Portal vascular responsiveness to sympathetic stimulation and nitric oxide in cirrhotic rats

doi:10.1016/S0168-8278(96)80333-3

Journal of Hepatology

Volume 25, Issue 1, July 1996, Pages 90-97

https://doi.org/10.1016/S0168-8278(96)80333-3 Get rights and content

Abstract

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 α₁-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 N^G-nitro-L-arginine methyl ester (L-NAME; 30 μM) 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 μM), 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.

References (43)

J Bosch et al.
Pathophysiology of portal hypertension
Gastroenterol Clin North Am
(1992)
ME Stark et al.
Role of nitric oxide in gastrointestinal and hepatic function and disease
Gastroenterology
(1992)
J Ryan et al.
Impaired reactivity of the peripheral vasculature to pressor agents in alcoholic cirrhosis
Gastroenterology
(1993)
PS Bhathal et al.
Reduction of the increased portal vascular resistance of the isolated perfused cirrhotic rat liver by vasodilators
J Hepatol
(1985)
AM Wheatley et al.
Effect of orthotopic transplantation and chemical denervation of the liver on hepatic hemodynamics in the rat
J Hepatol
(1993)
R Moreau et al.
Altered control of vascular tone by adenosine triphosphate-sensitive potassium channels in rats with cirrhosis
Gastroenterology
(1994)
E Proctor et al.
High yield micronodular cirrhosis in the rat
Gastroenterology
(1982)
CC Sieber et al.
Nitric oxide mediates hyporeactivity to vasopressors in mesenteric vessels of portal hypertensive rats
Gastroenterology
(1992)
A Abergel et al.
Persistence of a hyperdynamic circulation in cirrhotic rats following removal of the sympathetic nervous system
Gastroenterology
(1992)
P Pizcueta et al.
Modulation of the hyperdynamic circulation of cirrhotic rats by nitric oxide inhibition
Gastroenterology
(1992)

M Fernández et al.

Evidence against a role for inducible nitric oxide synthase in the hyperdynamic circulation of portal-hypertensive rats

Gastroenterology

(1995)

HJ Grossman et al.

Hemodynamic characteristics of the intrahepatic portal vascular bed over an extended flow range: a study in the isolated perfused rat liver

Hepatology

(1995)

H Ring-Larsen et al.

Sympathetic nervous activity and renal and systemic hemodynamics in cirrhosis: plasma norepinephrine concentration, hepatic extraction, and renal release

Hepatology

(1982)

DG Bichet et al.

Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhosis

New Engl J Med

(1982)

M Esler et al.

Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis

Ann Intern Med

(1992)

JS Floras et al.

Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings

Ann Intern Med

(1991)

RJ Groszmann

Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences

Hepatology

(1994)

A Bomzon et al.

The nitric oxide hypothesis and the hyperdynamic circulation in cirrhosis

Hepatology

(1994)

J Reichen

Liver function and pharmacological considerations in pathogenesis and treatment of portal hypertension

Hepatology

(1990)

F Ballet et al.

Differential response of normal and cirrhotic liver to vasoactive agents. A study in the isolated perfused rat liver

J Pharmacol Exp Ther

(1988)

T Zimmermann et al.

Metabolic and hemodynamic responses of bivascularly perfused rat liver to nerve stimulation, noradrenaline, acetylcholine and glucagon in thioacetamide-induced micronodular cirrhosis

Hepatology

(1992)

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Portal vascular responsiveness to sympathetic stimulation and nitric oxide in cirrhotic rats

Abstract

Gastroenterol Clin North Am

Gastroenterology

Gastroenterology

J Hepatol

J Hepatol

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Gastroenterology

Hepatology

Sympathetic nervous activity and renal and systemic hemodynamics in cirrhosis: plasma norepinephrine concentration, hepatic extraction, and renal release

Hepatology

Potential role of increased sympathetic activity in impaired sodium and water excretion in cirrhosis

New Engl J Med

Increased sympathetic nervous activity and the effects of its inhibition with clonidine in alcoholic cirrhosis

Ann Intern Med

Increased sympathetic outflow in cirrhosis and ascites: direct evidence from intraneural recordings

Ann Intern Med

Hyperdynamic circulation of liver disease 40 years later: pathophysiology and clinical consequences

Hepatology

The nitric oxide hypothesis and the hyperdynamic circulation in cirrhosis

Hepatology

Liver function and pharmacological considerations in pathogenesis and treatment of portal hypertension

Hepatology

Differential response of normal and cirrhotic liver to vasoactive agents. A study in the isolated perfused rat liver

J Pharmacol Exp Ther

Metabolic and hemodynamic responses of bivascularly perfused rat liver to nerve stimulation, noradrenaline, acetylcholine and glucagon in thioacetamide-induced micronodular cirrhosis

Hepatology