Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO

Abstract

In rats, cortical spreading hyperaemia is coupled to a spreading neuroglial depolarization wave (spreading depression) under physiological conditions, whereas cortical spreading ischaemia is coupled to it if red blood cell products are present in the subarachnoid space. Spreading ischaemia has been proposed as the pathophysiological correlate of the widespread cortical infarcts abundantly found in autopsy studies of patients with subarachnoid haemorrhage. The purpose of the present study was to investigate whether the extracellular ion changes associated with the depolarization wave may cause the vasoconstriction underlying spreading ischaemia. We induced spreading ischaemia in vivo with the nitric oxide (NO) scavenger oxyhaemoglobin and an elevated K+ concentration in the subarachnoid space while slow potential, pH, extracellular volume and concentrations of K+, Na+, Ca2+ and Cl- were measured in the cortex with microelectrodes. We then extraluminally applied an ionic cocktail (cocktail(SI)) to the isolated middle cerebral artery in vitro, matching the ionic composition of the extracellular space as measured during spreading ischaemia in vivo. Extraluminal application of cocktail(SI) caused middle cerebral artery dilatation in the absence and constriction in the presence of NO synthase inhibition in vitro, corresponding with the occurrence of spreading hyperaemia in the presence and spreading ischaemia in the absence of NO in vivo. The L-type Ca2+ inhibitor nimodipine caused the cocktail(SI)-induced vasoconstriction to revert to vasodilatation in the absence of NO in vitro similar to the reversal of spreading ischaemia to spreading hyperaemia in response to nimodipine in vivo. We found that K+ was the predominant vasoconstrictor contained in cocktail(SI). Its vasoconstrictor action was augmented by NO synthase inhibition. Our results suggest that, under elevated baseline K+ as a hallmark of any condition of energy deficiency, the extracellular ion changes represent the essential mediator of the vascular response to spreading neuroglial depolarization. In the presence of NO they mediate vasodilatation and in its absence they mediate constriction.

Spreading Depolarization, A Pathophysiological Mechanism of Stroke and Migraine Aura

“…The intracellular calcium concentration simultaneously increases from approximately 25 nmol/l to 25 µmol/l which outlasts the other changes of ion homeostasis [10,11]. The extracellular pH shows an initial alkalotic shift followed by a decline to approximately 6.9 [9,12]. The ion fluxes result in a net gain of solutes by the neurons followed by water influx.…”

“…It involves massive ionic changes between the intra-and extracellular compartments [6][7][8][9]. The extracellular potassium concentration ( 2+ ] o from approximately 1.3 to 0.08 mmol/l.…”

Ca2+-activated Cl− currents are dispensable for olfaction

“…Microelectrodes connected to a differential amplifier 49 were lowered at a low angle onto the surface of freshly dissected turbinates. [Cl -] was determined from calibration curves before and after measurements.…”

New concepts regarding cerebral vasospasm: glial-centric mechanisms

“…46 Cerebral ischemia and subsequent infarction with PIDs have been proposed as the underlying mechanism of widespread cortical infarction seen diffusely at autopsy following lethal SAH. Spreading ischemia or PID can be induced in rats with a topical application of oxyhemoglobin (as a NO scavenger) in the presence of elevated potassium concentration.…”

“…The change in diameter from baseline conditions approached 50% narrowing. 46 The predominant vasoconstrictor in the cocktail was the elevated concentration of potassium. Herein lies a mechanism relating the parenchymal alterations that are seen with PID with SAH and large conducting vessel constriction.…”