Abstract
BackgroundThe NO - cGMP system plays a key role in the regulation of sinusoidal tonus and liver blood flow with phosphodiesterase-5 (PDE-5) terminating the dilatory action of cGMP. We, therefore, investigated the effects of PDE-5 inhibitors on hepatic and systemic hemodynamics in rats.MethodsHemodynamic parameters were monitored for 60 min. after intravenous injection of sildenafil and vardenafil [1, 10 and 100 μg/kg (sil1, sil10, sil100, var1, var10, var100)] in anesthetized rats.ResultsCardiac output and heart rate remained constant. After a short dip, mean arterial blood pressure again increased. Systemic vascular resistance transiently decreased slightly. Changes in hepatic hemodynamic parameters started after few minutes and continued for at least 60 min. Portal (var10 -31%, sil10 -34%) and hepatic arterial resistance (var10 -30%, sil10 -32%) decreased significantly (p < 0.05). At the same time portal venous (var10 +29%, sil10 +24%), hepatic arterial (var10 +34%, sil10 +48%), and hepatic parenchymal blood flow (var10 +15%, sil10 +15%) increased significantly (p < 0.05). The fractional liver blood flow (total liver flow/cardiac output) increased significantly (var10 26%, sil10 23%). Portal pressure remained constant or tended to decrease. 10 μg/kg was the most effective dose for both PDE-5 inhibitors.ConclusionLow doses of phosphodiesterase-5 inhibitors have distinct effects on hepatic hemodynamic parameters. Their therapeutic use in portal hypertension should therefore be evaluated.
Highlights
The Nitric oxide (NO) - cyclic guanosine monophosphate (cGMP) system plays a key role in the regulation of sinusoidal tonus and liver blood flow with phosphodiesterase-5 (PDE-5) terminating the dilatory action of cGMP
Perisinusoidal stellate cells (Ito-cells) regulate sinusoidal tonus depending on concentration of NO synthesized by the sinusoidal endothelial cells
In a previous clinical pilot study we showed that the PDE5 inhibitor vardenafil increases portal venous flow in nor
Summary
The NO - cGMP system plays a key role in the regulation of sinusoidal tonus and liver blood flow with phosphodiesterase-5 (PDE-5) terminating the dilatory action of cGMP. The diameter of liver sinusoids is responsible for up to 1/3 of the intrahepatic vascular resistance and is regulated by an interplay of endothelial cells, hepatocytes and stellate cells [6,7]. NO is synthesized by endothelial cells and activates soluble guanylate cyclase of stellate cells This results in the formation of cGMP that regulates the tonus of stellate cells and sinusoids [8,9]. This action is terminated by phosphodiesterase-5 (PDE-5), which converts cGMP to 5'-GMP [10,11]. Data from the same group suggest an interplay between hepatic NO synthesis and heme oxygenase-1 regulation [16]
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