The renal cytochrome P450 system generates novel arachidonic acid metabolites.
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Animals↗
Biomedical subjects
D Sacerdoti
Publications and source records attributed to D Sacerdoti.
Prognostic indicators of survival in patients with cirrhosis and esophageal varices, without previous bleeding.
Sixty-one patients with cirrhosis with varices without previous bleeding were admitted to our Department over a period of 2 yr. Fifty had alcoholic cirrhosis. Child-Turcotte-Pugh class was A in 11 patients, B in 30, and C in 20. Varices were F1 in 18, and F2-F3 in 43. During follow-up of up to 40 months, one patient was lost to follow-up and 22 patients died, seven of gastrointestinal bleeding and 15 of liver failure. The probability of death from any cause was significantly related to Child-Turcotte-Pugh class, ascites, encephalopathy, s-albumin, s-bilirubin, prothrombin index, and galactose elimination capacity. Independent prognostic variables according to Cox's model resulted s-albumin, s-bilirubin, encephalopathy, and varices. Considering only patients who died from liver failure, survival was univariately related to the same determinants, whereas the Cox's model individuated s-bilirubin, s-albumin, ascites, and galactose elimination capacity as independent prognostic indicators. Considering only patients who died from gastrointestinal bleeding no Cox model could be performed due to the small number of deaths. In patients with F1 varices, the probability of death from liver failure was 5 times higher than that from gastrointestinal bleeding; in patients with F2-F3 varices, liver failure and gastrointestinal bleeding each accounted for approximately half of the deaths. These data could become useful when programming a clinical trial of prophylaxis which considers reduction in mortality as the main end-point.
Adult↗
Renal cytochrome P-450-dependent metabolism of arachidonic acid in spontaneously hypertensive rats.
Renal cytochrome P-450-dependent monooxygenases metabolize arachidonic acid to products some of which affect vascular tone and (Na+,K+)ATPase activity. We measured these metabolites in spontaneously hypertensive (SHR) and control normotensive Wister-Kyoto (WKY) rats. Systolic tail blood pressure in SHR increased from 112 to 202 mm Hg and in WKY from 97 to 136 mm Hg at 5 and 20 weeks respectively. Renal cortical and outer medullary microsomes were incubated with [14C]arachidonic acid; metabolites formed via the cytochrome P-450 pathway were defined as those dependent on NADPH, inhibited by SKF-525A, and unaffected by indomethacin. The P-450-dependent metabolites were higher in SHR vs WKY at 5, 7 and 11 weeks in the cortex and at 7 and 11 weeks in the outer medulla. In the outer medulla, the formation of these metabolites peaked at 7 weeks. Using reverse-phase HPLC, the cytochrome P-450-dependent metabolites were separated into three radioactive peaks: peak I had a retention time of 17.5 min and comigrated as 11,12-dihydroxyeicosatrienoic acid standard. Peak II had a retention time of 19 min and comigrated with omega-hydroxylation compounds. Peak III had a retention time of 27 min and comigrated with 11,12-epoxyeicosatrienoic acid. In the renal cortex, peak I was higher in SHR vs WKY at 5, 7, and 9 weeks and peak III at 5, 7, 9 and 11 weeks. In the outer medulla, peak I was higher in SHR at 5 and 7 weeks, and peaks II and III at 7 weeks. Cytochrome P-450 content in the renal cortex was always higher in SHR vs WKY. We conclude that renal cytochrome P-450-dependent metabolites of arachidonic acid may participate in the circulatory changes of SHR, particularly during the developmental stage.
7-Alkoxycoumarin O-Dealkylase↗
Long-term effect of nadolol on quantitative liver function tests in patients with cirrhosis.
Nadolol, a non-cardioselective beta adrenoreceptor blocking agent, has been reported to decrease portal pressure without affecting liver function in cirrhotic patients treated for 1 month. There were no data about the long-term effects of nadolol on liver function. In 11 patients with cirrhosis and portal hypertension galactose eliminating capacity, aminopyrine metabolic capacity, ICG clearance and IGC intrinsic hepatic clearance according to the "parallel tube" model were measured before and after 6 months of treatment with nadolol at a dose reducing resting heart rate by approximately 25%. No significant variation in any of these parameters was found. Thus 6 months of continuous oral administration of nadolol did not further impair liver function in cirrhotics.
Adult↗
Effects of iloprost, a prostacyclin analog derivative, on renal plasma flow, renal function, and renin-aldosterone system in humans.
