The cerebral microcirculation undergoes dynamic changes regarding neurovascular responses through the perinatal period. CO2 is one of the most potent regulator of cerebral blood flow, however its effector mechanisms involve multiple possibly yet unknown pathways in the neonate. Acid-sensing ion channel-1A (ASIC1A) appears to play a decisive role in this cerebrovascular response in adult mice, however, cortical ASIC1A expression and its possible contribution to the response in the translational piglet model of term neonates is unknown. Therefore, we investigated neocortical ASIC1A expression and the effect of the specific ASIC1A-inhibitor psalmotoxin-1 on the neurovascular response to graded hypercapnia in piglets. Anesthetized, mechanically ventilated newborn pigs were equipped with a closed or open cranial window to assess the cortical blood flow (CoBF) with laser speckle contrast imaging or the neuronal activity with multichannel electrodes, respectively. Graded hypercapnia was elicited by ventilation of 5%–10% CO2. ASIC1A was found to be ubiquitously expressed in neocortical neurons. Psalmotoxin-1 while unaffected the CoBF response to 5% CO2, it significantly attenuated further increases in CoBF to 10% CO2, accompanying the highly altered hypercapnia-induced changes in neuronal activity. We conclude that ASIC1A activation by hypercapnia-induced acidosis is partially responsible for the neurovascular response in the neonatal brain.
IadecolaCZhangF.Nitric oxide-dependent and -independent components of cerebrovasodilation elicited by hypercapnia. Am J Physiol Regul Integr Comp Physiol1994; 266(2): R546–52.
2.
FaraciFMBreeseKRHeistadDD.Cerebral vasodilation during hypercapnia: role of glibenclamide-sensitive potassium channels and nitric oxide. Stroke1994; 25(8): 1679–1683.
3.
BrianJE.Carbon dioxide and the cerebral circulation. Anesthesiology1998; 88: 1365–1386.
4.
AttwellDBuchanAMCharpakS, et al. Glial and neuronal control of brain blood flow. Nature2010; 468(7321): 232–243.
5.
HottaHMasamotoKUchidaS, et al. Layer-specific dilation of penetrating arteries induced by stimulation of the nucleus basalis of Meynert in the mouse frontal cortex. J Cereb Blood Flow Metab2013; 33(9): 1440–1447.
6.
KoehlerRC.Regulation of the cerebral circulation during development. Compr Physiol2021; 11(4): 2371–2432.
7.
HansenNBBrubakkAMBratlidD, et al. The effects of variations in Paco2 on brain blood flow and cardiac output in the newborn piglet. Pediatr Res1984; 18(11): 1132–1135.
8.
MooreLEKirschJRHelfaerMA, et al. Hypercapnic blood flow reactivity not increased by α-blockade or cordotomy in piglets. Am J Physiol1992; 262(6 Pt 2): H1884–H1890.
9.
BauerRBergmannRWalterB, et al. Regional distribution of cerebral blood volume and cerebral blood flow in newborn piglets - effect of hypoxia/hypercapnia. Develop Brain Res1999; 112(1): 89–98.
10.
PiccirilliEChiarelliAMSestieriC, et al. Cerebral blood flow patterns in preterm and term neonates assessed with pseudo-continuous arterial spin labeling perfusion MRI. Human Brain Mapp2023; 44(9): 3833–3844.
11.
WagerleLCMishraOP.Mechanism of CO2 response in cerebral arteries of the newborn pig: role of phospholipase, cyclooxygenase, and lipoxygenase pathways. Circ Res1988; 62(5): 1019–1026.
12.
BusijaDWLefflerCW.Dilator effects of amino acid neurotransmitters on piglet pial arterioles. Am J Physiol1989; 257(4): H1200–H1203.
13.
BusijaDWWeiM.Altered cerebrovascular responsiveness to N-methyl-D-aspartate after asphyxia in piglets. Am J Physiol1993; 265(1 Pt 2): H389–H394.
14.
DomokiFNagyKTemesváriP, et al. Selective inhibitors differentially affect cyclooxygenase-dependent pial arteriolar responses in newborn pigs. Pediatr Res2005; 57(6): 853–857.
15.
HoltDCFedinecALVaughnAN, et al. Age and species dependence of pial arteriolar responses to topical carbon monoxide in vivo. Exp Biol Med (Maywood)2007; 232(11): 1465–1469.
16.
LefflerCWParfenovaHJaggarJH.Carbon monoxide as an endogenous vascular modulator. Am J Physiol2011; 301(1): H1–H11.
17.
WillisAPLefflerCW.Endothelial NO and prostanoid involvement in newborn and juvenile pig pial arteriolar vasomotor responses. Am J Physiol Heart Circ Physiol2001; 281(6): H2366–H2377.
18.
RemzsőGNémethJTóth-SzűkiV, et al. NMDA attenuates the neurovascular response to hypercapnia in the neonatal cerebral cortex. Sci Rep2019; 9(1): 1–13.
19.
SimandleSAKerrBALaczaZ, et al. Piglet pial arteries respond to N-methyl-D-aspartate in vivo but not in vitro. Microvasc Res2005; 70(1–2): 76–83.
20.
FaraciFMBreeseKR.Nitric oxide mediates vasodilatation in response to activation of N- methyl-D-aspartate receptors in brain. Circ Res1993; 72(2): 476–480.
21.
FaraciFMTaugherRJLynchC, et al. Acid-sensing ion channels: novel mediators of cerebral vascular responses. Circ Res2019; 125(10): 907–920.
