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 (SnCl ₂ ), 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 SnCl ₂ in young SHRs was greatly reduced by prevention of its cytochrome P-450-depleting action.

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 (β = 1.91; SE(β) = 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.

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 muscle-specific 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.