The effects of iloprost, a stable analog derivative of prostacyclin, on heart rate, blood pressure, renal plasma flow (RPF), glomerular filtration rate, filtration fraction, urine flow, fractional excretion of sodium (FENa), proximal fractional sodium reabsorption (PFRNa), fractional sodium resorption at the ascending limb of Henle's loop (HFRNa), plasma renin activity (PRA), and plasma aldosterone concentration (PA) were evaluated in patients with peripheral vascular disease and normal renal function. In 10 patients the drug was administered intravenously for 6 hours daily for 6 days at a rate of 1 ng/kg/min. In 7 patients iloprost was also administered at a dose of 2 ng/kg/min for the same time. There was no significant change in heart rate and blood pressure at both iloprost doses. At the dose of 1 ng/kg/min the drug had no effect on renal hemodynamics and function, PRA, and PA. At the dose of 2 ng/kg/min iloprost significantly increased RPF (p less than 0.025) and FENa (p less than 0.025) and significantly decreased HFRNa (p less than 0.025) without affecting glomerular filtration rate, filtration fraction, urine flow, PFRNa, PRA, and PA. No correlation was found between the increase in RPF and FENa (r = 0.01). We conclude that at a dose of 2 ng/kg/min, but not 1 ng/kg/min, iloprost has a natriuretic effect secondary to inhibition of sodium reabsorption at the ascending limb of the Henle's loop and not related to the renal hemodynamic effect.
Aged↗
Novel renal arachidonate metabolites.
Cells of the thick ascending limb of the loop of Henle (TALH) metabolize arachidonic acid (AA) via the cytochrome P450 monooxygenase system to biologically active products that are resolved into two peaks, P1 and P2, on reverse-phase HPLC. Each peak contains materials that have characteristic biological activity. P1 contains a material that relaxes blood vessels and is structurally similar to a vasodilator, the 5,6 epoxyeicosatrienoic acid (EET). P2 contains a material that inhibits cardiac Na+-K+-ATPase, the major component of which has been identified as the 11,12 dihydroxyeicosatrienoic acid. In mTALH cells obtained from rabbits made hypertensive by aortic coarctation, there was a selective increase in P1 and P2 formation compared to other renomedullary cells. We have identified AA metabolites in bovine corneal epithelium with biological properties and chemical features similar to those of mTALH cells. 12(R)hydroxyeicosatetraenoic acid (12(R) HETE) a possible derivative of the 11,12-EET, is produced by the cornea and also has been shown to inhibit Na+-K+-ATPase activity. Renal microsomes obtained from spontaneously hypertensive rats (SHRs) also metabolize AA via a cytochrome P450 monooxygenase pathway to three principal biologically active metabolites that are formed in increased amounts during the developmental phase of hypertension.(ABSTRACT TRUNCATED AT 250 WORDS)
8,11,14-Eicosatrienoic Acid↗
Differential effects of partial hepatectomy on hepatic and renal heme and cytochrome P450 metabolism.
Partial hepatectomy has been suggested to affect hepatic and renal cytochrome P450 content and the related drug metabolizing enzyme system. In addition, cytochrome P450 and its dependent activities have been shown to be regulated by the availability of cellular heme. We, therefore, studied cytochrome P450 in addition to the level of heme oxygenase, the rate-limiting enzyme of heme catabolism, and delta-aminolevulinic acid (ALA) synthase, the rate-limiting enzyme of heme synthesis, in the remnant liver and intact kidneys of rats after two-thirds hepatectomy. The level of hepatic heme oxygenase was elevated threefold in partially hepatectomized rats as compared to sham-operated rats, while ALA synthase was decreased by 40%. This was reflected in decreased hepatic cytochrome P450 content, ie, from 0.689 +/- 0.175 nmole/mg to 0.505 +/- 0.089 nmole/mg protein and associated decreased drug metabolizing enzymes: aryl hydrocarbon hydroxylase, 7-ethoxycoumarin-O-deethylase, and benzphetamine N-demethylase, by 40%, 40%, and 47%, respectively. In contrast, renal heme oxygenase was not changed after hepatectomy, whereas renal ALA synthase was increased by fourfold. Renal cytochrome P450, aryl hydrocarbon hydroxylase, 7-ethoxycoumarin-O-deethylase, and benzphetamine N-demethylase were increased after partial hepatectomy by 84%, 360%, 165% and 406%, respectively. These data indicate that partial hepatectomy decreases liver cytochrome P450 levels by inducing heme oxygenase and inhibiting ALA synthase activities. In this situation the kidney plays a substitutive role in metabolizing endogenous substrates oxygenated by cytochrome P450 isozymes.
Animals↗
Renal effects of nadolol in cirrhosis.
The effects of nadolol on renal haemodynamics and function, and on the renin-angiotensin-aldosterone system and on renal prostaglandin production were studied in eighteen cirrhotics. After 1 month of treatment, nadolol had significantly decreased cardiac output by 25% without affecting arterial pressure, renal plasma flow or renal vascular resistance. Glomerular filtration rate, filtration fraction and the proportion of the cardiac output delivered to the kidneys were significantly increased. The renin-angiotensin-aldosterone system was suppressed and urinary PGE2 excretion was slightly increased. The latter effects were not correlated with those on renal haemodynamics and function.
