Hemodynamic, metabolic and hormonal responses to oral glibenclamide in patients with cirrhosis receiving glucose.

BACKGROUND: In patients with cirrhosis, glucose may induce splanchnic and renal vasodilation. Since the antidiabetic sulfonylurea glibenclamide is known to induce splanchnic and renal vasoconstriction in portal hypertensive animals, this drug may inhibit glucose-induced hemodynamic responses in patients with cirrhosis. The aim of the present study was to investigate, in patients with cirrhosis, the short-term effects of glibenclamide on hemodynamic and humoral responses to glucose. METHODS: Patients were randomly assigned to receive either glibenclamide (5-mg tablet) or a placebo. All patients received an infusion of 10% glucose (62.5 ml/h for 12 h) that was started at the same time as glibenclamide or placebo administration. Studies were performed prior to and 90 min after glibenclamide or placebo. RESULTS: Glibenclamide (i.e. glibenclamide plus glucose) significantly increased plasma insulin concentrations and glycemia while placebo (i.e. glucose alone) significantly increased glycemia but did not change plasma insulin levels. Glibenclamide did not significantly change the hepatic venous pressure gradient while this value was significantly increased following glucose alone. Glibenclamide did not significantly change renal blood flow and glomerular filtration rate while glucose alone significantly increased renal blood flow without affecting the glomerular filtration rate. Glibenclamide significantly decreased cardiac index while glucose alone did not change this value. CONCLUSIONS: In patients with cirrhosis receiving glucose, glibenclamide blunted glucose-induced splanchnic and renal vasodilation. In addition, glibenclamide per se induced a decrease in cardiac index. These findings should be taken into account when glibenclamide is administered to patients with cirrhosis and type 2 diabetes.

Aortic hyporeactivity to norepinephrine induced by lipopolysaccharide in cirrhotic rats: beneficial effects of a non-steroidal anti-inflammatory drug coupled with a nitric oxide donor.

BACKGROUND AND AIMS: Cirrhosis is associated with a hyperdynamic syndrome and arterial vasodilation that is related to nitric oxide (NO) synthase 3 overactivity. Septic shock is frequently associated with cirrhosis and with a vascular induction of NO synthase 2. The aims of this study were to compare the effects of lipopolysaccharide (LPS) in normal and cirrhotic rats, and to test the effects of a nonsteroidal anti-inflammatory drug (NSAID) coupled with a (NO) donor. METHODS: Cirrhotic rats received NO-flurbiprofen, flurbiprofen or vehicle followed by LPS or placebo 15 min later. The heart rate and mean arterial pressure of rats were monitered for 5 h. Thoracic aortic rings were removed and contracted with the use of norepinephrine. Nitric oxide synthase activity was measured in the aorta and stomach of cirrhotic rats. RESULTS: Arterial pressure decreased in cirrhotic rats in the vehicle/LPS and flurbiprofen/LPS groups. After LPS administration, the heart rate of rats increased in all groups. In the aortic rings, LPS induced hyporeactivity to norepinephrine in all groups except the NO-flurbiprofen group. This hyporeactivity was abolished after preincubation with Nw-nitro-L-arginine (L-NNA). Nw-nitro-L-arginine had no effect on norepinephrine-induced vasoconstriction in the NO-flurbiprofen/LPS group. Nitric oxide synthase 2 activity in the stomach and aorta of cirrhotic rats was increased in each group except in the NO-flurbiprofen group after LPS administration. Pretreatment with NO NSAID prevented aortic hyporeactivity to norepinephrine in cirrhotic rats treated with LPS as it probably inhibited the NO synthase 2 induction. CONCLUSIONS: These findings suggest that NO-flurbiprofen has a beneficial hemodynamic effect in cirrhotic rats and may help to prevent LPS aortic hyporeactivity.

Fulminant hepatitis A in patients with chronic liver disease.

Fulminant hepatitis is a rare complication of acute hepatitis A virus (HAV) infection. We report three cases of fulminant hepatic failure with death due to HAV infection in patients with pre-existing chronic liver disease. Data from the literature also indicate a high case fatality rate during HAV superinfection in patients with chronic hepatitis B, particularly those with cirrhosis, and in patients with alcoholic cirrhosis. In patients with chronic hepatitis C, results are conflicting with some reports indicating a high fatality rate of HAV superinfection and others not, irrespective of the presence or absence of cirrhosis. Based on our observations and this review of the literature, we suggest that patients with chronic liver disease should be vaccinated against hepatitis A.

Relationship between vascular reactivity in vitro and blood flows in rats with cirrhosis.

In cirrhosis there is a hyperdynamic circulation, which occurs mainly in the systemic and splanchnic regions. Using isolated-vessel models, previous studies have shown reduced aortic reactivity to vasoconstrictors in rats with cirrhosis. The aim of the present study was to evaluate and compare the vascular responsiveness to phenylephrine in arterial rings and the blood flows from different regions in rats with cirrhosis and controls. Reactivity was studied in isolated thoracic aortic, superior mesenteric arterial and carotid arterial rings from sham-operated and bile-duct-ligated rats by measuring the cumulative concentration-dependent tension induced by phenylephrine (10(-9)-10(-4) M). Blood flows were measured by the radioactive microsphere method. In rats with cirrhosis, a significant hyporeactivity to phenylephrine was observed in both the aorta and the superior mesenteric artery compared with the corresponding arteries of normal rats. This hyporesponsiveness was corrected by N(omega)-nitro-L-arginine (0.1 mM). In contrast, carotid artery reactivity and the responses to N(omega)-nitro-L-arginine were similar in the cirrhotic and control groups. In each case, cardiac output and mesenteric arterial blood flow were significantly higher in cirrhotic than in normal rats. Cerebral blood flows were not significantly different between the two groups. In cirrhotic rats, arterial hyporeactivity may be a consequence of increased regional blood flow and increased production of nitric oxide.

Elevated circulating cardiac troponin I in patients with cirrhosis.

It has been shown that certain patients with cirrhosis have asymptomatic cardiac abnormalities that have not yet been explained. Thus, cardiac troponin I, a specific marker of myocardial injury, has been measured in patients with cirrhosis without previous cardiac disease. Thirty-two consecutive patients (age 49 +/- 11) with cirrhosis and normal ECG were selected, 22 of which were alcoholic. Hemodynamic investigations were performed. Left ventricular function and mass were evaluated by echocardiography. Serum creatine kinase MB mass, myoglobin, and cardiac troponin I concentrations were measured. Cardiac troponin I concentrations were elevated in 10 patients (32%) (range 0.06-0.25 microg/L) whereas creatine kinase MB mass and myoglobin were normal in all patients. Abnormal troponin I values were not related to the severity of cirrhosis, to the degree of portal hypertension, or to other hemodynamic values. In contrast, elevated serum cardiac troponin I concentrations were related to a decreased stroke-volume index (P <. 05) and a decreased left ventricular mass (P <.05). These results show a high prevalence of slightly elevated serum cardiac troponin I in patients with cirrhosis, especially in those with alcoholic cirrhosis. Elevated troponin I is associated with subclinical left ventricular myocardial damage. These findings may be linked to a lack of left ventricular adaptation in certain patients with cirrhosis and alcoholic cardiomyopathy.