By monitoring myocardial interstitial levels of 5-HT and its metabolite, 5-hydroxyindole acetic acid, we investigated 5-HT kinetics during myocardial ischemia-reperfusion. 5-HT accumulates but 5-HT degradation is suppressed during ischemia. After reperfusion, 5-HT degradation is enhanced and this degradation is dependent on monoamine oxidase activity but not fluoxetine-sensitive uptake transporter.
The 5-HT reuptake function plays an important role in the clearance of myocardial interstitial 5-HT during reperfusion. When 5-HT reuptake function is intact, degradation of 5-HT by monoamine oxidase contributes to reduce myocardial interstitial 5-HT level throughout ischaemia-reperfusion.
BackgroundImpaired actin–myosin cross-bridge (CB) dynamics correlate with impaired left ventricular (LV) function in early diabetic cardiomyopathy (DCM). Elevated expression and activity of Rho kinase (ROCK) contributes to the development of DCM. ROCK targets several sarcomeric proteins including myosin light chain 2, myosin binding protein-C (MyBP-C), troponin I (TnI) and troponin T that all have important roles in regulating CB dynamics and contractility of the myocardium. Our aim was to examine if chronic ROCK inhibition prevents impaired CB dynamics and LV dysfunction in a rat model of early diabetes, and whether these changes are associated with changes in myofilament phosphorylation state.MethodsSeven days post-diabetes induction (65 mg/kg ip, streptozotocin), diabetic rats received the ROCK inhibitor, fasudil (10 mg/kg/day ip) or vehicle for 14 days. Rats underwent cardiac catheterization to assess LV function simultaneous with X-ray diffraction using synchrotron radiation to assess in situ CB dynamics.ResultsCompared to controls, diabetic rats developed mild systolic and diastolic dysfunction, which was attenuated by fasudil. End-diastolic and systolic myosin proximity to actin filaments were significantly reduced in diabetic rats (P < 0.05). In all rats there was an inverse correlation between ROCK1 expression and the extension of myosin CB in diastole, with the lowest ROCK expression in control and fasudil-treated diabetic rats. In diabetic and fasudil-treated diabetic rats changes in relative phosphorylation of TnI and MyBP-C were not significant from controls.ConclusionsOur results demonstrate a clear role for ROCK in the development of LV dysfunction and impaired CB dynamics in early DCM.Electronic supplementary materialThe online version of this article (doi:10.1186/s12933-015-0256-6) contains supplementary material, which is available to authorized users.
To elucidate the involvement of monoamine oxidase (MAO) in hydroxyl radical production and cardiomyocyte injury during ischemia as well as after reperfusion, we applied microdialysis technique to the heart of anesthetized rats. Dialysate samples were collected during 30 min of induced ischemia followed by 60 min of reperfusion. We monitored dialysate 3,4-dihydrobenzoic acid (3,4-DHBA) concentration as an index of hydroxyl radical production using a trapping agent (4-hydroxybenzoic acid), and dialysate myoglobin concentration as an index of cardiomyocyte injury in the ischemic region. The effect of local administration of a MAO inhibitor, pargyline, was investigated. Dialysate 3,4-DHBA concentration increased from 1.9 ± 0.5 nM at baseline to 3.5 ± 0.7 nM at 20-30 min of occlusion. After reperfusion, dialysate 3,4-DHBA concentration further increased reaching a maximum (4.5 ± 0.3 nM) at 20-30 min after reperfusion, and stabilized thereafter. Pargyline suppressed the averaged increase in dialysate 3,4-DHBA concentration by ∼72% during occlusion and by ∼67% during reperfusion. Dialysate myoglobin concentration increased from 235 ± 60 ng/ml at baseline to 1309 ± 298 ng/ml at 20-30 min after occlusion. After reperfusion, dialysate myoglobin concentration further increased reaching a peak (5833 ± 1017 ng/ml) at 10-20 min after reperfusion, and then declined. Pargyline reduced the averaged dialysate myoglobin concentration by ∼56% during occlusion and by ∼41% during reperfusion. MAO plays a significant role in hydroxyl radical production and cardiomyocyte injury during ischemia as well as after reperfusion.
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