mesenteric arteries in ascitic cirrhotic rats. In pressurized mesenteric arteries (diameter, 170-350 microm) of ascitic cirrhotic rats, we evaluated the effect of inhibition of BK(Ca), HO, and guanylyl-cyclase on dilatation induced by acetylcholine and by exogenous CO; and HO-1 and BK(Ca) subunit protein expression. Inhibition of HO and of BK(Ca) reduced acetylcholine-induced vasodilatation more in cirrhotic rats than in control rats, whereas inhibition of guanylyl-cyclase had a similar effect in the two groups. CO was more effective in cirrhotic rats than in control rats, and the effect was hindered by BK(Ca) inhibition. The expression of HO-1 and of BK(Ca) alpha-subunit was higher in mesenteric arteries of cirrhotic rats compared with that of control animals, whereas the expression of the BK(Ca) beta1-subunit was lower. In conclusion, an overexpression of BK(Ca) alpha-subunits, possibly due to HO up-regulation with increased CO production, participates in the endothelium-dependent alterations and mesenteric arterial vasodilatation of ascitic cirrhotic rats.
Bolognesi
Massimo
M
Department of Clinical and Experimental Medicine, University of Padova, Padova, Italy. massimo.bolognesi@unipd.it
Sacerdoti
David
D
Piva
Anna
A
Di Pascoli
Marco
M
Zampieri
Francesca
F
Quarta
Santina
S
Motterlini
Roberto
R
Angeli
Paolo
P
Merkel
Carlo
C
Gatta
Angelo
A
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D002248:Carbon Monoxide / Q000502:physiology*; D002252:Carbon Tetrachloride Poisoning / Q000473:pathology; D004730:Endothelium, Vascular / Q000502:physiology; D006162:Guanylate Cyclase / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006419:Heme Oxygenase (Decyclizing) / Q000037:antagonists & inhibitors / Q000378:metabolism; D066298:In Vitro Techniques; D051036:Large-Conductance Calcium-Activated Potassium Channels / Q000819:agonists*; D008103:Liver Cirrhosis / Q000503:physiopathology*; D008297:Male; D008638:Mesenteric Arteries / Q000187:drug effects; D008652:Mesoporphyrins / Q000494:pharmacology; D009942:Organometallic Compounds / Q000494:pharmacology; D010656:Phenylephrine / Q000494:pharmacology; D051381:Rats; D017208:Rats, Wistar; D015398:Signal Transduction / Q000502:physiology; D013152:Splanchnic Circulation / Q000187:drug effects*; D014655:Vascular Resistance / Q000187:drug effects; D014662:Vasoconstrictor Agents / Q000494:pharmacology; D014664:Vasodilation / Q000187:drug effects*; D014665:Vasodilator Agents / Q000494:pharmacology
D051036:Large-Conductance Calcium-Activated Potassium Channels; D008652:Mesoporphyrins; D009942:Organometallic Compounds; D014662:Vasoconstrictor Agents; D014665:Vasodilator Agents; C427471:chromium mesoporphyrin; C476530:tricarbonylchloro(glycinato)ruthenium(II); D010656:Phenylephrine; D002248:Carbon Monoxide; D006419:Heme Oxygenase (Decyclizing); D006162:Guanylate Cyclase; D000109:Acetylcholine