No abstract

Background-Inhibition of tyrosine kinases, including platelet-derived growth factor receptor, can reduce pulmonary arterial pressure in experimental and clinical pulmonary hypertension. We hypothesized that inhibition of the serine/threonine kinases Raf-1 (also termed c-Raf) and b-Raf in addition to inhibition of tyrosine kinases effectively controls pulmonary vascular and right heart remodeling in pulmonary hypertension. Methods and Results-We investigated the effects of the novel multikinase inhibitor sorafenib, which inhibits tyrosine kinases as well as serine/threonine kinases, in comparison to imatinib, a tyrosine kinase inhibitor, on hemodynamics, pulmonary and right ventricular (RV) remodeling, and downstream signaling in experimental pulmonary hypertension. Fourteen days after monocrotaline injection, male rats were treated orally for another 14 days with sorafenib (10 mg/kg per day), imatinib (50 mg/kg per day), or vehicle (nϭ12 to 16 per group). RV systolic pressure was decreased to 35.0Ϯ1.5 mm Hg by sorafenib and to 54.0Ϯ4.4 mm Hg by imatinib compared with placebo (82.9Ϯ6.0 mm Hg). In parallel, both sorafenib and imatinib reduced RV hypertrophy and pulmonary arterial muscularization. The effects of sorafenib on RV systolic pressure and RV mass were significantly greater than those of imatinib. Sorafenib prevented phosphorylation of Raf-1 and suppressed activation of the downstream ERK1/2 signaling pathway in RV myocardium and the lungs. In addition, sorafenib but not imatinib antagonized vasopressin-induced hypertrophy of the cardiomyoblast cell line H9c2. Conclusions-The multikinase inhibitor sorafenib prevents pulmonary remodeling and improves cardiac and pulmonary function in experimental pulmonary hypertension. Sorafenib exerts direct myocardial antihypertrophic effects, which appear to be mediated via inhibition of the Raf kinase pathway. The combined inhibition of tyrosine and serine/threonine kinases may provide an option to treat pulmonary arterial hypertension and associated right heart remodeling.

Standard procedures to achieve quality assessment (QA) of functional magnetic resonance imaging (fMRI) data are of great importance. A standardized and fully automated procedure for QA is presented that allows for classification of data quality and the detection of artifacts by inspecting temporal variations. The application of the procedure on phantom measurements was used to check scanner and stimulation hardware performance. In vivo imaging data were checked efficiently for artifacts within the standard fMRI post-processing procedure by realignment. Standardized and routinely carried out QA is essential for extensive data amounts as collected in fMRI, especially in multicenter studies. Furthermore, for the comparison of two different groups, it is important to ensure that data quality is approximately equal to avoid possible misinterpretations. This is shown by example, and criteria to quantify differences of data quality between two groups are defined. Hum Brain Mapp 25:237-246, 2005.

Sildenafil prevents myocardial remodelling in pulmonary hypertension through an indirect action via right-ventricular unloading.