Department of Cellular and Integrative Physiology, University of Nebraska Medical Center, Omaha, Nebraska 68198-5850, USA.
J Appl Physiol (1985). 2013 May;114(9):1141-50. doi: 10.1152/japplphysiol.01503.2012. Epub 2013 Feb 28.
Cardiovascular autonomic imbalance and breathing instability are major contributors to the progression of heart failure (CHF). Potentiation of the carotid body (CB) chemoreflex has been shown to contribute to these effects. Hydrogen sulfide (H2S) recently has been proposed to mediate CB hypoxic chemoreception. We hypothesized that H2S synthesis inhibition should decrease CB chemoreflex activation and improve breathing stability and autonomic function in CHF rats. Using the irreversible inhibitor of cystathione γ-lyase dl-propargylglycine (PAG), we tested the effects of H2S inhibition on resting breathing patterns, the hypoxic and hypercapnic ventilatory responses, and the hypoxic sensitivity of CB chemoreceptor afferents in rats with CHF. In addition, heart rate variability (HRV) and systolic blood pressure variability (SBPV) were calculated as an index of autonomic function. CHF rats, compared with sham rats, exhibited increased breath interval variability and number of apneas, enhanced CB afferent discharge and ventilatory responses to hypoxia, decreased HRV, and increased low-frequency SBPV. Remarkably, PAG treatment reduced the apnea index by 90%, reduced breath interval variability by 40-60%, and reversed the enhanced hypoxic CB afferent and chemoreflex responses observed in CHF rats. Furthermore, PAG treatment partially reversed the alterations in HRV and SBPV in CHF rats. Our results show that PAG treatment restores breathing stability and cardiac autonomic function and reduces the enhanced ventilatory and CB chemosensory responses to hypoxia in CHF rats. These results support the idea that PAG treatment could potentially represent a novel pathway to control sympathetic outflow and breathing instability in CHF.
心血管自主失衡和呼吸不稳定是心力衰竭（CHF）进展的主要原因。已经证明颈动脉体（CB）化学感受器反射的增强有助于产生这些影响。硫化氢（H2S）最近被提出介导 CB 低氧化学感受。我们假设 H2S 合成抑制应减少 CB 化学感受器反射的激活，并改善 CHF 大鼠的呼吸稳定性和自主功能。我们使用不可逆的半胱氨酸γ-裂解酶抑制剂 dl-炔丙基甘氨酸（PAG）来测试 H2S 抑制对 CHF 大鼠静息呼吸模式、低氧和高碳酸通气反应以及 CB 化学感受器传入纤维的低氧敏感性的影响。此外，心率变异性（HRV）和收缩压变异性（SBPV）被计算为自主功能的指标。与假手术大鼠相比，CHF 大鼠表现出呼吸间隔变异性和呼吸暂停次数增加、CB 传入放电和对低氧的通气反应增强、HRV 降低以及低频 SBPV 增加。值得注意的是，PAG 治疗将呼吸暂停指数降低了 90%，呼吸间隔变异性降低了 40-60%，并逆转了 CHF 大鼠中观察到的增强的低氧 CB 传入和化学感受器反射反应。此外，PAG 治疗部分逆转了 CHF 大鼠 HRV 和 SBPV 的改变。我们的结果表明，PAG 治疗可恢复呼吸稳定性和心脏自主功能，并降低 CHF 大鼠对低氧增强的通气和 CB 化学感受反应。这些结果支持 PAG 治疗可能代表一种控制 CHF 中交感神经输出和呼吸不稳定的新途径的观点。
