Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications
Abstract
:1. Introduction
2. Current Research Directions in Components of the NO-cGMP Pathway in Experimental Liver Damage
3. Role of the NO-cGMP Pathway in PH Pathophysiology
- These drugs are potential therapeutic alternatives for portal hypertension.
- PDE-5 inhibitors or sGC modulators may be useful for reversal of liver fibrosis/cirrhosis, as shown in animal studies.
- PDE-5 inhibitors are a promising therapy of hepatic encephalopathy in liver cirrhosis.
- Serum levels of cGMP can be used as a simple non-invasive marker of clinically significant portal hypertension.
4. Modulation of the NO-cGMP Pathway in a Healthy and Cirrhotic Liver
4.1. Effect in Portal Hypertension
4.2. Targeting the NO-cGMP Pathway May Contribute to Reversal of Liver Fibrosis/Cirrhosis
4.3. Role of Inhibitors of PDE-5 or Modulators of sGC in Hepatic Encephalopathy
4.4. Plasma/Serum cGMP as a Potential Marker of Clinically Significant Portal Hypertension (CSPH)
5. Conclusions
Funding
Institutional Review Board Statement
Informed Consent Statement
Data Availability Statement
Conflicts of Interest
Abbreviations
NO | nitric oxide |
GTP | guanosine triphosphate |
cGMP | cyclic guanosine monophosphate |
PKG | protein kinase G |
CaMKII | calcium/calmodulin-dependent protein kinase II |
eNOS | endothelial NO synthase |
nNOS | neuronal NO synthase |
sGC | soluble guanylate cyclase |
PDE-5 | phosphodiesterase-5 |
PDE-5-I | phosphodiesterase-5-inhibitor |
CSPH | clinically significant portal hypertension |
ANP | atria natriuretic factor |
MELD | Model End Stage Liver Disease |
HE | hepatic encephalopathy |
PVP | portal venous pressure |
MAP | mean arterial pressure |
PPHTN | porto-pulmonary hypertension |
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Model | Compound | Dosage and Route | ΔMAP | ΔPVP | Remarks | |
---|---|---|---|---|---|---|
Colle 2004 [63] | Wistar rats, BDL | Sildenafil | 0.01–10 mg/kg, i.v. | −1–20% even more in sham rats | +2– +6% even more in sham rats | |
Halverscheid 2009 [54] | Sprague-Dawley rats, non-cirrhotic | Sildenafil Vardenafil | 1, 10, or 100 µg/kg, i.v. 1, 10, or 100 µg/kg, i.v. | 1.1; −3.9; −2.6% −11.0; −8.7; −7.4% | In all groups no increase, but decrease over time | 3.3; 24.1; 18.3% 15.9; 29.2; 23.9% increase in portal flow |
Schaffner 2018 [42] | Wistar rats, TAA | Sildenafil | 0.1–1.0 mg/kg, i.v. | −14–−17% | −13–−19% | |
Uschner 2020 [43] | Sprague-Dawley rats, BDL or CCL4 | Udenafil Udenafil/propranolol Udenafil 1 or 5 mg/kg | 1 or 5 mg/kg 1 mg/kg | 1 mg/kg: −20%; 5 mg/kg: −22% −7.5% 1 mg/kg: −31%; 5 mg/kg: −34% | −30–−23% −40% −30–−0% | Significant reduction of portal pressure |
Lee 2010 [47] | Sprague-Dawley rats, BDL | Sildenafil, 1 week | 0.25 mg/kg twice daily p.o. | −25% | ||
Choi 2009 [55] | Sprague-Dawley rats, BDL | Udenafil for 3 weeks | 1, 5, or 25 mg/kg p.o. | −14, −13, −31% | ||
Deibert 2006 [56] | Human, cirrhotic (n = 18) | Vardenafil | 10 mg, p.o. | −19% (n = 5) | Hepatic arterial resistance and portal flow increased significantly | |
Bremer 2007 [57] | Human, cirrhotic PPHTN (n = 1) | Tadalafil | 10 mg, p.o. | −30% | Pulmonary arterial pressure −25% | |
Lee 2008 [58] | Human, cirrhotic (n = 7) | Sildenafil | 50 mg, p.o. | Unchanged | +1% | Pulmonary arterial and sinusoidal resistance significantly reduced |
Clemmesen 2008 [59] | Human, cirrhotic (n = 10) | Sildenafil | 50 mg, p.o. | −14% | −11% | |
Tandon 2010 [60] | Human, Cirrhotic (n = 12) | Sildenafil | 25 mg, p.o. | −8% | −4% n.s. | Dose of Sildenafil too low |
Kreisel 2015 [61] | Human, cirrhotic (n = 30) | Udenafil | 12.5; 25; 50; 75; 100 mg p.o. acute 6 days | −3.5; −4.5; −7.5; −25.1; −17.3%−14.4; 3.1; −14.0; −13.5; −16.8% | Significant reduction of HVPG with ≥75 mg Udenafil in the acute setting and after 6 days | |
Deibert 2018 [62] | Human, cirrhotic (n = 1) | Vardenafil Tadalafil | 10 mg 5 mg | −11% | −14% −15% | Sustaining reduction of HVPG > 10 months |
Schwabl [41] | BDL rats, CCl4, BDL | Riociguat | −20% in early cirrhosis | Improvement offibrosis | ||
Brusilovskaya [48] | BDL cirrhosis | Tadalafil Riociguat Cineciguat | 1.5 mg/kg bw 0.5 mg/kg bw 1 mg/kg bw | −20% −40% no effect | cGMP + 40% cGMP + 239% |
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Kreisel, W.; Lazaro, A.; Trebicka, J.; Grosse Perdekamp, M.; Schmitt-Graeff, A.; Deibert, P. Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. Int. J. Mol. Sci. 2021, 22, 10372. https://doi.org/10.3390/ijms221910372
Kreisel W, Lazaro A, Trebicka J, Grosse Perdekamp M, Schmitt-Graeff A, Deibert P. Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications. International Journal of Molecular Sciences. 2021; 22(19):10372. https://doi.org/10.3390/ijms221910372
Chicago/Turabian StyleKreisel, Wolfgang, Adhara Lazaro, Jonel Trebicka, Markus Grosse Perdekamp, Annette Schmitt-Graeff, and Peter Deibert. 2021. "Cyclic GMP in Liver Cirrhosis—Role in Pathophysiology of Portal Hypertension and Therapeutic Implications" International Journal of Molecular Sciences 22, no. 19: 10372. https://doi.org/10.3390/ijms221910372