Portal hypertensive-associated variceal bleeding in advanced cirrhosis carries a high mortality, and thus the landmark observation by Lebrec et al.  that beta-blockade with propranolol could significantly reduce the incidence of first variceal bleeding has defined the standard of care for the last three decades. Numerous mechanistic studies and clinical trials have followed showing that administration of non-selective beta-blockers (NSBB) results in both a decrease in cardiac output, because of β1 adrenoceptor blockade, and in addition a blockade of vasodilatory β2 receptors in the splanchnic circulation, resulting in decreased splanchnic blood flow, collectively lowering portal pressure. However, the lack of receptor selectivity with these agents leads to adverse events limiting the tolerance to this class of agent, and also partially accounts for the reported limited efficacy of NSBB, which is around 40–50 per cent. Moreover, experimental data in rodent models show that β1 receptors are relatively down-regulated in cirrhosis with a greater predominance of β2, perhaps also suggesting that the dose of NSBB is likely to be important and that in clinical studies, lack of clarity of achieving optimal dose may further cloud the interpretation of efficacy data.
As our knowledge of the pathobiology of cirrhosis has advanced over recent decades, so have our therapeutic aims in patients with portal hypertension. Elegant studies by several groups have showed that as well as increased splanchnic and portal inflow, increased intrahepatic resistance is central to the development of portal hypertension [3, 4]. Moreover, nitric oxide (NO) has been shown to be a key mediator of intrahepatic vascular tone, and that intrahepatic resistance in cirrhosis is partly because of endothelial dysfunction and decreased NO bioavailability. Indeed, several lines of investigation suggest that increased intrahepatic resistance may be the principal event signalling to the splanchnic and mesenteric vasculature, and may, therefore, precede the development of splanchnic vasodilatation in cirrhosis . More recent studies suggest that the presence of inflammation or/and infection exacerbates portal hypertension, in part, through further impact on endothelial dysfunction and increased intrahepatic resistance and underpins the rationale for use of antibiotics incorporated into guidelines for the management of variceal bleeding [6-9]. Collectively, informed by this greater mechanistic knowledge and with recent advances in cardiovascular pharmacology, attention has turned to new targets for therapy.
Whilst the first and second generation β-blockers have no significant ancillary properties, more recent generations of β-blockers may be selective or non-selective for β1 or β2 adrenoceptors, but in addition possess important further properties. Amongst these, Nebivolol and Carvedilol have been studied most intensively. Nebivolol is a highly selective β1-blocker with additional vasodilatory properties, acting through several pathways, which may include action on the β3 receptor. β3 adrenoceptor expression and its associated signalling G-protein alpha-s subunit have been noted to be increased in hepatic and mesenteric arteries of cirrhotic BDL rats, with consequent moderation of cAMP and calcium mobilization, resulting in vasodilation, in addition to promoting increased cGMP. This mechanism is thought to be most relevant in advanced stages of disease, when catecholamine levels are at their highest, perhaps perpetuating splanchnic vasodilatation. Traditional NSBB such as propranolol are believed to have little effect on β3 receptors.
In contrast, carvedilol is a non-selective B-blocker with additional α1 adrenoceptor-blocking properties, counteracting intrahepatic tonic vasoconstriction and augmenting the portal pressure lowering effect of NSBBs, as well as reducing portal-collateral blood flow (as with all other NSBBSs). However, these vasodilatory effects are not liver-specific, and therefore the potential exists for systemic hypotension, activation of renin–angiotensin and exacerbation of sodium and fluid retention in cirrhosis. The importance of unchecked tonic activities of the alpha adrenergic pathway in portal hypertension are highlighted by the observation of Villaneuva et al. that addition of the α1 blocking agent, Prazosin, to Nadolol has a greater effect on hepatic venous pressure gradient (HVPG) lowering than Nadolol plus nitrate donation through isosorbide mononitrate .
This said, the efficacy of carvedilol in the management of portal hypertension related bleeding has demonstrated a HVPG reduction between 16 and 43% vs. 12–13% with propanolol. Subsequently, two small RCTs have shown some efficacy in the use of carvedilol to prevent recurrent variceal haemorrhage [11, 12]. However, both of these studies have some limitations, especially in relation to the excess re-bleeding rates they describe. However, principally, concerns remain regarding the systemic circulatory effects of carvedilol in cirrhotic patients.
In this issue of the journal, Reiberger et al. have focused on Nebivolol as an alternative agent for the reduction of portal pressure in cirrhosis . Their elegant study shows that Nebivolol produces a paradoxical rise in portal pressure, principally through aggravation of the splanchnic vasodilation seen in cirrhosis, and that this appears to be a dose-responsive effect. Their data focus on the promotion of nitric oxide generation especially within the splanchnic bed as an explanation for the portal pressure rise. A limitation perhaps of this study is that it is not able to elucidate the exact mechanism by which this increased generation of splanchnic NO is facilitated, compared to the very modest (and beneficial) increase in intrahepatic NO. However, the literature would suggest that Nebivolol can activate eNOS and increase NO bioavailability, through actions at many levels. These mechanisms include augmented phosphorylation of eNOS , and reduction in the endogenous inhibitor of eNOS, asymmetric dimethylarginine (ADMA), a key mediator of elevated intrahepatic vascular tone in cirrhosis . These properties would make Nebivolol a potentially attractive agent for reducing intrahepatic resistance and in the treatment of portal hypertension.
It is therefore of interest that Reiberger and colleagues found that one week of Nebivolol treatment counter-intuitively, worsened portal hypertension in the well-established BDL rat model of cirrhosis. This finding was supported by flow data, demonstrating a dose-dependent increase in splanchnic flow in the Nebivolol treated groups, along with increased splanchnic NOx levels, suggesting higher NO bioavailability. Hepatic NOx production was also marginally increased, suggesting that intrahepatic NO generation was also enhanced, but not to the degree of increased splanchnic NO generation. Thus, this study elegantly highlights an important principle for the ideal therapeutic agent for portal hypertension – namely the effects on endothelial function must be liver-specific, because of the paradox of increased systemic/splanchnic NO but decreased intrahepatic NO in cirrhosis. Moreover, the relationship of significantly lowering intrahepatic resistance, whilst maintaining critical organ perfusion (including the liver) is central to efficient lowering of portal pressure and improving outcome. Thus, despite the fact that NSBBs remain the standard of care in cirrhosis and portal hypertension, several investigators have demonstrated decreased liver blood flow in patients on NSBBs, which may have functional consequences. Indeed, in patients with advanced cirrhosis, especially those with refractory ascites, a large retrospective study suggests increased mortality with NSBB, and this may in part result from systemic haemodynamic effects such as through increased post-paracentesis related circulatory dysfunction . Therefore, there remains considerable clinical interest in the development of alternate strategies to modify portal pressure.
Although liver-specific delivery of NO donors has not proven effective in portal hypertension, the liver-specific targeting of other NO modifying pathways is possible with novel molecular techniques. Interestingly, the authors found increased hepatic NOx generation with Nebivolol, but not through a mechanism altering intrahepatic redox stress. Although ADMA levels were not measured in this study, modifying intrahepatic ADMA is an example of an approach to improving intrahepatic endothelial dysfunction without reducing mean arterial pressure .
In conclusion, this important study adds to emerging data demonstrating the potential problems with systemic β-blocker therapies in cirrhosis and portal hypertension. Future therapies for portal hypertension must address the paradox of liver and splanchnic NO generation in cirrhosis – too much or not enough – ensuring maintenance of liver blood flow, whilst achieving effective reduction in intrahepatic resistance.