The Capsaicin-Sensitive Afferent Neuron in Skeletal Muscle Is Abnormal in Heart Failure
The Capsaicin-Sensitive Afferent Neuron in Skeletal Muscle Is Abnormal in Heart Failure
复制标题
心力衰竭时骨骼肌中辣椒素敏感的传入神经元异常
作者：
Scott A. Smith;Maurice A. Williams;Jere H. Mitchell;P. Mammen;M. Garry
背景——心力衰竭时，心血管对骨骼肌运动升压反射（EPR）激活的反应被夸大。 IV 组传入神经元主要受到骨骼肌工作代谢副产物的刺激，对 EPR 贡献显着。因此，推测 IV 组神经元活性的改变导致心力衰竭中出现的 EPR 功能障碍。方法和结果——通过皮下注射辣椒素，消除新生 Sprague-Dawley 大鼠的 IV 组传入纤维。在用辣椒素处理的新生成年动物中，通过电诱导静态肌肉收缩选择性激活 EPR，重现了在患有扩张型心肌病 (DCM) 的大鼠中观察到的心率和血压的过度增加。此外，与对照动物相比，新生辣椒素治疗的大鼠和 DCM 大鼠对后肢动脉内施用辣椒素的升压反应均降低，这是一种选择性兴奋 IV 组传入神经元的操作。此外，与对照组相比，DCM 动物中辣椒素受体 TRPv1（IV 组纤维标记物）的 mRNA 表达下调。结论——这些发现表明心力衰竭中的 EPR 功能障碍部分是由于 IV 族纤维的功能和分子改变所致。此外，这些代谢敏感神经元的反应性在 DCM 中似乎减弱，表明它们对 EPR 的贡献可能会减少。尽管心力衰竭的 EPR 总体上被夸大，但这种情况还是发生了。这些对 EPR 功能障碍基本机制的见解对于制定旨在提高心力衰竭运动能力的有效治疗策略至关重要。
Background—In heart failure, the cardiovascular response to activation of the skeletal muscle exercise pressor reflex (EPR) is exaggerated. Group IV afferent neurons, primarily stimulated by the metabolic by-products of skeletal muscle work, contribute significantly to the EPR. Therefore, it was postulated that alterations in the activity of group IV neurons contribute to the EPR dysfunction manifest in heart failure. Methods and Results—Group IV afferent fibers were ablated in neonatal Sprague-Dawley rats by subcutaneous administration of capsaicin. In neonatal capsaicin-treated adult animals, selective activation of the EPR, by electrically induced static muscle contraction, recapitulated the exaggerated increases in heart rate and blood pressure observed in rats with dilated cardiomyopathy (DCM). Furthermore, compared with control animals, both neonatal capsaicin-treated and DCM rats displayed a decreased pressor response to the intra-arterial administration of capsaicin within the hindlimb, a maneuver that selectively excites group IV afferent neurons. Moreover, expression of mRNA for the capsaicin receptor TRPv1, a marker of group IV fibers, was downregulated in DCM animals compared with controls. Conclusions—These findings suggest that EPR dysfunction in heart failure results in part from functional and molecular alterations in group IV fibers. Furthermore, the responsiveness of these metabolically sensitive neurons appears to be blunted in DCM, indicating that their contribution to the EPR may be reduced. This occurs despite an overall exaggeration of the EPR in heart failure. These insights into the basic mechanisms of EPR dysfunction are essential to the development of effective therapeutic strategies aimed at improving exercise capacity in heart failure.