Substance P Is Markedly Increased in Plasma of Patients With Hepatic Coma

Hörtnagl, Heide; Lenz, Kurt; Singer, Ernst A.; Kleinberger, G; Lochs, Herbert

doi:10.1016/s0140-6736(84)92851-4

Cited by 82 publications

(25 citation statements)

References 19 publications

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“…Thus, in cirrhosis and portal hypertension, gastrointestinal derived vasodilatory substances, such as glucagon, vasoactive intestinal polypeptide,32 substance P,33vasodilatory prostaglandins (PGE 2 and prostacyclin),34 and endotoxins,35 which are normally removed by the liver, enter the systemic circulation via shunting through the collateral vessels. It is generally believed that an increase in the circulating levels of these gastrointestinally derived vasoactive agents in cirrhosis and portal hypertension may be responsible for peripheral vasodilatation and splanchnic pooling characteristic of this condition.…”

Section: Discussionmentioning

confidence: 99%

Hepatosplanchnic haemodynamics and renal blood flow and function in rats with liver failure

Javlé

Yates

Kynaston

et al. 1998

Gut

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C aminopyrine breath test).Results-Progressive liver dysfuntion was accompanied by the development of a hyperdynamic circulation, a highly significant decrease in renal blood flow and function, and an increase in intrarenal shunting 36, 42, and 48 hours after administration of D-galactosamine. The alterations in renal blood flow and function were accompanied by significant increases in portal pressure, portal venous inflow, and intrahepatic portal systemic shunting in galactosamine treated rats compared with controls. There was a significant correlation between changes in renal blood flow and changes in portal pressure, intrahepatic portal systemic shunting, and deterioration in liver function (r=0.8, p<0.0001). Conclusions-The results of this study suggest that both increased intrahepatic portal systemic shunting and hepatocyte impairment may contribute to alterations in renal haemodynamics and function. (Gut 1998;43:272-279)

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Section: Discussionmentioning

confidence: 99%

Hepatosplanchnic haemodynamics and renal blood flow and function in rats with liver failure

Javlé

Yates

Kynaston

et al. 1998

Gut

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“…Activation of the sympathetic tone is required for the maintenance of systemic blood pressure in the face of compromised cardiac output and marked peripheral vasodilation. Peripheral vasodilation is thought to be the result of substance P from the intestinal tract [17,26], which escapes clearance by the diseased liver. Peripheral vasodilation in liver disease may also be caused by bacterial endotoxin [49], which, again, escapes hepatic inactivation [30,52].…”

Section: Renal Failure Secondary To Alterations In Systemic Haemodynamentioning

confidence: 99%

New clues to the pathophysiology of hepatorenal failure

1993

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In patients with advanced liver disease, decreases in renal blood flow, glomerular filtration rate, and urinary output are frequently observed. The deterioration in renal function is usually not due to a unique cause but is the result of the concerted action of several mechanisms operating in parallel; decreased plasma protein formation and increased intrahepatic vascular resistance lead to sequestration of blood volume, favoring hypovolemia and reduction in cardiac output. At the same time enhanced formation of nitroxide leads to peripheral vasodilation; bacterial endotoxin escaping clearance by the diseased liver stimulates the expression of a long-acting nitroxide synthase. Furthermore, vasodilating intestinal mediators such as substance P escape inactivation by the liver. In the face of peripheral vasodilation the maintenance of blood pressure requires an increase in cardiac output, which is achieved by activation of sympathetic nervous tone, renal vasoconstriction, enhanced release of renin, angiotensin, aldosterone, and antidiuretic hormone, leading to renal retention of sodium and water. Renal vasoconstriction is opposed by vasodilatatory prostaglandins, and renal failure may be triggered by inhibition of prostaglandin formation. On the other hand, vasoconstrictive eicosanoids, such as thromboxane B2 and leukotriene E2, which escape hepatic inactivation, may contribute to renal vasoconstriction. Beyond these mechanisms disturbed hepatic regulation of renal function may participate in the generation of hepatorenal syndrome. The liver regulates renal function via both a hepatorenal reflex decreasing renal blood flow and a hypothetical liver-borne diuretic factor increasing renal blood flow. Both enhanced hepatorenal reflex activity and decreased formation of the liver-borne diuretic factor could participate in the pathogenesis of hepatorenal syndrome.

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“…There was no correlation of plasma SP with the occurrence or severity of itch. Increased SP levels have been reported before in patients with hepatic coma [22] and in patients with liver cirrhosis [23,24]. Similarly, tryptase release by mast cells is thought to be associated with itch signaling by activation of the PAR2 receptor.…”

Section: Resultsmentioning

confidence: 80%

The Molecular Mechanism of Cholestatic Pruritus

Elferink

Kremer

Martens

et al. 2011

Dig Dis

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Pruritus is a frequent symptom in patients with cholestatic liver diseases. Pruritus can be excruciating and, in rare cases, become a primary indication for liver transplantation. The molecular mechanism of itch signal transduction is largely unclear. It was our hypothesis that compounds which accumulate in the circulation during cholestasis act as direct or indirect pruritogens by affecting signaling in itch fibers. To test this, we screened plasma samples of a large group of patients with various cholestatic conditions for their capacity to activate neuroblastoma cells. Quite strikingly, we found that samples from itchy cholestatic patients caused a significantly higher activation than samples from non-itchy cholestatic patients and healthy controls. Purification revealed lysophosphatidic acid (LPA) as the active compound. LPA is a very potent signaling lipid that can activate cells through various LPA receptors. Subsequently, we could demonstrate that cholestatic patients with pruritus have highly elevated levels of serum autotaxin (ATX), the enzyme that converts lysophosphatidylcholine into LPA. This is a striking finding as ATX has never been connected to itch perception thus far. We have also shown that LPA, when injected intradermally, causes itching in mice. On the basis of our results, we hypothesize that during cholestasis, expression of ATX is induced and gives rise to increased local formation of LPA near unmyelinated nerve endings of itch fibers. LPA then activates these neurons through one of the LPA receptors, which in turn potentiates action potentials along itch fibers.

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Substance P Is Markedly Increased in Plasma of Patients With Hepatic Coma

Cited by 82 publications

References 19 publications

Hepatosplanchnic haemodynamics and renal blood flow and function in rats with liver failure

Hepatosplanchnic haemodynamics and renal blood flow and function in rats with liver failure

New clues to the pathophysiology of hepatorenal failure

The Molecular Mechanism of Cholestatic Pruritus

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