Background: Sustained pressure overload of the right ventricle (RV) causes RV hypertrophy and failure. Cyclic-GMP has previously been shown to modulate left ventricular hypertrophy. Aim: To evaluate the effects of sildenafil, a phosphodiesterase-5 (PDE5) inhibitor elevating c-GMP, on myocardial hypertrophy and function in rats with RV hypertrophy. Methods: Rats were pulmonary trunk banded (PTB) and randomized to receive sildenafil (SIL) or vehicle (VEC) for three (n = 14) and nine weeks (n = 18). In addition, rats with established RV hypertrophy were randomized to SIL or VEC (n = 17) three weeks after PTB. Right ventricular function was evaluated by echocardiography and RV hypertrophy by histology and RV weight. Results: Sildenafil failed to inhibit the development of RV hypertrophy when given for both 3 and 9 weeks. On the contrary, sildenafil increased RV hypertrophy after 3 weeks (RV/bodyweight: SIL 0.099 ± 0.016 vs. VEC 0.081 ± 0.011; p b 0.05) and total heart weight after 9 weeks (SIL 1.05 ± 0.10 vs. VEC 0.93 ± 0.08 g; p b 0.05). Sildenafil also failed to reverse established RV hypertrophy, but significantly improved RV myocardial function as measured by Tricuspid Annular Plane Systolic Excursion (TAPSE: SIL 1.85 ± 0.027 vs. VEC 1.39 ±0.037 mm; p b 0.05). Conclusion: PDE5 inhibition by sildenafil failed to prevent or reverse RV hypertrophy in rats operated by pulmonary trunk banding. It actually increased RV hypertrophy and improved RV contractile function when given to rats with established RV hypertrophy.

BackgroundThe present study investigated whether changes in gene expression in the right ventricle following pulmonary hypertension can be attributed to hypoxia or pressure loading.Methodology/Principal FindingsTo distinguish hypoxia from pressure-induced alterations, a group of rats underwent banding of the pulmonary trunk (PTB), sham operation, or the rats were exposed to normoxia or chronic, hypobaric hypoxia. Pressure measurements were performed and the right ventricle was analyzed by Affymetrix GeneChip, and selected genes were confirmed by quantitative PCR and immunoblotting. Right ventricular systolic blood pressure and right ventricle to body weight ratio were elevated in the PTB and the hypoxic rats. Expression of the same 172 genes was altered in the chronic hypoxic and PTB rats. Thus, gene expression of enzymes participating in fatty acid oxidation and the glycerol channel were downregulated. mRNA expression of aquaporin 7 was downregulated, but this was not the case for the protein expression. In contrast, monoamine oxidase A and tissue transglutaminase were upregulated both at gene and protein levels. 11 genes (e.g. insulin-like growth factor binding protein) were upregulated in the PTB experiment and downregulated in the hypoxic experiment, and 3 genes (e.g. c-kit tyrosine kinase) were downregulated in the PTB and upregulated in the hypoxic experiment.Conclusion/SignificancePressure load of the right ventricle induces a marked shift in the gene expression, which in case of the metabolic genes appears compensated at the protein level, while both expression of genes and proteins of importance for myocardial function and remodelling are altered by the increased pressure load of the right ventricle. These findings imply that treatment of pulmonary hypertension should also aim at reducing right ventricular pressure.

It was hypothesized that dysregulation of renal epithelial sodium channel (ENaC) subunits and/or 11␤-hydroxysteroid dehydrogenase (11␤HSD2) may play a role in the increased sodium retention in liver cirrhosis (LC). Experimental LC was induced in rats by CCl 4 (1 ml/kg, intraperitoneally, twice a week) for 12 wk (protocol 1) or for 11 wk (protocol 2). In both protocols, one group of rats with cirrhosis showed significantly decreased urinary sodium excretion and urinary Na/K ratio (group A), whereas a second group exhibited normal urinary sodium excretion (group B) compared with controls, even though extensive ascites was seen in both groups of rats with cirrhosis. In group A, protein abundance of ␣-ENaC was unchanged, whereas ␤-ENaC abundance was decreased in the cortex/outer stripe of outer medulla compared with controls. The ␥-ENaC underwent a complex change associated with increased abundance of the 70-kD band with a concomitant decrease in the main 85-kD band, corresponding to an aldosterone effect. In contrast, no changes in the abundance of ENaC subunit were observed in group B. Immunoperoxidase microscopy revealed an increased apical targeting of ␣-, ␤-, and ␥-ENaC subunits in distal convoluted tubule (DCT2), connecting tubule (CNT), and cortical and medullary collecting duct segments in group A but not in group B. Immunolabeling intensity of 11␤HSD2 in the DCT2, CNT, and cortical collecting duct was significantly reduced in group A but not in group B, and this was confirmed by immunoblotting. In conclusion, increased apical targeting of ENaC subunits combined with diminished abundance of 11␤HSD2 in the DCT2, CNT, and cortical collecting duct is likely to play a role in the sodium retaining stage of liver cirrhosis.

Animal models of disease are essential for cardiovascular research. However, animal models of right-sided heart failure are few and remain poorly characterized. The aim with this study was to establish a rat model of right-sided heart failure (HF) using pulmonary trunk banding (PTB) and subsequently to characterize the systemic and cardiac changes in this model, including protein expression of SERCA2 and a-sarcomeric actin. Rats underwent banding or sham operation. To evaluate the development of HF over time three groups were included in this study. They were killed 2-3, 5-7 or 16-17 weeks after operation, respectively. PTB rats showed marked hypertrophy of the right ventricle (RV). Catheterization of the RV showed a three-to four-fold increase in right ventricular systolic and diastolic pressures as well as increased dP/dT max and dP/dT min. Plasma analyses revealed increased liver enzymes in most PTB groups and post mortem examination revealed congestion of the liver as well as formation of ascites and hydrothorax in many PTB rats. Immunoblotting of the RV revealed no changes in SERCA2 or a-sarcomeric actin. In conclusion, PTB was an effective method to induce right-sided HF. The presence of HF was confirmed by severe signs of backward failure in conjunction with markedly elevated RV pressures and reduced RV ejection fraction (EF). r