Brain Advance Access originally published online on May 18, 2005
Brain 2005 128(9):2042-2051; doi:10.1093/brain/awh545
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Ion changes in spreading ischaemia induce rat middle cerebral artery constriction in the absence of NO
Departments of 1 Neurology and Experimental Neurology and 2 Physiology, Charité University Medicine, Berlin, Germany
Correspondence to: Jens P. Dreier, Department of Neurology, Campus Charité Mitte, Charité University Medicine, Schumannstr. 20/21, 10117 Berlin, Germany E-mail: jens.dreier{at}charite.de
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 (cocktailSI) 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 cocktailSI 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 cocktailSI-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 cocktailSI. 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.
Key Words: subarachnoid haemorrhage; spreading depression; ion measurements; coupling; cerebral blood flow
Abbreviations: ACSF = artificial cerebrospinal fluid; ANOVA = analysis of variance; [Ca2+]o = extracellular calcium concentration; cGMP = cyclic guanosine monophosphate; [Cl–]o = extracellular chloride concentration; cocktailSI = ionic cocktail applied to the isolated middle cerebral artery in vitro matching the ionic composition of the extracellular space as measured during spreading ischaemia in vivo (cocktailSI,K3 = cocktailSI, containing 3 mM potassium; cocktailSI,K50 = cocktailSI, containing 50 mM potassium); ECS = extracellular space; [K+]ACSF = potassium concentration of the artificial cerebrospinal fluid; [K+]e = extraluminal potassium concentration at the middle cerebral artery; [K+]o = extracellular potassium concentration; L-NNA = NG-nitro-L-arginine; [Mg2+]o = extracellular magnesium concentration; MOPS = 3-(N-morpholino)propanesulphonic acid; [Na+]ACSF = sodium concentration of the artificial cerebrospinal fluid; [Na+]o = extracellular sodium concentration; NOS = nitric oxide synthase; TPA = tetrapropylammonium
Received December 23, 2004. Revised April 18, 2005. Accepted April 23, 2005.
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