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Portal vascular responsiveness to sympathetic stimulation and nitric oxide in cirrhotic rats
R T Mathie1, V Ralevic, G Burnstock
1Department of Surgery, Royal Postgraduate Medical School, Hammersmith Hospital, London, UK.
Aims/Methods:
The modulatory role of nitric oxide in portal vasoconstrictor responses was investigated in the isolated perfused liver of cirrhotic rats (induced by carbon tetrachloride/phenobarbitone; n = 6). Age-matched (n = 5) and phenobarbitone-treated rats (n = 5) served as controls.
Results:
At a constant flow rate of 5 ml/min there was no difference in basal perfusion pressure between the groups. Responses to electrical field stimulation of perivascular nerves caused frequency-dependent increases in perfusion pressure that were not significantly different between the groups. In contrast, dose-dependent vasoconstrictor responses to bolus injections of noradrenaline were up to two-fold greater than those observed in controls (p < 0.05). Vasoconstrictor responses to bolus injections of methoxamine (a selective alpha 1-adrenoceptor agonist) or adenosine 5'-triphosphate (ATP, a cotransmitter with noradrenaline in sympathetic nerves) were dose-dependent and similar between the groups. Infusion of the nitric oxide synthesis inhibitor NG-nitro-L-arginine methyl ester (L-NAME; 30 microM) had no effect on basal tone or on responses to electrical field stimulation or injected agents. A step-wise increase in flow to 10, 15 and 20 ml/min produced a similar increase in perfusion pressure within each group. At increased flow, there was a decrease in responsiveness to noradrenaline (5 nmol) in preparations from all groups. In the presence of the K+ channel inhibitor glibenclamide (5 microM), the effect of noradrenaline in the cirrhotic group at flow rates of 5, 10 and 15 ml/min was maintained to a significantly greater extent than in either control group, suggesting that ATP-sensitive K+ channels in the portal venous bed may be activated in cirrhosis.
Conclusions:
We conclude that portal vasoconstriction associated with noradrenaline, but not with sympathetic nerve stimulation, methoxamine or ATP, is enhanced in cirrhosis. Nitric oxide does not appear to play a modulatory role in these responses.