22.
DomokiFZolei-SzenasiDOlahO, et al. Comparison of cerebrocortical microvascular effects of different hypoxic-ischemic insults in piglets: a laser-speckle imaging study. J Physiol Pharmacol2014; 65(4): 551–558.
23.
KovácsVRemzsőGTóth-SzűkiV, et al. Inhaled H2 or CO2 do not augment the neuroprotective effect of therapeutic hypothermia in a severe neonatal hypoxic-ischemic encephalopathy piglet model. Int J Mol Sci2020; 21(18): 1–22.
24.
YangZJNiXCarterEL, et al. Neuroprotective effect of acid-sensing ion channel inhibitor psalmotoxin-1 after hypoxia-ischemia in newborn piglet striatum. Neurobiol Dis2011; 43(2): 446–454.
25.
KellenbergerSSchildL. International union of basic and clinical pharmacology. XCI. structure, function, and pharmacology of acid-sensing ion channels and the epithelial Na+ channel. Pharmacol Rev2015; 67(1): 1–35.
26.
DomokiFZöleiDOláhO, et al. Evaluation of laser-speckle contrast image analysis techniques in the cortical microcirculation of piglets. Microvasc Res2012; 83(3): 311–317.
27.
KadirSNGoodmanDFMHarrisKD.High-dimensional cluster analysis with the masked EM algorithm. Neural Comput2014; 26: 2379–2394.
28.
LivakKJSchmittgenTD.Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods2001; 25(4): 402–408.
29.
NemethJToth-SzukiVVargaV, et al. Molecular hydrogen affords neuroprotection in a translational piglet model of hypoxic-ischemic encephalopathy. J Physiol Pharmacol2016; 67(5): 677–689.
30.
BabiniEPaukertMGeislerHS, et al. Alternative splicing and interaction with di- and polyvalent cations control the dynamic range of acid-sensing ion channel 1 (ASIC1). J Biol Chem2002; 277(44): 41597–41603.
31.
VulloSKellenbergerS.A molecular view of the function and pharmacology of acid-sensing ion channels. Pharmacol Res2020; 154: 104166.
32.
ChenXKalbacherHGründerS.The tarantula toxin psalmotoxin 1 inhibits acid-sensing ion channel (ASIC) 1a by increasing its apparent H+ affinity. J Gen Physiol2005; 126(1): 71–79.
33.
GründerSChenX.Structure, function, and pharmacology of acid-sensing ion channels (ASICs): focus on ASIC1a. Int J Physiol Pathophysiol Pharmacol2010; 2(2): 73–94.
34.
WaldmannRChampignyGBassilanaF, et al. A proton-gated cation channel involved in acid-sensing. Nature1997; 386: 173–177.
35.
SherwoodTWFreyENAskwithCC.Structure and activity of the acid-sensing ion channels. Am J Physiol Cell Physiol2012; 303(7): C699–C710.
36.
WemmieJAPriceMPWelshMJ.Acid-sensing ion channels: advances, questions and therapeutic opportunities. Trends Neurosci2006; 29(10): 578–586.
37.
XiongZGPignataroGLiM, et al. Acid-Sensing Ion Channels (ASICs) as pharmacological targets for neurodegenerative diseases. Curr Opin Pharmacol2008; 8(1): 25–32.
38.
PignataroGSimonRPXiongZG.Prolonged activation of ASIC1a and the time window for neuroprotection in cerebral ischaemia. Brain2007; 130(1): 151–158.
39.
Alvarez de la RosaDKruegerSRKolarA, et al. Distribution, subcellular localization and ontogeny of ASIC1 in the mammalian central nervous system. J Physiol2003; 546(1): 77–87.
40.
LinLHJinJNashelskyMB, et al. Acid-sensing ion channel 1 and nitric oxide synthase are in adjacent layers in the wall of rat and human cerebral arteries. J Chem Neuroanat2014; 61–62: 161–168.
41.
YangACVestRTKernF, et al. A human brain vascular atlas reveals diverse mediators of Alzheimer’s risk. Nature2022; 603(7903): 885–892.
42.
WeiEPKontosHAPattersonJL.Dependence of pial arteriolar response to hypercapnia on vessel size. Am J Physiol1980; 238(5): 697–703.
43.
RemzsőGNémethJVargaV, et al. Brain interstitial pH changes in the subacute phase of hypoxic-ischemic encephalopathy in newborn pigs. PLoS One2020; 15(5): e0233851.
44.
ZhangZChenMZhanW, et al. Acid-sensing ion channel 1a modulation of apoptosis in acidosis-related diseases: implications for therapeutic intervention. Cell Death Discov2023; 9(1): 330.
45.
WemmieJAChenJAskwithCC, et al. The acid-activated ion channel ASIC contributes to synaptic plasticity, learning, and memory. Neuron2002; 34(3): 463–477.
46.
Alonso-AlconadaDChillidaMCatalanA, et al. Sex dimorphism in brain cell death after hypoxia-ischemia in newborn piglets. Pediatr Res2025; 98(3): 1120–1127.
47.
LefflerCWBusijaDWArmsteadWM, et al. Ischemia alters cerebral vascular responses to hypercapnia and acetylcholine in piglets. Pediatr Res1989; 25(2): 180–183.
48.
DomokiFKisBNagyK, et al. Diazoxide preserves hypercapnia-induced arteriolar vasodilation after global cerebral ischemia in piglets. Am J Physiol Heart Circ Physiol2005; 289(1): H368–H373.
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