Cytochrome P-450-dependent metabolites of arachidonic acid (AA) increased in the kidneys of young, spontaneously hypertensive rats (SHRs) during the period of rapid elevation of blood pressure (BP) but not in adult SHRs or in Wistar Kyoto rats (WKYs) with normal BP. Treatment of SHRs and WKYs with stannous chloride (SnCl2), which selectively depletes renal cytochrome P-450, restored BP to normal, coincident with a natriuresis, in young but not in adult SHRs and did not affect either BP or sodium excretion in WKYs. Depletion of renal cytochrome P-450 was associated with decreased generation of these AA metabolites only in young SHRs. The antihypertensive effect of SnCl2 in young SHRs was greatly reduced by prevention of its cytochrome P-450-depleting action.

Renal and hormonal responses were studied in a group of healthy individuals fed, in random order, for three weeks, a vegetable protein diet (N = 10), an animal protein diet (N = 10), or an animal protein diet supplemented with fiber (N = 7), all containing the same amount of total protein (chronic study). In seven additional subjects the acute renal, metabolic and hormonal response to ingestion of a meat or soya load of equivalent total protein content was investigated (acute study). In the chronic study GRF, RPF and fractional clearance of albumin and IgG were significantly higher on the animal than the vegetable protein diets (GFR: 121 +/- 4 vs. 111 +/- 4 ml/min/1.73 m2, P less than 0.001; RPF: 634 +/- 29 vs. 559 +/- 26 ml/min/1.73 m2, P less than 0.001; theta alb: 19.5 +/- 3.1 vs. 10.2 +/- 1.6 x 10(-7), P less than 0.01; theta IgG: 11.6 +/- 3.1 vs. 7.5 +/- 1.7 x 10(-7), P less than 0.05). Renal vascular resistance was lower on the animal than vegetable protein diet (82 +/- 5 vs. 97 +/- 5 mmHg/min/liter; P less than 0.001). Fiber supplementation to APD did not have any effect on the renal variables measured which were indistinguishable from APD. In the acute study, GFR and RPF both rose significantly by approximately 16% (P less than 0.005) and approximately 14% (P less than 0.05), respectively, after the meat load, while RVR fell by approximately 12% (P less than 0.05). There were no significant changes in these parameters following the soya load.(ABSTRACT TRUNCATED AT 250 WORDS)

No abstract

In the prevention of variceal rebleeding, it is already established that hemodynamic response to drug treatment (decrease in hepatic venous pressure gradient [HVPG] to 12 mm Hg or by >20%) is predictive of clinical effectiveness. In primary prophylaxis very few clinical data are available. We assessed the role of the hemodynamic response to beta-blockers or beta-blockers plus nitrates in predicting clinical efficacy of prophylaxis. A total of 49 cirrhotic patients with varices at risk of bleeding, without prior variceal bleeding, were investigated by hepatic vein catheterization before and after 1 to 3 months of chronic treatment with nadolol or nadolol plus isosorbide mononitrate, and were followed during treatment for up to 5 years. A total of 30 patients (61%) were good hemodynamic responders, and among them in 12 (24%) HVPG was <12 mm Hg during treatment. During treatment 9 patients had variceal bleeding: 7 were poor responders and 2 were good responders. The probability of bleeding at 3 years of follow-up was significantly higher in poor responders (41%) than in good responders (7%; P ‫؍‬ .0008). No patient reaching an HVPG of 12 mm Hg or less during treatment had variceal bleeding during follow-up. Cox's regression analysis showed that poor hemodynamic response was the main factor predicting bleeding (␤ ‫؍‬ 1.91; SE(␤) ‫؍‬ 0.80; P ‫؍‬ .01). During follow-up 11 patients died of hepatic causes. Survival was related to Child-Pugh class and to initial value of HVPG, according to Cox's analysis. In conclusion, the assessment of hemodynamic response to drugs in terms of HVPG is the best predictor of efficacy of prophylaxis of variceal bleeding in patients treated with beta-blockers or beta-blockers plus nitrates. (HEPATOLOGY 2000;32:930-934.)It is clearly established that prophylaxis with beta-blockers decreases the risk of first variceal bleeding in cirrhotic patients with portal hypertension and esophageal varices at risk of bleeding. 1 Recently, it was also shown that the efficacy of beta-blockers may be enhanced by the addition of long-acting nitrates. 2 These treatments, however, do not abolish the risk of bleeding but decrease it by half or by three quarters, respectively. For these reasons, it may be useful to know factors predicting clinical response or nonresponse to treatment to allow treatment of nonresponders with alternative methodologies.In patients treated with beta-blockers 3-5 or beta-blockers plus nitrates 6 for prevention of rebleeding, it was observed that a decrease in portal pressure under chronic treatment, expressed as a decrease in hepatic venous pressure gradient (HVPG), is a strong predictor of clinical effectiveness. Indeed, decreases of HVPG to 12 mm Hg or less, or decreases by at least 20% from baseline values were associated with a negligible risk of rebleeding, whereas risk of rebleeding was confined to patients not meeting these hemodynamic end points. A single report was unable to confirm the clinical value of these hemodynamic end points. 7 In the clinical setting of prophylaxi...

