Hyperdynamic mesenteric circulation in cirrhosis: humoral or neural mechanism?

Portal hypertension is associated with hyperdynamic circulation which is comprised of increased cardiac output and decreased peripheral resistance, i.e. peripheral vasodilatation. Vasodilatation, particularly in the splanchnic circulation, may contribute to the pathogenesis of many complications in cirrhosis such as ascites, oesophageal varices and encephalopathy. However, the mechanism of vasodilatation is not clear. There are currently two theories to explain this phenomenon; one is the humoral factor hypothesis. This theory contends that in cirrhosis, portosystemic collaterals allow gut-derived humoral substances, such as glucagon 1, bile acid 2 and calcitonin gene-related peptide (CGRP) 3 to directly enter the systemic circulation without detoxification by the liver. Moreover, portosystemic shunts also allow gut-derived endotoxemia which stimulate local vasodilators such as prostaglandins, nitric oxide (NO) and carbon monoxide. These local vasodilators in turn induce hyperdynamic circulation in portal hypertension. Among them, nitric oxide is the most intensively investigated factor. NO, an endothelial-derived relaxing factor, is perhaps the most important vasodilator that mediates the excessive arterial vasodilatation in portal hypertension 4. In the splanchnic vascular bed of rats with portal hypertension, an overproduction of NO responsible for vasopressor hyposensitivity has been clearly demonstrated 5. Furthermore, inhibition of NO production reduces portosystemic shunting and largely prevents the development of the hyperdynamic circulation 6 However, NO cannot entirely explain the hyperdynamic circulation. Using eNOS/iNOS double knockout mice, Iwakiri et al. showed that these mice still develop hyperdynamic circulation after portal vein stenosis 7. Another theory is neural dysregulation. The cardiovascular system is controlled by neural influences that include the central nervous system (CNS) and peripheral afferent and efferent nerves. In the brainstem and hypothalamus, cardiovascular-regulatory nuclei include the nucleus of the solitary tract (NTS), paraventricular nucleus, ventrolateral medulla and supraoptic nucleus. The neural theory proposes that portal hypertension activates receptors (chemoreceptors? baroreceptors?) in the mesenteric area; the signals are relayed to central cardiovascular-regulatory nuclei via afferent nerves. These nuclei then process the inputs and send out signals to the cardiovascular system through efferent pathways. In the CNS, neurons that have been activated show nuclear Fos (the protein product of the immediate-early gene c-fos) staining by immunohistochemistry. Lee's lab has demonstrated that neurons in the CV-regulatory nuclei listed above show persistent activation in portal hypertensive and cirrhotic rats 8, 9. Using capsaicin to denervate the primary afferent nerves, Lee and Sharkey in 1993 first demonstrated that capsaicin-treated portal hypertensive and cirrhotic rats normalized their abnormal cardiac output and systemic vascular resistance 10. Capsaicin itself did not cause any haemodynamic disturbance in sham-operated rats. Capsaicin-treated portal-hypertensive rats did not demonstrate a splanchnic or renal hyperaemia. The authors suggested that capsaicin treatment blocked the generalized vasodilatation in cirrhotic and portal hypertensive rats. This study elucidated that afferent nerves are essential for the development of the hyperdynamic circulation in portal hypertension 10. After confirming the importance of afferent innervation on hyperdynamic circulation in portal hypertension, we further demonstrated that the signals were relayed to higher central neural regulatory areas via the vagal nerve 11. We also showed that early gene (c-fos) activation in the CNS is a prerequisite for the development of hyperdynamic circulation in portal hypertension; when c-fos antisense was injected into the NTS, the hyperdynamic circulation was abrogated in portal vein-ligated (PVL) rats 12. However, the exact relationship between efferent nerves and hyperdynamic circulation remains unclear. Ezkurdia et al.'s work published in this issue 13 addresses this question. In a previous microarray study, they had found that a group of genes implicated in neurotransmission, especially adrenergic transmission, is significantly downregulated in mesenteric arteries of PVL and cirrhotic rats. This sympathetic neural downregulation could partially contribute to chronic splanchnic vasodilation 14. Tyrosine hydroxylase is a well-accepted marker