Cyclooxygenase-derived products modulate the increased intrahepatic resistance of cirrhotic rat livers

Abstract

In cirrhotic livers, increased resistance to portal flow, in part due to an exaggerated response to vasoconstrictors, is the primary factor in the pathophysiology of portal hypertension. Our aim was to evaluate the response of the intrahepatic circulation of cirrhotic rat livers to the I n cirrhotic livers, increased resistance to portal blood flow is the primary factor in the pathophysiology of portal hypertension. 1 This increased resistance is determined in part by the architectural distortion of the hepatic structure caused by cirrhosis. However, substantial evidence shows that a dynamic component, caused by the active contraction of vascular and extravascular contractile cells, plays a major role in further increasing intrahepatic resistance. 2 This dynamic component of hepatic vascular resistance is believed to be the consequence of an imbalance between the vasodilator/vasoconstrictor forces that regulate hepatic vascular tone. 1 In addition, the hepatic vascular resistance of cirrhotic livers exhibits a hyperresponse to several vasoconstrictors, such as endothelin 1, 3 norepinephrine, 4 or leukotriene D 4 . 5 Nitric oxide blunts the response of the hepatic vascular bed to several vasoconstrictors, 6 and its production is decreased in the cirrhotic liver. It is therefore possible that an insufficient availability of NO 7 could account for the hyperresponse to vasoconstrictors observed in cirrhotic livers.In addition, it has been shown that the activation of G protein-coupled receptors, such as those for ␣ 1 -adrenergic agonists, vasopressin, or endothelin 1, stimulates release of arachidonic acid, leading to the formation of its vasoactive-derived metabolites, including prostaglandins (PGs), thromboxanes (TXs), and leukotrienes. [8][9][10] Cyclooxygenase (COX)

Ascorbic acid improves the intrahepatic endothelial dysfunction of patients with cirrhosis and portal hypertension

“…2,4 This latter component, which results from an insufficient hepatic bioavailability of NO 5,30 and an increased production of circulating and local vasoconstrictors (angiotensin, endothelin, cysteinyl-leukotrienes, thromboxane, and prostaglandins, among others), [31][32][33][34][35] is theoretically amenable to treatment with vasodilators. 36 Attempts to correct the intrahepatic NO deficiency in experimental cirrhosis have involved NOS overexpression by transfecting the liver with adenovirus encoding eNOS, nNOS, or constitutively active AKT 10,37,38 or by selective NO donors.…”

Increased intrahepatic resistance in severe steatosis: endothelial dysfunction, vasoconstrictor overproduction and altered microvascular architecture

“…21,22 Increase in TXA2 production and cyclooxygenase overexpression have been demonstrated in perfusion models in rats. 37,38 The increase in TXAS points towards an increase in TXA2 production in rats with severe steatosis. ET-1, which mainly acts as a vasoconstrictor via the ET A receptor on smooth muscle cells, is also overexpressed in rats with severe steatosis, and its serum concentration is elevated.…”

The eNOS cofactor tetrahydrobiopterin improves endothelial dysfunction in livers of rats with CCl4 cirrhosis

“…Endothelial nitric oxide synthase (eNOS) uncoupling due to deficiency of tetrahydrobiopterin (BH 4 ) results in decreased production of NO and plays a major role in endothelial dysfunction in other conditions. We examined whether eNOS uncoupling is involved in the pathogenesis of endothelial dysfunction of livers with cirrhosis.…”

“…Endothelial dysfunction, characterized by an impairment in the endothelium-dependent response to vasodilators, is considered one of the mechanisms leading to the increased vascular tone of livers with cirrhosis 2 and has been attributed to reduced NO bioavailability 3 and to increased release of COX-1-derived vasoconstrictive prostanoids. 4 The unconjugated pterin cofactor (6R)-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH 4 ) plays a crucial role in the regulation of eNOS activity. In the absence of BH 4, NOS cannot catalyze L-arginine oxidation 5,6 ; rather, it receives electrons from NADPH and donates them to O 2 , resulting in the formation of superoxide anion (O 2 Ϫ ) instead of NO, leading to reduced NO bioavailability.…”

“…4 The unconjugated pterin cofactor (6R)-L-erythro-5, 6, 7, 8-tetrahydrobiopterin (BH 4 ) plays a crucial role in the regulation of eNOS activity. In the absence of BH 4, NOS cannot catalyze L-arginine oxidation 5,6 ; rather, it receives electrons from NADPH and donates them to O 2 , resulting in the formation of superoxide anion (O 2 Ϫ ) instead of NO, leading to reduced NO bioavailability. This situation is known as NOS "uncoupling."…”