ABSTRACT
RATIONALE: Ca/calmodulin-dependent protein kinase II (CaMKII) was shown to increase diastolic sarcoplasmic reticulum (SR) Ca leak, which can result in delayed afterdepolarizations and triggered arrhythmias. Since increased CaMKII expression and activity has been mechanistically linked to arrhythmias in human heart failure (HF) and atrial fibrillation (AF), specific strategies aimed at CaMKII inhibition may have therapeutic potential. OBJECTIVE: We tested the antiarrhythmic and inotropic effects of a novel selective and ATP-competitive CaMKII inhibitor (GS-680). METHODS AND RESULTS: Trabeculae were isolated from right atrial appendage biopsies of patients undergoing cardiac surgery. Premature atrial contractions (PACs) were induced by stimulation with isoproterenol (ISO, 100â¯nM) at increased [Ca]o (3.5â¯mM). Interestingly, compared to vehicle, PACs were significantly inhibited by exposure to GS-680 (at 100 and 300â¯nM). GS-680 also significantly decreased early and delayed afterdepolarizations in isolated human atrial myocytes. Moreover, GS-680 (at 100 or 300â¯nM) significantly inhibited diastolic SR Ca leak, measured as frequency of spontaneous SR Ca release events (Ca sparks) in isolated human atrial myocytes (Fluo-4 loaded) similar to the well-established peptide CaMKII inhibitor AIP. In accordance, GS-680 significantly reduced CaMKII autophosphorylation (Western blot) but enhanced developed tension after 10 or 30â¯s pause of electrical stimulation (post-rest behavior). Surprisingly, we found a strong negative inotropic effect of GS-680 in atrial trabeculae at 1â¯Hz stimulation rate, which was not observed at 4â¯Hz and abolished by beta-adrenergic stimulation. In contrast, GS-680 did not impair systolic force of isolated ventricular trabeculae from explanted hearts of heart transplant recipients at 1â¯Hz, blunted the negative force-frequency relationship (1-3â¯Hz) and significantly increased the Ca transient amplitude. CONCLUSION: The novel ATP-competitive and selective CaMKII inhibitor GS-680 inhibits pro-arrhythmic activity in human atrium and improves contractility in failing human ventricle, which may have therapeutic implications.
Subject(s)
Arrhythmias, Cardiac/enzymology , Calcium-Calmodulin-Dependent Protein Kinase Type 2/antagonists & inhibitors , Protein Kinase Inhibitors/pharmacology , Pyridines/pharmacology , Pyrrolidines/pharmacology , Thiophenes/pharmacology , Arrhythmias, Cardiac/complications , Arrhythmias, Cardiac/pathology , Arrhythmias, Cardiac/physiopathology , Calcium/metabolism , Calcium-Calmodulin-Dependent Protein Kinase Type 2/metabolism , Diastole/drug effects , Heart Atria/drug effects , Heart Atria/physiopathology , Heart Failure/complications , Heart Failure/physiopathology , Humans , Myocardial Contraction/drug effects , Myocytes, Cardiac/drug effects , Myocytes, Cardiac/metabolism , Phosphorylation , Protein Kinase Inhibitors/chemistry , Pyridines/chemistry , Pyrrolidines/chemistry , Sarcoplasmic Reticulum/drug effects , Sarcoplasmic Reticulum/metabolismABSTRACT
OBJECTIVES: Effects of endurance training in multiple sclerosis (MS) patients complaining of motor fatigue. MATERIALS AND METHODS: Thirty MS patients complaining of fatigue with low to moderate disabilities randomly allocated to the intervention (thrice weekly 45-min intervals of endurance exercise) or control treatment (three 45-min episodes of stretching, balance training and coordination), both as 'add-on' therapy for 3 weeks during inpatient rehabilitation. RESULTS: Maximal walking distance before intervention averaged 1043 +/- 568 and 1163 +/- 750 m in the two groups. The intervention group increased its maximal walking distance by 650 +/- 474 m. The control group extended its walking distance by 96 +/- 70 m. CONCLUSIONS: The present data confirm a strong effect of endurance exercise on maximal walking distance. Remarkably, there were no parallel improvements on the Modified Fatigue Impact Scale, the Beck Depression Inventory and the Hamburg Quality of Life Questionnaire for MS.