Enhanced vasodilatation to endothelin antagonism in patients with compensated cirrhosis and the role of nitric oxide

Abstract

Background and aims: Patients with advanced cirrhosis have systemic vasodilatation and increased nitric oxide (NO) production despite activated vasopressor systems, including the endothelin system. The aims of this study were to assess the contribution of endogenous endothelin 1 (ET-1) and NO to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis (n=7) and in age and sex matched healthy controls (n=7).

Methods: Using venous occlusion plethysmography, forearm blood flow (FBF) responses to subsystemic locally active intra-arterial infusion of BQ-123 (a selective endothelin type A receptor (ET(A)) receptor antagonist; 10 nmol/min) were measured before and during application of an "NO clamp": a balanced co-infusion of L-N(G)-monomethyl-arginine (a selective NO synthase inhibitor) and sodium nitroprusside (an exogenous NO donor) to block endogenous NO production and restore NO mediated basal FBF, respectively.

Results: L-NMMA infusion produced a reduction in FBF (p<0.001) which was similar in both groups. Before applying the "NO clamp", BQ-123 caused an increase in FBF in both groups (p<0.001) that was greater in patients with cirrhosis (p<0.01). During the "NO clamp", BQ-123 induced vasodilatation was abolished in controls and attenuated in patients (p<0.001) but remained significantly greater in patients with cirrhosis (p<0.01).

Conclusions: These findings indicate a greater ET(A) mediated contribution of endogenous ET-1 to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis. In addition, enhanced vasodilatation to ET(A) receptor antagonism in cirrhosis cannot be entirely attributed to NO release but is likely to be related to reversal of direct ET-1 mediated tone.

Figure 1

Schematic diagram of the study protocols. F=Bilateral forearm blood flow measurements each for three minutes. BQ-123 was given at 10 nmol/min.l-N^G-monomethyl-arginine (l-NMMA) was given at 4 μmol/min. Sodium nitroprusside (SNP) was given at titrated doses ranging from 80 to 600 ng/min to achieve a stable blood flow close to the baseline value. *Time for blood sampling; †time for measuring vascular bioimpedance.

Figure 2

Percentage change in forearm blood flow (FBF) after BQ-123 infusion (10 nmol/min for 60 minutes) in patients with cirrhosis and controls, with and without application of the “NO clamp”. p<0.001 for each response except with “NO clamp” in controls (one way ANOVA). ***p<0.001 without “NO clamp” versus with “NO clamp” in patients with cirrhosis and controls (two way ANOVA with repeated measures); **p<0.01 patients versus controls with or without “NO clamp” (two way ANOVA with repeated measures).