| 摘要: | Heart rate variability (HRV) is the cardiac index representing the oscillation of the intervals between consecutive heartbeats (RR intervals in the ECG). It reflects the influences of the autonomic nervous system (ANS) on the sinus node. In order to investigate the involvement of tyrosine phosphorylation in cardiac function of the whole rat system and its effect on HRV, we employed a potent selective inhibitor of Src family kinases, PP2 (4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyramidine), to inhibit the activity of Src kinases that include Src, Fyn, and Yes. Heart rate was decreased 20% by PP2 at the dose of 0.2 mg/kg. PP3, a negative control compound of PP2, which does not inhibit the activity of Src kinases decreased heart rate by 8% (when at the identical dose of 0.2 mg/kg) when compared with the basal. Interestingly, HRV was not significantly altered at a relatively low dose of PP2 (0.2 mg/kg) when compared with that of PP3 or the basal. Unlike that of PP2, HRV was significantly decreased after application of 0.4 μg/kg isoproterenol. Similar to that of PP2, ZD7288, a specific inhibitor of HCN channels, when at the low dose of 0.2 mg/kg, was able to decrease the heart rate without significant change of HRV in comparison to isoproterenol. Furthermore, atrial ventricular block (AV block) can be induced at the higher dose of PP2 (0.3 mg/kg) whereas in ZD7288, higher dose application (0.7 mg/kg) can elicit both premature ventricular contraction (PVC) and AV block. Although PP2 and ZD7288 slightly increased the short-term (SD1) and the long-term (SD2) HRV, larger degree of increase in SD1 or SD2 was observed in isoproterenol. The fractal scaling exponent alpha 1 (α1) in basal level was 0.640, which was comparable to that of PP3 (0.605), but slightly decreased in PP2 (0.328) and ZD7288 (0.144) at the low dose of 0.2 mg/kg. Overall, PP2, like ZD7288, can serve as a potential candidate in the treatment of tachycardia-induced arrhythmias via inhibition of Src-mediated tyrosine phosphorylation. |
