Background: The beneficial effects of parasympathetic stimulation have been reported in left heart failure, but whether it would be beneficial for pulmonary arterial hypertension (PAH) remains to be explored. Here, we investigated the relationship between parasympathetic activity and right ventricular (RV) function in patients with PAH, and the potential therapeutic effects of pyridostigmine (PYR), an oral drug stimulating the parasympathetic activity through acetylcholinesterase inhibition, in experimental pulmonary hypertension (PH).

Methods: Heart rate recovery after a maximal cardiopulmonary exercise test was used as a surrogate for parasympathetic activity. RV ejection fraction was assessed in 112 patients with PAH. Expression of nicotinic (α-7 nicotinic acetylcholine receptor) and muscarinic (muscarinic acetylcholine type 2 receptor) receptors, and acetylcholinesterase activity were evaluated in RV (n=11) and lungs (n=7) from patients with PAH undergoing heart/lung transplantation and compared with tissue obtained from controls. In addition, we investigated the effects of PYR (40 mg/kg per day) in experimental PH. PH was induced in male rats by SU5416 (25 mg/kg subcutaneously) injection followed by 4 weeks of hypoxia. In a subgroup, sympathetic/parasympathetic modulation was assessed by power spectral analysis. At week 6, PH status was confirmed by echocardiography, and rats were randomly assigned to vehicle or treatment (both n=12). At the end of the study, echocardiography was repeated, with additional RV pressure-volume measurements, along with lung, RV histological, and protein analyses.

Results: Patients with PAH with lower RV ejection fraction (<41%) had a significantly reduced heart rate recovery in comparison with patients with higher RV ejection fraction. In PAH RV samples, α-7 nicotinic acetylcholine receptor was increased and acetylcholinesterase activity was reduced versus controls. No difference in muscarinic acetylcholine type 2 receptor expression was observed. Chronic PYR treatment in PH rats normalized the cardiovascular autonomic function, demonstrated by an increase in parasympathetic activity and baroreflex sensitivity. PYR improved survival, increased RV contractility, and reduced RV stiffness, RV hypertrophy, RV fibrosis, RV inflammation, and RV α-7 nicotinic acetylcholine receptor and muscarinic acetylcholine type 2 receptor expression, as well. Furthermore, PYR reduced pulmonary vascular resistance, RV afterload, and pulmonary vascular remodeling, which was associated with reduced local and systemic inflammation.

Conclusions: RV dysfunction is associated with reduced systemic parasympathetic activity in patients with PAH, with an inadequate adaptive response of the cholinergic system in the RV. Enhancing parasympathetic activity by PYR improved survival, RV function, and pulmonary vascular remodeling in experimental PH.

背景：副交感神经刺激对左心衰竭的有益作用已有报道，但是否会有益于肺动脉高压（PAH）尚待探讨。在这里，我们研究了PAH患者副交感神经活性与右心室（RV）功能之间的关系，以及吡ido斯的明（PYR）（一种通过乙酰胆碱酯酶抑制刺激副交感神经活性的口服药物）在实验性肺动脉高压（PH）中的潜在治疗作用。 。

方法：经过最大程度的心肺运动试验后的心率恢复被用作副交感神经活动的替代指标。在112例PAH患者中评估了RV射血分数。在接受心脏/肺移植的PAH患者的RV（n = 11）和肺（n = 7）中评估了烟碱（α-7烟碱乙酰胆碱受体）和毒蕈碱（毒蕈碱型乙酰胆碱2型受体）受体的表达以及乙酰胆碱酯酶活性并与从对照组获得的组织进行比较。此外，我们研究了PYR（每天40 mg / kg）在实验性PH中的作用。通过SU5416（皮下注射25 mg / kg）注射，然后缺氧4周，在雄性大鼠中诱发PH。在一个亚组中，通过功率谱分析评估了交感/副交感调制。在第6周，通过超声心动图检查确认了PH状态，然后将大鼠随机分配至媒介物或治疗组（均n = 12）。在研究结束时，重复进行超声心动图检查，并进行额外的RV压力体积测量以及肺，RV的组织学和蛋白质分析。

结果：与RV射血分数较高的患者相比，RV射血分数较低（<41％）的PAH患者的心率恢复显着降低。在PAH RV样品中，与对照组相比，α-7烟碱型乙酰胆碱受体增加，乙酰胆碱酯酶活性降低。没有观察到毒蕈碱型2型乙酰胆碱受体表达的差异。PH大鼠的慢性PYR治疗使心血管自主功能正常化，这由副交感神经活性和压力反射敏感性的增加证明。PYR改善了生存率，增加了RV收缩力，并降低了RV刚度，RV肥大，RV纤维化，RV炎症以及RVα-7烟碱型乙酰胆碱受体和毒蕈碱型2型乙酰胆碱受体的表达。此外，PYR降低了肺血管阻力，RV后负荷，

结论： RV功能障碍与PAH患者的全身副交感神经活动减少有关，并且对RV胆碱能系统的适应性反应不足。通过PYR增强副交感神经活动可改善实验PH的生存率，RV功能和肺血管重构。