Inocencio Ishmael Miguel, Kaur Navneet, Tran Nhi T, Wong Flora Y
The Ritchie Centre, The Hudson Institute of Medical Research, Melbourne, VIC, Australia.
Department of Paediatrics, Monash University, Melbourne, VIC, Australia.
Front Physiol. 2023 Jan 25;14:1101647. doi: 10.3389/fphys.2023.1101647. eCollection 2023.
Neurovascular coupling (NVC) leads to an increase in local cerebral blood flow and oxygenation in response to increased neural activity and metabolic demand. Impaired or immature NVC reported in the preterm brain, potentially reduces cerebral oxygenation following increased neural activity, predisposing to cerebral tissue hypoxia. Endogenous nitric oxide (NO) is a potent vasodilator and a major mediator of NVC and the cerebral haemodynamic response. NO modulators, such as inhaled nitric oxide (iNO) and sildenafil, induce vasodilation and are used clinically to treat pulmonary hypertension in preterm neonates. However, their impact on NVC in the preterm brain are unknown. We aimed to characterise the cerebral functional haemodynamic response in the preterm brain exposed to NO modulators. We hypothesized that iNO and sildenafil in clinical dosages would increase the baseline cerebral perfusion and the cerebral haemodynamic response to neural activation. Preterm lambs (126-7 days' gestation) were delivered and mechanically ventilated. The cerebral functional haemodynamic response was measured using near infrared spectroscopy as changes in cerebral oxy- and deoxyhaemoglobin (ΔoxyHb, ΔdeoxyHb), following left median nerve stimulations of 1.8, 4.8, and 7.8 s durations in control preterm lambs ( = 11), and following 4.8 and 7.8 s stimulations in preterm lambs receiving either sildenafil citrate ( = 6, 1.33 mcg/kg/hr) or iNO ( = 8, 20 ppm). Following 1.8, 4.8, and 7.8 s stimulations, ∆oxyHb in the contralateral cortex increased (positive functional response) in 7/11 (64%), 7/11 (64%), and 4/11 (36%) control lambs respectively ( < 0.05). Remaining lambs showed decreased ΔoxyHb (negative functional response). Following 4.8 s stimulations, more lambs receiving sildenafil or iNO (83% and 100% respectively) showed positive functional response compared to the controls ( < 0.05). No significant difference between the three groups was observed at 7.8 s stimulations. In the preterm brain, prolonged somatosensory stimulations increased the incidence of negative functional responses with decreased cerebral oxygenation, suggesting that cerebral oxygen delivery may not match the oxygen demand. Sildenafil and iNO increased the incidence of positive functional responses, potentially enhancing NVC, and cerebral oxygenation.
神经血管耦合（NVC）会导致局部脑血流量和氧合增加，以响应神经活动增加和代谢需求。据报道，早产儿脑内的NVC受损或不成熟，这可能会在神经活动增加后降低脑氧合，从而使脑组织易发生缺氧。内源性一氧化氮（NO）是一种强效血管舒张剂，也是NVC和脑血流动力学反应的主要介质。NO调节剂，如吸入一氧化氮（iNO）和西地那非，可诱导血管舒张，并在临床上用于治疗早产儿的肺动脉高压。然而，它们对早产儿脑内NVC的影响尚不清楚。我们旨在描述暴露于NO调节剂的早产儿脑内的功能性脑血流动力学反应。我们假设临床剂量的iNO和西地那非会增加基线脑灌注以及对神经激活的脑血流动力学反应。早产羔羊（妊娠126 - 7天）出生后进行机械通气。在对照早产羔羊（n = 11）中，通过对左侧正中神经进行1.8、4.8和7.8秒时长的刺激，以及在接受枸橼酸西地那非（n = 6，1.33微克/千克/小时）或iNO（n = 8，20 ppm）的早产羔羊中进行4.8和7.8秒刺激后，使用近红外光谱测量脑功能性血流动力学反应，以脑氧合血红蛋白和脱氧血红蛋白的变化（Δ氧合血红蛋白，Δ脱氧血红蛋白）来表示。在1.8、4.8和7.8秒刺激后，对侧皮质中的Δ氧合血红蛋白在对照羔羊中分别有7/11（64%）、7/11（64%）和4/11（36%）增加（正向功能反应）（P < 0.05）。其余羔羊显示Δ氧合血红蛋白降低（负向功能反应）。在4.8秒刺激后，与对照组相比，接受西地那非或iNO的羔羊中更多（分别为83%和100%）显示出正向功能反应（P < 0.05）。在7.8秒刺激时，三组之间未观察到显著差异。在早产儿脑中，延长的体感刺激增加了负向功能反应的发生率，同时脑氧合降低，这表明脑氧输送可能无法满足氧需求。西地那非和iNO增加了正向功能反应的发生率，可能增强了NVC和脑氧合。
