The paradox of nitric oxide in cirrhosis and portal hypertension: Too much, not enough

Abstract

C hronic liver diseases are often characterized by portal hypertension, an important component of which is increased intrahepatic vascular resistance (IHVR). We have long understood that structural changes, viewed by light microscopy, are largely irreversible with our current therapeutic tools. In supplementing liver histology with liver and vascular physiology, we have encountered the existence of dynamic, nonstructural components that are in fact, reversible.Bhatal et al. first showed in in-vitro perfused cirrhotic rat livers, that nitroprusside and papaverine reduced portal resistance up to 15%. This change represents up to 28% of the magnitude by which the IHVR of the cirrhotic liver exceeds that of normal livers. 1 Interestingly the magnitude of effect in the diseased liver seems to be similar for different vasodilators, whereas it is almost negligible in the normal liver. 2 This difference shows the presence of an enhanced intrinsic vascular tone in the intrahepatic microvascular bed of the cirrhotic liver that is not present in nondiseased livers.For years, nitrovasodilators were in clinical use as vasorelaxants before a mechanism of action was uncovered. Investigators identified nitric oxide (NO), an endothelium-derived relaxing factor, in 1987. 3 It is now established that NO is a key factor in the hemodynamic abnormalities associated with liver cirrhosis and chronic portal hypertension. Owing to the lack of a basement membrane and to the presence of fenestrae, sinusoidal endothelial cells are anatomically and biologically distinct from endothelial cells in other vasculature. They are, however, similar to other endothelial cells in that they produce and release NO. 4 By means of sinusoidal and other endothelial cells, the liver modulates local intrahepatic vascular tone and resistance and determines the physiological adaptation or pathophysiological dysfunction of the intrahepatic microcirculation.Under physiologic and tightly regulated conditions, nitric oxide synthases (NOS) generate NO. Alterations in the synthesis of NO, which is seen in cirrhosis, may therefore form a basis for future developments in its therapy. Furthermore, the development of optimal potential therapy is dependent on a detailed knowledge of the chemistry and metabolism of NO, and especially the diverse effects it induces. Therefore, the purpose of this review is to (1) summarize the chemical reactions in which NO participates and the effects mediated by those reactions, (2) give a short overview of the regulation of NOS, and (3) to outline the available data and current concepts regarding the involvement of NO in the hemodynamic abnormalities associated with liver cirrhosis. By no means, in this review, are we denying the participation of other mediators not only in the increased intrahepatic vascular resistance (e.g., endothelins) but also in the vasodilatation and hyperdynamic state observed in the splanchnic (e.g., anandamide) and systemic circulation (e.g., sodium and water retention). However, the focus of this review is NO.

Hemostatic balance in patients with liver cirrhosis: Report of a consensus conference

“…In cirrhosis, endothelial dysfunction has been surmised by the observation of changes in levels of nitric oxide-derived by-products [61,62], flow mediated vasodilatory response of the brachial artery [63] and VWF levels [64][65][66][67][68]. Currently, there is no single marker that can detect endothelial dysfunction in patients with cirrhosis.…”

Pregnancy with Portal Hypertension

“…9 In patients suffering from liver cirrhosis, splanchnic arterial vasodilatation occurs, due to an increased local release of nitric oxide and other vasodilators related to portal hypertension, resulting in severely impaired circulatory function. 10,11 Consequently compensatory mechanisms essential in maintenance of arterial pressure in cirrhotic patients, unfortunately result in development of marked hemodynamic disturbances known as hyperdynamic syndrome. The pregnant woman has a 20-27% chance of esophageal bleed which increases markedly in case she has demonstrable varices.…”

Atorvastatin lowers portal pressure in cirrhotic rats by inhibition of RhoA/Rho-kinase and activation of endothelial nitric oxide synthase

“…4,5 Increased sensitivity of the intrahepatic microcirculation to vasoconstrictors [4][5][6][7] and decreased levels of the vasodilator nitric oxide (NO) and its downstream signaling cyclic guanosine 3Ј,5Ј-monophosphate (cGMP)/protein kinase G (PKG) are responsible for this elevated contractile state. 4,8,9 We previously showed that increased RhoA/ Rho-kinase signaling essentially contributes to increased intrahepatic resistance as well as increased sensitivity to vasoconstrictors in rats with secondary biliary cirrhosis. 10 The RhoA/Rho-kinase pathway is involved in vasoconstrictor-induced contraction of vascular smooth muscle.…”