Journal
PHARMACOLOGICAL REPORTS
Volume 72, Issue 6, Pages 1706-1716Publisher
SPRINGER HEIDELBERG
DOI: 10.1007/s43440-020-00094-2
Keywords
Forskolin; Sinus node cells; Hypoxia; reoxygenation; Pacemaker current; Calcium current; Sodium; calcium exchange current; Intracellular calcium
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Funding
- National Natural Science Foundation of China [81870249]
- Natural Science Foundation of Fujian Province [2015J01370, 2019J01189]
- Key Innovation Project of Fujian Province Health Department [2017-CX-6]
- Fujian Provincial Hospital [2017LHJJ02]
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Background In this study, we investigated the effect of forskolin (FSK, a selective adenylate cyclase agonist) on the automatic diastolic depolarization of sinus node cells (SNC) with hypoxia/reoxygenation (H/R) injury. Methods The SNC of the newborn rat was randomly assigned into the control group, the H/R (H/R injury) group, or the H/R + FSK (H/R injury + FSK treatment) group. Patch-clamp was performed to record the action potential and electrophysiological changes. The cellular distribution of intracellular calcium concentration was analyzed by fluorescence staining. Results Compared with the control cells, spontaneous pulsation frequency (SPF) and diastolic depolarization rate (DDR) of H/R cells were reduced from 244.3 +/- 10.6 times/min and 108.7 +/- 7.8 mV/s to 130.5 +/- 7.6 times/min and 53.4 +/- 6.5 mV/s, respectively. FSK significantly increased SPF and DDR of H/R cells to 208.3 +/- 8.3 times/min and 93.2 +/- 8.9 mV/s (n = 15, both p < 0.01), respectively. H/R reduced the current densities of I-f, I-Ca,I-T and inward I-NCX, which were significantly increased by 10 mu M FSK treatment (n = 15, p < 0.01). Furthermore, reduced expression of HCN4 and NCX1.1 channel protein were significantly increased by FSK. Inhibitor studies showed that both SQ22536 (a selective adenylate cyclase inhibitor) and H89 (a selective protein kinases A [PKA] inhibitor) blocked the effects of FSK on SPF and DDR. Conclusions H/R causes pacemaker dysfunction in newborn rat sinoatrial node cells leading to divergence of the DD and the slow of spontaneous APs, which change can be dramatically reversed by FSK through increasing I-NCX and I-f current in H/R injury.
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