Cardiomyocyte proteostasis is mediated by the ubiquitin/proteasome system (UPS) and autophagy/lysosome system and is fundamental for cardiac adaptation to both physiologic (e.g., exercise) and pathologic (e.g., pressure overload) stresses. Both the UPS and autophagy/lysosome system exhibit reduced efficiency as a consequence of aging, and dysfunction in these systems is associated with cardiomyopathies. The musclespecific ubiquitin ligase atrogin-1 targets signaling proteins involved in cardiac hypertrophy for degradation. Here, using atrogin-1 KO mice in combination with in vivo pulsed stable isotope labeling of amino acids in cell culture proteomics and biochemical and cellular analyses, we identified charged multivesicular body protein 2B (CHMP2B), which is part of an endosomal sorting complex (ESCRT) required for autophagy, as a target of atrogin-1-mediated degradation. Mice lacking atrogin-1 failed to degrade CHMP2B, resulting in autophagy impairment, intracellular protein aggregate accumulation, unfolded protein response activation, and subsequent cardiomyocyte apoptosis, all of which increased progressively with age. Cellular proteostasis alterations resulted in cardiomyopathy characterized by myocardial remodeling with interstitial fibrosis, with reduced diastolic function and arrhythmias. CHMP2B downregulation in atrogin-1 KO mice restored autophagy and decreased proteotoxicity, thereby preventing cell death. These data indicate that atrogin-1 promotes cardiomyocyte health through mediating the interplay between UPS and autophagy/lysosome system and its alteration promotes development of cardiomyopathies.

The impaired left ventricular relaxation in the presence of high stroke volume suggests a myocardial involvement in LC. The pseudo normalization of the E/A ratio and DT in patients with tense ascites could reflect loading conditions masking the relaxation abnormality.

No abstract

Information on changes in splanchnic hemodynamics after liver transplantation is incomplete. In particular, data on long-term changes are lacking, and the relationship between changes in arterial and portal parameters is still under debate. The effect of liver transplantation on splanchnic hemodynamics was analyzed with echo-Doppler in 41 patients with cirrhosis who were followed for up to 4 years. Doppler parameters were also evaluated in 7 patients transplanted for acute liver failure and in 35 controls. In cirrhotics, portal blood velocity and flow increased immediately after transplantation (from 9.1 ؎ 3.7 cm/sec to 38.3 ؎ 14.6 and from 808 ؎ 479 mL/min to 2,817 ؎ 1,153, respectively, P < .001). Hepatic arterial resistance index (pulsatility index) also augmented (from 1.36 ؎ 0.32 to 2.34 ؎ 1.29, P < .001) and was correlated with portal blood velocity and flow. The early changes in these parameters were related, in agreement with the hepatic buffer response theory. Portal flow returned to normal values after 2 years. Superior mesenteric artery flow normalized after 3 to 6 months. Splenomegaly persisted after 4 years, when spleen size was related to portal blood flow. In 7 patients transplanted for acute liver failure, portal flow, and hepatic arterial resistance index were normal after transplantation. In conclusion, a high portal flow was present in cirrhotics until 2 years after transplantation, probably because of maintenance of elevated splenic flow. An early increase in hepatic arterial resistance indices is a common finding, but it is transient and is related to the increase in portal blood flow. A normal time course of portal-hepatic hemodynamics was detected in patients transplanted for acute liver failure. (HEPATOLOGY 2002;35:601-608.) A fter orthotopic liver transplantation (OLT) performed in patients with liver cirrhosis, splanchncic hemodynamics change dramatically. 1 The understanding of such changes is important, as a correct interpretation of data during follow-up would allow a better prevention and diagnosis of vascular complications. Moreover, some clues on the pathophysiology of splanchnic hemodynamics may be obtained. Published articles on this topic showed an increase in hepatic and portal blood flow after OLT, 2-8 but whether and when splanchnic hemodynamic parameters subsequently normalize is not clearly defined. Furthermore, the changes in splanchnic hemodynamics in the very first days after OLT, and after 24 months, have not yet been reported, and the relationship between arterial and portal parameters is under debate. Finally, the relationship between pre-existing portal circulation abnormalities and the time course of hemodynamic parameters have never been investigated. In the past few years, we had the opportunity to follow the portal and hepatic hemodynamics of a group of patients undergoing liver transplantation for liver cirrhosis or for acute liver failure (ALF). These 2 groups allowed us to analyze the possible role of increased portal blood inflow and of splenomegaly in de...