Low doses of isosorbide mononitrate attenuate the postprandial increase in portal pressure in patients with cirrhosis

Abstract

Postprandial hyperemia is associated with a significant increase in portal pressure in cirrhosis, which may contribute to progressive dilation and rupture of gastroesophageal varices. In cirrhosis, an insufficient hepatic production of nitric oxide (NO) may impair the expected hepatic vasodilatory response to increased blood flow, further exaggerating the postprandial increase in portal pressure. This study was aimed at investigating whether low doses of an oral NO donor might counteract the postprandial peak in portal pressure. Twenty-three portal hypertensive cirrhotics, 8 of them under propranolol therapy, were randomized to receive orally 5-isosorbide mononitrate (ISMN; 10 mg; n ‫؍‬ 11) or placebo (n ‫؍‬ 12) and a standard liquid meal 15 minutes later. S everal studies have shown that, in normal subjects, food intake induces marked changes in splanchnic hemodynamics. [1][2][3][4][5] The main finding is a postprandial increase in splanchnic blood flow, caused by splanchnic arteriolar vasodilatation occurring in the submucosal and mucosal layers of the small intestine. This postprandial splanchnic vasodilatation and hyperemia occur owing to the interaction of intrinsic mechanisms (such as changes in arteriolar transmural pressure and/or increase in vasodilator tissue metabolites) and extrinsic mechanisms (action of autonomic nervous system) and to the effect of gastrointestinal hormones. [1][2][3][4]6,7 On the other hand, in cirrhotic patients, the postprandial hyperemia determines a significant increase of portal and collateral blood flow, which results in an increased hepatic venous pressure gradient (HVPG). 3,[7][8][9][10][11][12][13][14][15] This is observed rapidly, the maximum changes in splanchnic hemodynamics being observed at 30 minutes after the meal, returning to basal levels at 120 minutes. 3,8,9,[11][12][13][14] These data suggest that, in cirrhotic patients, the repeated increase in portal venous pressure because of food intake may contribute to the progressive portal-systemic collateral dilation and to the development and dilation of the varices that eventually lead to variceal bleeding.Propranolol administration has been reported to reduce the postprandial peak in portal pressure, 10 but sub-

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

“…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. 39,40 In humans this has been attempted by the administration of low doses of isosorbide-5-mononitrate 8 or by modulating the post-translational regulation of eNOS by simvastatin. 9 However, the strategy of increasing NO bioavailability by reducing its degradation has not been addressed so far.…”

“…A 7 F balloon-tipped catheter (Medi-Tech; Boston Scientific Cork Ltd., Cork, Ireland) was then advanced into the main right hepatic vein to measure wedged and free hepatic venous pressures as previously described. 8,9 Preceded by a priming dose of 5 mg, a solution of indocyanine green (Pulsion Medical Systems, Munich, Germany) was infused intravenously at a constant rate of 0.2 mg/min. After an equilibration period of at least 40 minutes, 4 separate sets of simultaneous samples of peripheral and hepatic venous blood were obtained for the measurement of hepatic blood flow (HBF) as previously described.…”

“…The hepatic vascular resistance (dyne ⅐ s ⅐ cm Ϫ5 ) was estimated as HVPG (mmHg) ϫ 80/HBF (L/min). 8,9 The systemic vascular resistance (dyne ⅐ s ⅐ cm Ϫ5 ) was calculated as MAP (mmHg) Ϫ right atrial pressure, mmHg ϫ 80/CO (L/ min).…”

“…3 g, intravenously in 100 mL saline during 15 minutes, n ϭ 15) or placebo (100 mL saline solution 0.9%, n ϭ 12), followed by a mixed liquid meal (400 mL) containing 26 g proteins, 74 g carbohy-drates, and 21 g lipids for a total of 613 kcal (85 g of Scandishake Mix, International SHS, Spain; plus 25 g Resource Protein Instant, Novartis, Spain and 16 g sucrose), which was ingested within approximately 5 minutes. The test meal used in the current study was a homemade equivalent to that used in our previous studies (Ensure plus®), 8,9 modified to be free of ascorbic acid and other antioxidants. The 3-g dose of ascorbic acid has been shown to revert endothelial dysfunction in other vascular disorders 20,22 by scavenging superoxide.…”

“…Thus, the liver with cirrhosis, unlike a normal liver, cannot accommodate a volume load, such as that caused by meals, which results in an abrupt postprandial increase in portal pressure. 8 Recent studies have shown that such increase can be attenuated by increasing hepatic NO delivery. 8,9 Altogether these data suggest an insufficient NO bioavailability as the cause of the impaired vasorelaxation in response to blood flow, which define what is known as endothelial dysfunction.…”