Cardiac Output↗
Effects of isosorbide dinitrate on portal hypertension in alcoholic cirrhosis.
It has recently been reported that vasodilators lower portal pressure in patients with cirrhosis. This effect, however, is not definitively proven. The effect of isosorbide dinitrate (5 mg sublingually) on splanchnic and systemic hemodynamics was investigated in 13 patients with alcoholic cirrhosis and portal hypertension. The administration of isosorbide dinitrate reduced hepatic venous pressure gradient by 34% (P less than 0.001), mean arterial pressure by 30% (P less than 0.001), cardiac index by 17% (P less than 0.001) and systemic vascular resistance by 11% (P = 0.05). Hepatic blood flow was not affected by the treatment. Significant correlations were found between the decrease in hepatic venous pressure gradient and that of cardiac index (P less than 0.05) and mean arterial pressure (P less than 0.05). These data indicate that isosorbide dinitrate lowers portal pressure in patients with cirrhosis. Decrease in cardiac output, rise in splanchnic arterial vascular resistance and decrease in porto-hepatic resistance seem to participate in determining the effect.
Adult↗
Long-term effects of beta-adrenergic blockade with nadolol on hepatic and renal haemodynamics and function in cirrhotics.
Non-cardioselective beta-blockers are used for prevention of re-bleeding from oesophageal varices in cirrhotics with portal hypertension. Nadolol, a non-cardioselective beta-blocker with a low liposolubility and a low hepatic metabolism, has been demonstrated to decrease portal pressure in cirrhotic patients. Since cirrhotics need long-term treatment, we investigated long-term effects of beta-adrenergic blockade with nadolol on hepatic and renal haemodynamics and function in a group of patients with cirrhosis and portal hypertension. In 19 patients with cirrhosis, after one and six months of treatment with nadolol hepatic venous pressure gradient showed a significant and persistent decrease, averaging 19% and 22%, respectively. Hepatic function and renal haemodynamics and function remained unaffected. Oesophageal varices severity was lowered in 11/19 patients after one month, in 9/16 after six months, in 8/14 after 12 months and in 5/10 after 18 months. Our results showed that, also after long-term treatment, nadolol decreases portal pressure and, in approximately 50% of patients, oesophageal varices severity, without side-effects on liver and renal function.
Adult↗
Nadolol for prevention of variceal rebleeding in cirrhosis: a controlled clinical trial.
Nadolol, a nonselective beta-blocker, has been shown to decrease portal pressure in patients with cirrhosis at the same degree as propranolol. No data are available, however, about its effect on rebleeding rate and mortality in patients undergoing prevention of rebleeding from esophageal varices. A prospective randomized clinical trial was performed in patients with cirrhosis who survived a documented episode of variceal hemorrhage. 12 patients received nadolol, 12 placebo. Patients with child's C grade, tense ascites, renal failure, contraindications to beta-blocker, or age greater than 70 were not included. After a follow-up of up to 145 weeks, 9 patients in the nadolol group and 4 in the placebo group survived free from rebleeding (log-rank test: chi 2 = 4.35, p less than 0.05). Survival was not statistically different in the two groups (1 death in the nadolol group, 3 in the placebo group). In conclusion, nadolol appears to represent an effective therapy in the prevention of variceal rebleeding in cirrhotic patients.
Adult↗
Effect of somatostatin on liver blood flow and liver metabolic activity in patients with cirrhosis.
In a group of 10 patients with cirrhosis, protal hypertension, and previous gastro-intestinal bleedings, hepatic plasma flow, indocyanine green clearance and intrinsic hepatic clearance were determined before and during i.v. infusion of somatostatin (7.5 micrograms/min). The same study protocol was performed in a further seven patients with cirrhosis infused with placebo. All these parameters were significantly decreased by the drug (p less than 0.05; less than 0.01; less than 0.01, respectively) mean decrease being 12, 9 and 8%, respectively, while no significant change occurred in the placebo-infused patients. These data indicate that somatostatin infused at a dose of 7.5 micrograms/min in cirrhotics provokes a slight decrease in hepatic plasma flow and in liver metabolic activity. This effect may contribute to further decrease hepatic removal of harmful substances and may increase systemic concentration of drugs metabolized by the liver.
Adult↗
[Semiquantitative angiographic assessment of portal perfusion in cirrhotic patients: relation to hepatic plasma flow].
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Adult↗
Redistribution of renal blood flow in patients with liver cirrhosis. The role of renal PGE2.
