BMC Pharmacology

, 7:P18 | Cite as

Activation of soluble guanylate cyclase by nitric oxide in lymphocytes correlates with minimal hepatic encephalopathy in cirrhotic patients

  • Vicente Felipo
  • Blanca Piedrafita
  • Amparo Urios
  • Miguel A Serra
  • A del Olmo
  • José M Rodrigo
  • Carmina Montoliu
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Keywords

Nitric Oxide Liver Disease Cognitive Impairment Liver Cirrhosis Hepatic Encephalopathy 

Background

Altered modulation of cGMP levels in brain seems to be responsible for the impairment of some types of cognitive function [1]. The homeostasis of cGMP is also strongly altered in blood in patients with liver disease, who show increased plasma cGMP but reduced cGMP content in lymphocytes [2]. Activation of soluble guanylate cyclase by NO is also altered in lymphocytes of patients with liver cirrhosis [2]. This suggests that alterations in cGMP homeostasis in blood could reflect the alterations in brain and be therefore associated with the appearance of minimal hepatic encephalopathy (MHE). The aim was to assess whether there is a correlation between the alterations in different parameters involved in modulation of cGMP levels and the presence of MHE.

Methods

We studied in 46 patients with liver cirrhosis and 26 controls the performance in the PHES battery of psychometric tests, critical flicker frequency (CFF), cGMP in plasma and lymphocytes, activation of guanylate cyclase by NO in lymphocytes, ammonia, nitric oxide metabolites and atrial natriuretic peptide (ANP).

Results

Activation of guanylate cyclase by NO in lymphocytes and cGMP in plasma were higher and CFF lower in patients with than without MHE. Ammonia, ANP and metabolites of nitric oxide were higher in patients than in controls but were no different in patients with or without MHE (Figures 1, 2, 3, 4; Table 1).
Figure 1

Critical flicker frequency.

Figure 2

Plasma cGMP.

Figure 3

Basal cGMP in lymphocytes.

Figure 4

NO-induced increase in cGMP in lymphocytes.

Table 1

Values of the different parameters analyzed in controls and in patients.

PARAMETERS

CONTROLS Media ± SD (n)

PATIENTS WITHOUT MHE p vs. Control

PATIENTS WITH MHE P vs. control

PATIENTS WITH MHE p vs. without MHE

Basal cGMP in lymphocytes (pmoles/mg prot)

0.47 ± 0.15

(n = 26)

0.049 ± 0.02

(n = 22) p < 0.001 **

0.025 ± 0.015

(n = 12) p < 0.001 **

p > 0.05

SNAP-induced cGMP increase (fold)

12 ± 6

(n = 26)

31 ± 15

(n = 23) p < 0.001 **

47 ± 18

(n = 12) p < 0.001 ***

p < 0.05 *

cGMP in Plasma (μM)

4.4 ± 1.7

(n = 17)

12 ± 4

(n = 24) p < 0.001 **

18 ± 4

(n = 12) p < 0.001 ***

p < 0.001 **

Nitrates + Nitrites (μM)

22 ± 9

(n = 26)

31 ± 13

(n = 31) p < 0.05*

38 ± 14

(n = 13) p < 0.001 ***

p = 0.09

(ns)

ANP in Plasma (pg/ml)

78 ± 13

(n = 13)

119 ± 25

(n = 14) p < 0.001 **

140 ± 50

(n = 9) p < 0.001**

p = 0.193

(ns)

Ammonia concentration (μM)

76 ± 30

(n = 23)

156 ± 86

(n = 23) p = 0.001 ***

151 ± 51

(n = 9) p < 0.001 ***

p = 0.89

(ns)

CFF (Hz)

46 ± 3

(n = 26)

41 ± 3

(n = 24) p < 0.001 ***

33 ± 4

(n = 15) p < 0.001 **

p < 0.001 **

SCORE PHES

-0.15 ± 1

(n = 26)

-0.57 ± 1

(n = 31)

-8.7 ± 2.1

(n = 15)

p < 0.001 **

Age

43 ± 12

50 ± 8

55 ± 11

p > 0.05

(ns)

Conclusion

Alteration in activation of guanylate cyclase by NO in lymphocytes correlates with PHES performance, CFF and ammonia levels (Table 2). This suggests that altered modulation of guanylate cyclase by NO in lymphocytes would reflect a parallel alteration in brain occurring in patients with MHE that would be involved in their cognitive impairment.
Table 2

Correlations between different parameters analysed.

CORRELATION WITH

PARAMETER

PHES

CFF

AMMONIA

cGMP in plasma

NO

p = 0.06, r = -0.235

YES

p = 0.004, r = -0.368

YES

p = 0.011, r = 0.386

cGMP in lymphocytes

NO

p = 0.67, r = -611

YES

p = 0.029, r = -0.281

NO

p = 0.28, r = -0.165

Activation of sGC by

NO

YES

p = 0.004, r = -0.369

YES

p < 0.0001, r = -0.544

YES

p = 0.003, r = 0.433

Ammonia

NO

p = 0.28, r = -0.156

YES

p = 0.021, r = 0.333

 

References

  1. 1.
    Erceg S, Monfort P, Hernandez-Viadel M, Llansola M, Montoliu C, Felipo V: Restoration of learning ability in hyperammonemic rats by increasing extracellular cGMP in brain. Brain Res. 2005, 1036: 115-121. 10.1016/j.brainres.2004.12.045.CrossRefPubMedGoogle Scholar
  2. 2.
    Montoliu C, Kosenko E, Del Olmo JA, Serra MA, Rodrigo JM, Felipo V: Correlation of nitric oxide and atrial natriuretic peptide changes with altered cGMP homeostasis in liver cirrhosis. Liver Int. 2005, 25: 787-795. 10.1111/j.1478-3231.2005.01066.x.CrossRefPubMedGoogle Scholar

Copyright information

© Felipo et al; licensee BioMed Central Ltd. 2007

This article is published under license to BioMed Central Ltd.

Authors and Affiliations

  • Vicente Felipo
    • 2
  • Blanca Piedrafita
    • 2
  • Amparo Urios
    • 2
  • Miguel A Serra
    • 1
  • A del Olmo
    • 1
  • José M Rodrigo
    • 1
  • Carmina Montoliu
    • 1
  1. 1.Servicio de HepatologíaHospital Clínico Universitario, Departamento de Medicina, Universidad de ValenciaValenciaSpain
  2. 2.Laboratory of NeurobiologyCentro de Investigacion Principe FelipeValenciaSpain

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