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AIM:

To measure circulating angiotensins at different stages of human cirrhosis and to further evaluate a possible relationship between renin angiotensin system (RAS) components and hemodynamic changes.

METHODS:

Patients were allocated into 4 groups: mild-to-moderate liver disease (MLD), advanced liver disease (ALD), patients undergoing liver transplantation, and healthy controls.

Blood was collected to determine plasma renin activity (PRA), angiotensin (Ang) I, Ang II, and Ang-(1-7) levels using radioimmunoassays.

During liver transplantation, hemodynamic parameters were determined and blood was simultaneously obtained from the portal vein and radial artery in order to measure RAS components.

RESULTS:

• PRA and angiotensins were elevated in ALD when compared to MLD and controls (P < 0.05).
• In contrast, Ang II was significantly reduced in MLD. Ang-(1-7)/Ang II ratios were increased in MLD when compared to controls and ALD.
• During transplantation, Ang II levels were lower and Ang-(1-7)/Ang II ratios were higher in the splanchnic circulation than in the peripheral circulation (0.52 ± 0.08 vs 0.38 ± 0.04, P < 0.02), whereas the peripheral circulating Ang II/Ang I ratio was elevated in comparison to splanchnic levels (0.18 ± 0.02 vs 0.13 ± 0.02, P < 0.04).
• Ang-(1-7)/Ang II ratios positively correlated with cardiac output (r = 0.66) and negatively correlated with systemic vascular resistance (r = -0.70).

CONCLUSION:

Our findings suggest that the relationship between Ang-(1-7) and Ang II may play a role in the hemodynamic changes of human cirrhosis.

Keywords: Renin-angiotensin system, Liver cirrhosis, Angiotensin-(1-7), Angiotensin II, Splanchnic circulation, Angiotensin converting enzyme 2

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INTRODUCTION

The renin angiotensin system (RAS) is now viewed as a dual system composed of 2 arms: vasoconstriction encompassing angiotensin converting enzyme (ACE)-angiotensin (Ang) II-Ang II type 1 (AT₁) receptor and vasodilation encompassing ACE2-Ang-(1-7)-Mas receptor.

The ACE2-Ang-(1-7)-Mas receptor arm mainly acts as a counter-regulatory mechanism to the vasoconstrictor arm[¹].

According to this novel concept, the final functional effect of the RAS may reflect a balance between these 2 arms[^2–4].

Apart from the circulating RAS, the existence of local systems has been described in a number of organs, including the liver[⁵].

These local systems act in response to various physiological and pathophysiological stimuli, and the locally generated angiotensins have been implicated in the modulation of cell growth and proliferation, generation of reactive oxygen species, hormone secretion, and in the control of local inflammation and fibrosis[⁶].

The circulating RAS is well recognized for its role in hemodynamic regulation through Ang II, a potent vasoconstrictor, and the counter-regulatory peptide, Ang-(1-7), a vasodilator.

The local and circulating RAS can interact with each other and with other regulatory systems[⁷].

Liver cirrhosis has 2 major circulatory dysfunctions: portal hypertension and a hyperdynamic circulation characterized by elevated cardiac output and low systemic vascular resistance[⁸].

It is well established that Ang II plays a role in the pathogenesis of portal hypertension by increasing intrahepatic vascular resistance and also by contributing to liver fibrosis[⁵].

The development of portal hypertension in cirrhosis is associated with arterial vasodilation in the splanchnic circulation, leading to a decrease in systemic vascular resistance[⁹].

Early in the course of the disease, the decrease in systemic vascular resistance is compensated by the development of a hyperdynamic circulation[¹⁰].

Despite a reduction in systemic vascular resistance, the effective arterial blood volume remains normal, as does the circulating RAS components and antidiuretic hormone[⁸].

However, as the disease progresses and arterial vasodilation increases, the hyperdynamic circulation is insufficient to correct the effective arterial hypovolemia[⁸].

hypotension develops, leading to activation of the circulating RAS, sympathetic nervous system and secretion of antidiuretic hormone[⁸].

The splanchnic circulation is resistant to the effect of Ang II, noradrenaline and vasopressin, and the maintenance of arterial pressure is a result of vasoconstriction in extra-splanchnic vascular areas[⁸].

Liver cirrhosis has been studied recently in light of the new view of the RAS. It is becoming clear that the RAS can influence liver cirrhosis through its 2 main arms.

While the ACE-Ang II-AT1 receptor arm contributes to liver tissue injury and fibrosis[⁶] and the maintenance of basal vascular tonus in non-compensated cirrhosis[¹¹], the activation of the ACE2-Ang-(1-7)-Mas arm exerts anti-fibrotic actions[^6,12,13].

In addition, it has been speculated that this counter-regulatory arm also has a role in the arterial vasodilation in liver cirrhosis[¹⁴].

In this regard, we have recently shown that chronic treatment with propranolol in cirrhotic patients was characterized by marked changes in the precursors of the RAS cascade (renin and Ang I), with repercussions on the 2 main RAS components, Ang II and Ang-(1-7), in the splanchnic and peripheral circulations[¹⁵].

Our previous data suggested that a possible therapeutic approach for advanced human cirrhosis could be the combination of a beta-blocker with an AT₁ receptor blocker or ACE inhibitor[¹⁵].

Therefore, the aim of the present study was to evaluate circulating levels of angiotensins in mild-to-moderate and advanced stages of human cirrhosis without the interference of any kind of RAS blockade such as beta-blockers, ACE inhibitors and AT₁ receptor blockers.

In addition, we also evaluated a correlation between RAS peptides and hemodynamic parameters in systemic and splanchnic circulations of cirrhotic patients during liver transplantation.

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World J Gastroenterol. 2009 May 28; 15(20): 2512–2519.

Walkíria Wingester Vilas-Boas, Jerusa Almeida, Ana Paula Nadu, Robson Augusto Souza dos Santos, Laboratory of Hypertension, Department of Physiology, Biological Sciences institute, Federal University of Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG, 31270-901, Brazil Antônio Ribeiro-Oliveira Jr, Renata da Cunha Ribeiro, Laboratory of Endocrinology, Department of Medicine, Faculty of Medicine, Federal University of Minas Gerais, Av. Alfredo Balena, 190, Belo Horizonte, MG, 30130-100, Brazil Regina Maria Pereira, Hospitalar Foundation of the State of Minas Gerais, FHEMIG, Belo Horizonte, MG, Brazil Ana Cristina Simões e Silva, Department of Pediatrics, Faculty of Medicine, Federal University of Minas Gerais, Av. Alfredo Balena, 190, Belo Horizonte, MG, 30130-100, Brazil

Author contributions: Vilas-Boas WW, Santos RAS designed the study; Vilas-Boas WW, Ribeiro RC, Almeida J, Nadu AP performed the research; Vilas-Boas WW, Ribeiro-Oliveira Jr A, Pereira RM, Simões e Silva AC analyzed the data; Vilas-Boas WW, Ribeiro-Oliveira Jr A, Pereira RM, Simões e Silva AC, Santos RAS wrote the paper. Correspondence to: Robson Augusto Souza dos Santos, Laboratory of Hypertension, Department of Physiology, Biological Sciences institute, Federal University of Minas Gerais, Av. Antonio Carlos, 6627, Belo Horizonte, MG, 31270-901, Brazil.

robsonsant@gmail.com World J Gastroenterol. 2009 May 28; 15(20): 2512–2519. Published online 2009 May 28. doi: 10.3748/wjg.15.2512.

SEE FULLTEXT

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2686910&tool=pmcentrez

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