Vascular hyporesponsiveness to vasodilators in rats with cirrhosis.
OBJECTIVE
In cirrhosis, the activation of nitric oxide and prostacyclin contributes to vasodilation, and ATP-sensitive K+ (KATP) channel activation or L-type calcium (Ca2+) channel inhibition may also play a role in this process. At the same time in cirrhosis, certain endogenous mechanisms may be stimulated which limit the influence of vasodilator mechanisms on vascular tone, thus altering vascular responses to exogenous substances such as nitric oxide donors, exogenous prostacyclin, KATP channel openers or L-type Ca2+ channel blockers. The aim of the present study was to examine the arterial depressor to these exogenous substances in normal rats and in rats with secondary biliary cirrhosis.


METHODS
Arterial depressor dose-response curves to nitroprusside (a nitric oxide donor, 5-60 micrograms.kg-1.min-1), prostacyclin (0.5-5 micrograms.kg-1) and aprikalim (a KATP channel opener, 10-200 micrograms.kg-1) were obtained in both groups. The effects of different L-type Ca2+ channel blockers, i.e. nicardipine (a dihydropyridine, 0.02-0.5 mg.kg-1), diltiazem (a benzothiazepine, 0.5-5 mg.kg-1) and verapamil (a phenylalkylamine, 0.02-0.2 mg.kg-1. min-1), were also studied.


RESULTS
Cirrhosis produced hyporeactivity to the arterial depressor effect of all doses of nitroprusside, the lowest dose of prostacyclin and the highest doses of aprikalim or diltiazem. Cirrhosis did not significantly change depressor responses to nicardipine or verapamil.


CONCLUSIONS
Rats with cirrhosis are hyporeactive to exogenous nitric oxide, prostacyclin, KATP channel opener and benzothiazepine (an L-type Ca2+ channel blocker). Therefore, cirrhosis-induced mechanisms seem to limit the decrease in vascular tone by most vasodilators. However, these mechanisms appear to be more marked in nitric oxide-mediated vasodilation than in other vasorelaxation mechanisms.
Safka
V
V
Laboratoire d'Hémodynamique Splanchnique, INSERM U-24, Hôpital Beaujon, Clichy, France.
Moreau
R
R
Gadano
A
A
Lebrec
D
D
D000818:Animals; D001794:Blood Pressure / Q000187:drug effects*; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D011464:Epoprostenol / Q000494:pharmacology; D008106:Liver Cirrhosis, Experimental / Q000503:physiopathology*; D008297:Male; D009599:Nitroprusside / Q000494:pharmacology; D010847:Picolines / Q000494:pharmacology; D011714:Pyrans / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D014665:Vasodilator Agents / Q000494:pharmacology*
D002121:Calcium Channel Blockers; D010847:Picolines; D011714:Pyrans; D014665:Vasodilator Agents; D009599:Nitroprusside; C061043:aprikalim; D011464:Epoprostenol