A role of the sodium pump in spreading ischemia in rats

Abstract

In rats, spreading depolarization induces vasodilation/hyperemia in naïve tissue but the inverse response when artificial cerebrospinal fluid is topically applied to the brain containing (a) a nitric oxide-lowering agent and (b) elevated K þ . The inverse response is characterized by severe vasoconstriction/ischemia. The perfusion deficit runs together with the depolarization in the tissue (¼spreading ischemia). Here, we found in male Wistar rats that pre-treatment with artificial cerebrospinal fluid containing elevated K þ in vivo led to a selective decline in a 2 /a 3 Na þ /K þ -ATPase activity, determined spectrophotometrically ex vivo. Moreover, spreading ischemia, recorded with laser-Doppler flowmetry and electrocorticography, resulted from artificial cerebrospinal fluid containing a nitric oxide-lowering agent in combination with the Na þ /K þ -ATPase inhibitor ouabain at a concentration selectively inhibiting a 2 /a 3 activity. Decline in a 2 /a 3 activity results in increased Ca 2þ uptake by internal stores of astrocytes, vascular myocytes, and pericytes since Ca 2þ outflux via plasmalemmal Na þ /Ca 2þ -exchanger declines. Augmented Ca 2þ mobilization from internal stores during spreading depolarization might enhance vasoconstriction, thus, contributing to spreading ischemia. Accordingly, spreading ischemia was significantly shortened when intracellular Ca 2þ stores were emptied by pre-treatment with thapsigargin, an inhibitor of the sarco(endo)plasmic reticulum Ca 2þ -ATPase (SERCA). These findings might have relevance for clinical conditions, in which spreading ischemia occurs such as delayed cerebral ischemia after subarachnoid hemorrhage.

Molecular mechanisms of K+ clearance and extracellular space shrinkage—Glia cells as the stars

“…The key role of the Na + /K + ‐ATPase in the CNS is underscored by mice with homozygous deletion of the genes coding for α2 ( ATP1A2 ) or α3 ( ATP1A3 ) dying at birth (Ikeda et al, ; Ikeda et al, ). Reduced Na + /K + ‐ATPase activity, possibly following cerebral ischemia, leads to excitotoxicity and cortical spreading depression (Haglund & Schwartzkroin, ; Major et al, ; Reiffurth, Alam, Zahedi‐Khorasani, Major, & Dreier, ), while altered expression of the Na + /K + ‐ATPase is observed in connection with diverse disease states (Grisar, Franck, & Delgado‐Escueta, ; Guillaume, Grisar, Delgado‐Escueta, Laschet, & Bureau‐Heeren, ; Lewis, Mutsuga, Schuette, & Van Buren, ; Scarrone et al, ). Mutations in the genes encoding the α2 or α3 isoforms are associated with severe neurological conditions, each of which strictly associates with mutations in one of the isoforms (Benarroch, ; Bottger, Doganli, & Lykke‐Hartmann, ; de Vries, Frants, Ferrari, & van den Maagdenberg, ): A range of mutations in ATP1A2 gives rise to familial hemiplegic migraine type 2 (FHM2) (de Fusco et al, ); a migraine associated with hemiparesis, seizures, and epilepsy (Bottger et al, ; Pietrobon, ), whereas mutations in ATP1A3 cause alternating hemiplegia of childhood (AHC), rapid‐onset dystonia parkinsonism (RDP), or early life epilepsy (Bottger et al, ; de Carvalho et al, ; Heinzen et al, ; Sweney, Newcomb, & Swoboda, ).…”

A new direction for spreading depolarization: Investigation in the fly brain

“…For example, ouabain also induces SD in the mammalian brain. 7 Nevertheless, some may be skeptical of what the fly can really tell us about mammalian SD due to obvious CNS differences such as the presence in mammals, versus the absence in insects, of a vascular supply within neural tissue. Certainly the influence of the vasculature for providing oxygen and nutrients and for clearing metabolites, to say nothing of the release of modulators, greatly complicates the SD process in the mammalian CNS.…”

The impact of age on the elicitation of spreading depolarization and the implication of prostanoids in the associated cerebral blood flow response Hertelendy Péter

“…This progressive accumulation of extracellular K + is thought to build up due to the reduced availability of ATP, which opens ATP-sensitive K + channels to hyperpolarize neurons via K + efflux (Sun and Hu, 2010), and, more importantly, reduces the efficiency of neuronal Na + /K + -ATPase and thus K + reuptake . In addition, extracellular levels of K + typical of the ischemic penumbra were shown also to decrease Na + /K + -ATPase activity by 50% (Major et al, 2017), therefore K + itself may amplify its extracellular accumulation. The central role of Na + /K + -ATPase in SD initiation is clearly supported by the fact that tissue exposure to ouabain, a Na + /K + -ATPase inhibitor, readily produces SD (Balestrino et al, 1999).…”

“…SD is a transient eventalthough its duration depends on the actual tissue metabolic conditions. The repolarization phase of SD, or recovery of the tissue from SD is mediated by neuronal Na + /K + -ATPase to serve K + reuptake (Major et al, 2017). Importantly, surplus K + is also removed effectively by astrocytes, utilizing various mechanisms including, for instance, astrocytic Na + /K + -ATPase, and K + siphoning via Kir 4.1 inwardly rectifying K + channels or water flux mediated through aquaporin-4 channels .…”

“…The proper function of neuronal and astrocytic Na + /K + ATPase, and K + and glutamate clearance mechanisms of astrocytes significantly contribute to the cessation of SD Major et al, 2017), which is hampered in the old ischemic brain with respect to the young Menyhart et al, 2015).…”