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Introduction: We previously reported that Xin Su Ning (XSN) prolongs action potential duration (APD) of isolated cardiac myocytes1,2. In this study we aimed to identify the cardio-protective effect of XSN in Ischemia-reperfusion (I/R) induced injury in isolated heart. Methods: CHL cell line stably transfected human NaV1.5 channel were used for electrophysiological assay using Axopatch 200B patch clamp system with external and internal solutions prepared as previously described3. For isolated hearts study, male Sprague-Dawley rats (280 ∼ 320g) were divided into control, I/R, XSN 0.05 g/L and 0.1 g/L groups. The hearts were isolated and perfused in retrograde mode at constant pressure of 60 mmHg at 37°C as previously reported3. The extracts of XSN in the form of frozen dried power were administrated by dissolving in the perfusing solution. The measurements used to evaluate XSN’s effects were: Left ventricular developed pressure (LVDP), the rate of pressure development and rate of relaxation (max/min dP/dt), and heart rate (HR). Rate pressure product (RPP) was calculated by multiplying LVDP by HR. The differences between control and other groups were tested using Student’s t-test. Results: XSN blocks human NaV1.5 channel in a dose dependent manner with an IC50 = 0.184±0.017 g/L. XSN at 0.1 g/L produced the significant recovery of LVDP during 60 min reperfusion as shown in Figure 1. Max dP/dt, min dP/dt and HR after 60 min perfusion with vehicle and difference concentrations of XSN were shown in Table 1. Fig. 1 (A) Dose response curve of XSN on human NaV1.5 channel (n=5); (B) Experimental protocol of contractile function of I/R perfused rat heart; (C) percent rate of LVDP of rat hearts with/without XSN treatment after reperfusion 0, 5, 10, 20, 30, 40, 60 min (n=5). The data were presented as mean±SEM. * p<0.05, ** p<0.01, ** p<0.001 vs. I/R group. Table 1 Myocardial contractile function measured ex vivo in a rat I/R heart (mean±SEM, n=5). %pre-ischemia LVDP max dP/dt min dP/dt HR RPP I/R 48.11±2.18 56.82±4.91 48.06±3.67 97.61±5.80 46.82±3.06 XSN 0.05 g/L 61.28±6.08 57.50±7.82 58.07±6.05* 79.15±4.34 48.85±6.43 XSN 0.1 g/L 87.36±4.34*** 93.39±4.53** 90.27±4.25*** 75.56±3.94* 70.57±5.38** * p<0.05, ** p<0.01, ** p<0.001 vs. I/R group. Conclusions: XSN blocked NaV1.5 channel dose dependently, and together with the APD prolongation which could be the cellular electrophysiological mechanisms of the anti-tachyarrhythmic effect of XSN. XSN improved cardiac systolic function on ischemia-reperfusion injured rat heart by increasing LVDP, RPP, max dP/dt and min dP/dt, the protective effect may contribute to the anti-arrhythmic effect of XSN on ischemic heart. References: 1. Ma Y-L et al. (2015). Proceedings of the British Pharmacological Society at http://www.pA2online.org/abstracts/Vol16Issue1abst093P.pdf. 2. Zhai J et al. (2017). The Lancet 390:S61. 3. Mavropoulos SA et al. (2017). Mol Med 23: 120-133.

Type

Conference paper

Publisher

British Pharmacological Society

Volume

18

Pages

117 - 117