Cirrhotic patients frequently show a decrease in renal blood flow and redistribution of the flow from the outer cortex to the juxtamedullary cortex. The cause of the maintenance of juxtamedullary perfusion is not presently known. Prostaglandin E2 (PGE2) has its vasodilating effect on medullary and juxtamedullary vessels where it is synthesized. Therefore, its increased production, frequently shown in cirrhotics, could be responsible for the relative preservation of juxtamedullary blood flow. To verify this hypothesis we examined 13 cirrhotic patients. In these patients we determined mean renal blood flow (MRBF), blood flow in the 1st compartment (ICBF) and in the 2nd compartment (IICBF) with the 133-Xenon washout technique and PGE2 plasma levels in the renal veins (PGE2V). MRBF and ICBF were significantly reduced as compared to control subjects (P less than 0.01); IICBF resulted unaltered. Significant correlation was found between IICBF and PGE2V (P less than 0.01). Our data confirm the decrease in renal blood flow and the redistribution of intrarenal blood flow in cirrhotic patients. The maintenance of IICBF is likely to be a consequence of PGE2 renal production.
Adult↗
Effect of nadolol on liver haemodynamics and function in patients with cirrhosis.
Beta-adrenoceptor blockers used in the medical management of portal hypertension decrease liver blood flow. The sporadic onset of hepatic encephalopathy during propranolol treatment was ascribed to this decrease. The aim of the present study was to evaluate the effect of chronic treatment with nadolol on liver blood flow and liver function. Nadolol, a non-cardioselective beta-adrenoceptor blocker, has been reported to be as powerful as propranolol in decreasing portal pressure. Before and after 1 month of treatment with nadolol at a dose reducing heart rate by 25%, in 15 cirrhotic patients with portal hypertension, the following parameters were determined: hepatic venous pressure gradient, hepatic blood flow, galactose eliminating capacity, aminopyrine metabolic activity, ICG clearance and intrinsic hepatic clearance. Hepatic venous pressure gradient and hepatic blood flow were decreased by nadolol. However liver function was not affected by the drug. We conclude that, despite a lowered hepatic blood flow, liver function is not affected by 1 month of nadolol treatment.
Adult↗
Blood flow of experimental liver metastases in rat as evaluated by the locally injected 133-Xenon washout.
The investigations on blood flow in liver metastases are interesting from both a pathophysiological and a therapeutic point of view. Available data, however, are few and not definitive, as these studies are complex and difficult to perform. In a group of 25 Sprague-Dawley rats, in which liver metastases of Walker-256 carcinoma had been implanted, the blood flows in a metastasis and in the normal liver surrounding it were determined by means of the locally injected 133-Xenon washout. Thirteen sham-operated rats were a control group. Blood flow in the metastases was decreased as a group compared to that in the normal liver surrounding metastases and to that in liver of sham-operated rats. Small metastases showed normal or increased blood flow, large ones decreased or stagnant blood flow. Moreover, a significant inverse correlation was found between blood flow and diameter of metastasis. It is concluded that liver metastases of Walker-256 carcinoma show a decrease in blood flow which is related to the size of metastasis.
Animals↗
Use of a nonselective beta-blocker, nadolol, in the treatment of portal hypertension in cirrhotics.
Recently a medical treatment with propranolol has been proposed in order to decrease portal pressure and lessen the risk of recurrent gastrointestinal bleeding in cirrhotic patients. No data are available about another beta-blocker, nadolol, which, unlike propranolol, has a low hepatic metabolism, a low lipid solubility, a long serum half-life and does not reduce renal blood flow in patients with arterial hypertension. In 18 cirrhotics with portal hypertension, the effects of nadolol were studied on systemic and hepatic haemodynamics and liver function, at a dosage which reduced the heart rate by 25%. After one month of treatment, a significant decrease in cardiac output, portohepatic gradient and estimated hepatic blood flow were found. The degree of oesophageal varices was reduced in 11 patients, unchanged in the other seven. Hepatic function, evaluated by galactose eliminating capacity, did not change significantly. Although the small number of treated patients does not allow definitive conclusions, nadolol seems to have the features needed to be used in the medical treatment of portal hypertension in patients with liver cirrhosis.
Cardiac Output↗
Effects of nadolol treatment on renal and hepatic hemodynamics and function in cirrhotic patients with portal hypertension.
Twelve cirrhotic patients with portal hypertension and esophageal varices were treated with nadolol for 1 month, and the effects on renal and hepatic hemodynamics and function were studied. A significant decrease in cardiac output, portohepatic gradient, and effective hepatic blood flow was found, whereas mean arterial pressure, liver function, effective renal blood flow, glomerular filtration rate, and urinary sodium and potassium excretions were not affected. In seven patients esophageal varices were also reduced. A significant correlation was found between the decrease in portohepatic gradient and that in cardiac output. The percentage of cardiac output distributed to the kidneys was significantly increased after nadolol treatment. In conclusion, nadolol seems to have properties useful for the treatment of portal hypertension in patients with liver cirrhosis.
Adrenergic beta-Antagonists↗