Citations

For many years, β-adrenergic receptor antagonists (β-blockers or βAR antagonists) have provided significant morbidity and mortality benefits in patients who have sustained acute myocardial infarction. More recently, β-adrenergic receptor antagonists have been found to provide survival benefits in patients suffering from heart failure, although the efficacy of different β-blockers varies widely in this condition. One drug, carvedilol, a nonsubtype-selective βAR antagonist, has proven particularly effective in the treatment of heart failure, although the mechanism(s) responsible for this are controversial. Here, we report that among 16 clinically relevant βAR antagonists, carvedilol displays a unique profile of in vitro signaling characteristics. We observed that in β2 adrenergic receptor (β2AR)-expressing HEK-293 cells, carvedilol has inverse efficacy for stimulating G s -dependent adenylyl cyclase but, nonetheless, stimulates ( i ) phosphorylation of the receptor's cytoplasmic tail on previously documented G protein-coupled receptor kinase sites; ( ii ) recruitment of β-arrestin to the β2AR; ( iii ) receptor internalization; and ( iv ) activation of extracellular regulated kinase 1/2 (ERK 1/2), which is maintained in the G protein-uncoupled mutant β2AR T68F,Y132G,Y219A (β2AR TYY ) and abolished by β-arrestin2 siRNA. Taken together, these data indicate that carvedilol is able to stabilize a receptor conformation which, although uncoupled from G s , is nonetheless able to stimulate β-arrestin-mediated signaling. We hypothesize that such signaling may contribute to the special efficacy of carvedilol in the treatment of heart failure and may serve as a prototype for a new generation of therapeutic β2AR ligands.

Abstract Folylpolyglutamate synthase (FPGS) catalyzes the polyglutamation of folic acid, methotrexate, and pemetrexed to produce highly active metabolites. To characterize genetic variation in the FPGS gene, FPGS, have resequenced the gene in four different ethnic populations. Thirty-four single nucleotide polymorphisms were identified including five nonsynonymous coding single nucleotide polymorphisms that altered the FPGS protein sequence: F13L and V22I polymorphisms in the mitochondrial isoform of FPGS, and R466/424C, A489/447V, and S499/457F polymorphisms, which exist in both the mitochondrial and cytosolic isoforms. When expressed in AuxB1 cells, the A447V cytosolic variant was functionally similar to the wild-type cytosolic (WT Cyt) allozyme, whereas the R424C and S457F cytosolic variants were reduced by ∼2-fold in protein expression compared with WT Cyt (P < 0.01). The intrinsic clearance of glutamate was reduced by 12.3-fold (R424C, P < 0.01) and 6.2-fold (S457F, P < 0.01), whereas the intrinsic clearance of methotrexate was reduced by 4.2-fold (R424C, P < 0.05) and 5.4-fold (S457F, P < 0.05) in these two cytosolic variants when compared with the WT Cyt isoform. Additionally, the in vitro enzyme velocity at saturating pemetrexed concentrations was reduced by 1.6-fold (R424C, P < 0.05) and 2.6-fold (S457F, P < 0.01) compared with WT Cyt. AuxB1 cells harboring these same cytosolic variant allozymes displayed significant increases in the EC50 for folic acid and in the IC50 values for both methotrexate and pemetrexed relative to the WT Cyt form of FPGS. These observations suggest that genetic variations in FPGS may alter the efficacy of antifolate therapy in cancer patients. [Cancer Res 2007;67(18):8772–82]

Purpose The purposes of this study were to investigate the differences between open and arthroscopic closure of the rotator interval (RI) on glenohumeral translation and range of motion. We also sought to determine if the addition of either an open or arthroscopic RI closure increases stability of the shoulder. Methods Fourteen fresh‐frozen (10 paired) cadaveric shoulder specimens were mounted in a custom testing apparatus, and glenohumeral translation and rotation were obtained by using an optoelectric tracking system (Optotrak Certus; Northern Digital, Ontario, Canada). Specimens were randomly allocated to either open (n = 7) or arthroscopic (n = 7) plication of the RI. The following were measured first with an intact and vented specimen and subsequently after an RI closure using either open or arthroscopic techniques: (1) range of motion in neutral and 90° abduction; (2) anterior and posterior translation at neutral rotation; (3) anterior translation at 90° abduction with external rotation; and (4) posterior translation at 90° flexion with internal rotation. Results Posterior stability was not improved from the intact state by either open (1.0‐mm change) or arthroscopic (0.1‐mm change) repair. The sulcus stability was improved in the open group (5.7 mm to 2.9 mm, P = .028), but not arthroscopically (5.1 to 4.1 mm, P = .499). Neutral anterior stability was improved after open repair (7.2 to 2.6 mm, P = .018), but not arthroscopically (2.3 to 2.4 mm, P = 0.5). However, anterior stability in external rotation (ER) at 90° abduction was improved in the arthroscopic repair group (5.5 to 3.1 mm, P = .006). The mean loss of ER in neutral was greater in the open group (40.8°) versus the arthroscopic group (24.4°, P = .0038). The arthroscopic group showed an 11.7° loss of ER in 90° abduction ( P = .018) versus the open group loss of 4.8°. There were no significant differences in loss of IR in either neutral or 90° abduction. Conclusions Posterior stability was not improved by either open or arthroscopic rotator interval repair, and sulcus stability only improved with the open technique. Anterior stability in neutral was improved after open repair and in the arthroscopic repair group with the arm abducted. There was a large loss of external rotation with both techniques. Clinical Relevance This study suggests that arthroscopic RI closure adds little to the overall posterior and inferior stability of the shoulder joint, although anterior stability may be improved. There is a potentially large loss of external rotation after either repair method.