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The Sphingosine-1-Phosphate Receptor Agonist FTY720 Increases Heart Rate Variability in Isolated Murine Ischemic Heart Model

Emmanuel E. Egom, Thierno Madjou Bah, Ming Lei

Despite considerable improvements in the management of hypertension, only half of adults with hypertension have their blood pressure under control. Uncontrolled hypertension may contribute to the development of left ventricular hypertrophy-induced myocardial ischemia. Accumulating evidence also suggests that hypertension may lead to lower heart rate variability (HRV), which is associated with an increased risk of cardiovascular disease. This forms the basis for the hypothesis that interventions aiming at raising HRV and reducing ischemia-induced injury in hypertensive patients, especially after AMI, may reduce the risk of cardiac events and mortality. In experiments reported here, we investigated the effects of the sphingosine-1-phosphate receptor agonist FTY720 on HRV in isolated, denervated murine ischaemic hearts. Our results demonstrated the presence of one major concentration of power centred on the ultra low frequency bands (ULF) which accounted for more than 99.9% of the total power (TP). TP and ULF decreased by 98% and 98.5% during ischemia respectively whilst these parameters increased by 1074% and 1073% during ischemia + 25 nFTY720 respectively (n=8, p<0.001). The Poincaré plot of the ischemia + 25 nM FTY720 condition exhibits greater dispersion of points than that of the control and ischemia conditions. The reconstructed ellipses had larger SD2 in the ischemia + 25 nM FTY720 condition than in the control and ischemia conditions (n=8, p<0.001). These data provide the first evidence that FTY720 may increase HRV, especially after myocardial ischemia and may represent a therapeutic approach for the treatment and prevention of coronary artery disease.