VASCULAR HYPORESPONSIVENESS TO VASODILATORS IN RATS WITH CIRRHOSIS

Background/Aims: In cirrhosis, the activation of nitric oxide and pros tacyclin contributes to vasodilation, and ATP-sensitive K+ (K-ATP) cha nnel activation or L-type calcium (Ca2+) channel inhibition may also p lay a role in this process. At the same time in cirrhosis, certain end ogenous mechanisms may be stimulated which limit the influence of vaso dilator mechanisms on vascular tone, thus altering vascular responses to exogenous substances such as nitric oxide donors, exogenous prostac yclin, K-ATP channel openers or L-type Ca2+ channel blockers, The aim of the present study was to examine the arterial depressor to these ex ogenous substances in normal rats and in rats with secondary biliary c irrhosis. Methods: Arterial depressor dose-response curves to nitropru sside (a nitric oxide donor, 5-60 mu g . kg(-1) . min(-1)), prostacycl in (0.5-5 mu g . kg(-1)) and aprikalim (a K-ATP channel opener, 10-200 mu g . 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)), we re also studied. Results: Cirrhosis produced hyporeactivity to the art erial depressor effect of all doses of nitroprusside, the lowest dose of prostacyclin and the highest doses of aprikalim or diltiazem. Cirrh osis did not significantly change depressor responses to nicardipine o r verapamil. Conclusions: Rats with cirrhosis are hyporeactive to exog enous nitric oxide, prostacyclin, K-ATP channel opener and benzothiaze pine (an L-type Ca2+ channel blocker). Therefore, cirrhosis-induced me chanisms seem to limit the decrease in vascular tone by most vasodilat ors. However, these mechanisms appear to be more marked in nitric oxid e-mediated vasodilation than in other vasorelaxation mechanisms.