Abstract
Liver cirrhosis is a frequent condition with high impact on patients’ life expectancy and health care systems. Cirrhotic portal hypertension (PH) gradually develops with deteriorating liver function and can lead to life-threatening complications. Other than an increase in intrahepatic flow resistance due to morphological remodeling of the organ, a functional dysregulation of the sinusoids, the smallest functional units of liver vasculature, plays a pivotal role. Vascular tone is primarily regulated by the nitric oxide-cyclic guanosine monophosphate (NO-cGMP) pathway, wherein soluble guanylate cyclase (sGC) and phosphodiesterase-5 (PDE-5) are key enzymes. Recent data showed characteristic alterations in the expression of these regulatory enzymes or metabolite levels in liver cirrhosis. Additionally, a disturbed zonation of the components of this pathway along the sinusoids was detected. This review describes current knowledge of the pathophysiology of PH with focus on the enzymes regulating cGMP availability, i.e., sGC and PDE-5. The results have primarily been obtained in animal models of liver cirrhosis. However, clinical and histochemical data suggest that the new biochemical model we propose can be applied to human liver cirrhosis. The role of PDE-5 as potential target for medical therapy of PH is discussed.
Highlights
The two cyclic nucleotides cyclic adenosine monophosphate and cyclic guanosine monophosphate are intracellular second messengers regulating important metabolic or regulatory pathways
In this review we extend this view on the nitric oxide-cyclic guanosine monophosphate (NO-cyclic guanosine monophosphate (cGMP)) pathway in liver cirrhosis with more current data suggesting a focus-shift from NO availability to cGMP availability
The current view of pathophysiology of portal hypertension (PH) has led to the hypothesis of the “NO-paradox” which describes a reduced NO availability inside the liver and an elevated NO production in the peripheral systemic circulation, necessitating a tailored therapeutic approach
Summary
The two cyclic nucleotides cyclic adenosine monophosphate (cAMP) and cyclic guanosine monophosphate (cGMP) are intracellular second messengers regulating important metabolic or regulatory pathways. They are formed by adenylate cyclases (ACs) or guanylate cyclases (GCs) and degraded by phosphodiesterases (PDEs). PH often occurs in patients suffering from liver cirrhosis It is defined as an increase in portal venous pressure (PVP), which is partly caused by disturbed regulation of sinusoidal tone. The latter, in turn, is controlled primarily by the NO-cGMP pathway. The role of PDE-5 as potential target for medical therapy of PH is discussed
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