Gao Zhaohui, Xing Jihong, Sinoway Lawrence, Li Jianhua
Heart & Vascular Institute and Department of Medicine, Pennsyvania State College of Medicine and Milton S. Hershey Medical Center, Hershey, Pennsyvania 17033, USA.
Am J Physiol Heart Circ Physiol. 2007 Feb;292(2):H939-45. doi: 10.1152/ajpheart.00911.2006. Epub 2006 Sep 29.
A previous report from this laboratory demonstrated that the ATP-sensitive P2X receptor-mediated muscle pressor reflex was augmented in rats with heart failure (HF). The purpose of this study was to better understand the underlying mechanisms for this greater response in HF rats. We examined 1) responsiveness of the P2X receptor to alpha,beta-methylene ATP (alpha,beta-me-ATP), a P2X receptor agonist, in control and HF rats induced by myocardial infarction (MI); 2) the relationship between P2X-induced blood pressure response and left ventricular (LV) function; and 3) the expression of P2X receptors in the dorsal root ganglion (DRG) of control rats and rats with HF. Eight to 14 wk after coronary artery ligation, the severity of the MI was determined by echocardiography. In the first group of the experiment, alpha,beta-me-ATP (0.0625, 0.125, 0.25, and 0.5 mM) was injected into the arterial blood supply of the hindlimb muscles to evoke a pressor response in 17 decerebrated rats (6 controls, 6 small MIs with infarcts of the LV between 10 and 35%, and 5 large MIs with infarcts >35%). The P2X agonist increased blood pressure, and the effect was significantly accentuated in large MI rats compared with small MI rats and control rats. A significant correlation was observed between alpha,beta-me-ATP-evoked pressor response and the LV fractional shortening, an index of LV function. In the second group of the experiment, immunocytochemistry was used to examine the immunoreactivity of P2X receptor in the DRG neurons of small diameter fibers in six healthy control rats, five small MI, and five large MI rats. The percentage of P2X immunostaining-positive neurons in the DRG was markedly greater in large MI rats (52% vs. 29% in controls and 34% in small MIs, P < 0.05). In conclusion, our findings demonstrate that 1) muscle afferent-mediated pressor response of P2X activation was exaggerated in MI animals, and the responsiveness was related to the degree of LV dysfunction; and 2) augmented reflex response was associated with upregulated P2X receptors in the DRG neurons of thin fiber afferent nerves following MI. The data suggest that P2X-mediated responsiveness in the processing of muscle afferent signals may have important implications for understanding cardiovascular responses to exercise in HF.
本实验室之前的一份报告表明，在心力衰竭（HF）大鼠中，ATP敏感性P2X受体介导的肌肉升压反射增强。本研究的目的是更好地理解HF大鼠这种更强反应的潜在机制。我们研究了：1）在由心肌梗死（MI）诱导的对照大鼠和HF大鼠中，P2X受体对P2X受体激动剂α,β-亚甲基ATP（α,β-me-ATP）的反应性；2）P2X诱导的血压反应与左心室（LV）功能之间的关系；3）对照大鼠和HF大鼠背根神经节（DRG）中P2X受体的表达。冠状动脉结扎8至14周后，通过超声心动图确定MI的严重程度。在实验的第一组中，将α,β-me-ATP（0.0625、0.125、0.25和0.5 mM）注入后肢肌肉的动脉血供中，以在17只去大脑大鼠（6只对照、6只小面积MI且LV梗死面积在10%至35%之间、5只大面积MI且梗死面积>35%）中诱发升压反应。P2X激动剂升高了血压，与小面积MI大鼠和对照大鼠相比，大面积MI大鼠的这种作用明显增强。在α,β-me-ATP诱发的升压反应与LV缩短分数（LV功能指标）之间观察到显著相关性。在实验的第二组中，使用免疫细胞化学检测6只健康对照大鼠、5只小面积MI大鼠和5只大面积MI大鼠中小直径纤维DRG神经元中P2X受体的免疫反应性。大面积MI大鼠DRG中P2X免疫染色阳性神经元的百分比明显更高（对照为29%，小面积MI为34%，大面积MI为52%，P<0.05）。总之，我们的研究结果表明：1）在MI动物中，P2X激活的肌肉传入介导的升压反应被夸大了，且反应性与LV功能障碍程度有关；2）MI后，反射反应增强与细纤维传入神经DRG神经元中P2X受体上调有关。数据表明，P2X介导的肌肉传入信号处理中的反应性可能对理解HF患者运动时心血管反应具有重要意义。
