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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 (ETA) receptor antagonist; 10 nmol/min) were measured before and during application of an NO clamp”: a balanced co-infusion of l-NG-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 ETA mediated contribution of endogenous ET-1 to the maintenance of basal forearm vascular tone in patients with preascitic cirrhosis. In addition, enhanced vasodilatation to ETA 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.

  • forearm blood flow
  • L-NMMA
  • nitric oxide clamp
  • BQ-123
  • vascular reactivity
  • ET-1, endothelin 1
  • ETA receptor, endothelin type A receptor
  • ETB receptor, endothelin type B receptor
  • NO, nitric oxide
  • l-NMMA
  • l-NG-monomethyl-arginine
  • eNOS, endothelial nitric oxide synthase
  • SNP, sodium nitroprusside
  • MAP, mean arterial pressure
  • HR, heart rate
  • FBF, forearm blood flow
  • CI, cardiac index
  • SI, stroke index
  • TPVRI, total peripheral vascular resistive index
  • BMI, body mass index

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