of sympathetic activity. Using in situ hybridization and immunohistochemistry, they showed that tyrosine hydroxylase mRNA and protein expression in superior mesenteric ganglial cells and inside axonal fibres surrounding superior mesenteric artery were significantly decreased in PVL rats. Moreover, the number of nervous structures, total nervous area and tyrosine hydroxylase-stained nervous area were significantly reduced in PVL rats. These structural changes had a strong correlation with haemodynamic parameters, mainly with mesenteric arterial resistance 15. Although it is well known that the sympathetic nervous system is activated in cirrhotic patients and animal models 16, sympathetic activity in the splanchnic territory has been generally neglected. Ezkurdia et al. had previously demonstrated sympathetic atrophy in superior mesenteric ganglion in PVL rats 13. Correcting sympathetic dysfunction in the mesenteric bed would be expected to decrease portal hypertension and alleviate hyperdynamic circulation. Neuropeptide Y (NPY) is co-stored and co-released with norepinephrine, and augments α1-adrenergic vasoconstriction. Intravenous injection of NPY corrected the vasodilation in splanchnic arteries, ameliorated portal hypertension and hyperdynamic circulation in cirrhotic rats 17. In this study 13, Ezkurdia et al. used capsaicin to denervate afferent nerves. They confirmed the findings of Lee and Sharkey that after portal vein stenosis the capsaicin-treated rats do not develop hyperdynamic circulation. The novel finding of Ezkurdia's study is that capsaicin prevented sympathetic atrophy in the mesenteric bed and simultaneously blocked the mesenteric vasodilatation in portal hypertension. Thus, the study provides new insight into the mechanism of gut hyperaemia and the balance of vasodilation and constriction in mesenteric arteries. Another finding is that capsaicin did not impact nNOS. Although capsaicin decreased CGRP, this did not affect the splanchnic vascular tone in either portal hypertensive or sham-control rats. This further suggests that it is the sympathetic atrophy that plays a major role in mesenteric hyperaemia in portal hypertension, rather than a direct effect of a humoral factor. Vasodilators, at least CGRP and nNOS in this study, appear to be unimportant in mesenteric hyperaemia in prehepatic portal hypertension. Hyperdynamic circulation involves three factors: cardiac output, blood flow and vascular resistance. Does capsaicin have any affect on blood flow/cardiac output? Lee and Sharkey had demonstrated that capsaicin reverses the increased cardiac output in both prehepatic portal hypertension and cirrhotic rats 10. BDL-cirrhotic rats have increased cardiac output and renal blood flow, decreased systemic vascular resistance, arterial pressure, renal vascular resistance, and glomerular filtration rate, and develop ascites. We previously demonstrated that neonatal capsaicin treatment completely blocks the development of hyperdynamic circulation and ascites, and improves renal function in cirrhotic rats 18. These circulatory ameliorations were associated with abrogation of brainstem neuronal activation in capsaicin treated cirrhotic rats 18. These observations indicate that sodium retention and ascites formation is also dependent on the intact afferent innervation. Consistent with the above study 18, Coll et al. showed that the nervous structure and protein expression of sympathetic nerves in renal arteries of capsaicin treated rats showed no differences between sham-control and PVL rats 15. These data raise questions about the sympathetic status of other parts of the body. Is the mesentery the only area where the sympathetic system is defunctionalised? This highlights one of the limitations of this study, that the authors generally confined their haemodynamic measurements to the splanchnic circulation. Cardiovascular variables measured included the mean arterial pressure, and superior mesenteric artery blood flow and resistance, but not the cardiac output. Therefore, peripheral vascular resistance cannot be calculated and the systemic hyperdynamic circulation is not really evaluated. The previous work in neural mechanisms and the current study strongly suggest that it is the portal hypertension that activates the CNS via the afferent nerves, and central neural activation further results in the sympathetic atrophy associated with mesenteric vasodilatation. Thus, neuronal integrity is a sine qua non for the development of the hyperdynamic circulation in portal hypertension.

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