Summary: Changes in extracellular ion activities were measured during par tial ischaemia of the cerebral cortex of primates anaesthetised with a chloralose. Triple-barrelled, double-ion-sensitive microelectrodes were used to measure the extracellular potassium (K,.) and calcium (Ca,.) activity at the same point simultaneously. The ion changes were related to local cerebral blood flow, and it was shown that at a blood flow of approximately 10 ml 100 g-l min-I, there is a threshold below which ion homeostasis is disturbed. This is associated with a dramatic rise in Kl' and fall in Cae. Cae falls from a normal value of 1.31 ± 0.1 mM to approximately 0.28 mM in densely ischaemic tissue. In ischaemia, Kl' reaches 13.4 ± 3.8 mM before C� begins to fall. The faIl in Cae, although related to reduced blood flow, is closely associated with and follows the rise in Ke. The change in Cal' is probably due to an increase in membrane permeability, as a result of either depolarisation or a critical lower ing of cellular energy reserves.
SUMMARY The effects of a calcium antagonist, nimodipine, were tested on the response of the cerebral circulation to arterial pC0 2 and blood pressure changes. The effects of reduced blood flow upon oedema formation and extracellular ion homeostasis under nimodipine preloading were studied. Both open and closed skull primate models were used, with alpha-chloralose anaesthesia. Nimodipine infusion increased basal blood flow in the open skull, but not the closed skull animals. Autoregulation to increased blood pressure was little affected. Responses to arterial pC0 2 changes and autoregulation to reduced blood pressure were severely impaired. Residual blood flow after middle cerebral artery occlusion was significantly higher with nimodipine than in controls. The threshold levels of blood flow for the development of cortical oedema and for disturbance of ion homeostasis were, however, increased, suggesting that nimodipine interferes with cellular energy metabolism and increases the susceptibility of tissue to ischaemic damage. Stroke, Vol 13, No 6, 1982 THERE HAS BEEN CONSIDERABLE RECENT DISCUSSION on the mechanism of cell injury in ischaemia, much of which has centred on the role of calcium. 1,2 The hypotheses put forward propose that increased intracellular calcium activity exerts its pathological effects not only by the physical effects of mitochondrial calcium accumulation, 3 but also through stimulation of membrane phospholipid breakdown. 1,2A possible basis for the suggestion that calcium plays a major role in the pathophysiology of ischaemia was provided by Schanne,4 who showed that a range of membrane-active toxins only caused toxic cell death in the presence of normal extracellular calcium activity. When the extracellular calcium activity was reduced to that of normal intracellular activity, the toxins had little effect.Calcium antagonists 5 are supposed to block calcium entry into cells under certain conditions. Their use appeared to be the obvious means to test whether an influx of calcium into the cells is involved in the pathophysiology of ischaemia. Fleckenstein 5 described the action of calcium antagonists as a selective inhibition of the influx of calcium into the cell, by blockade of the so-called slow channels of the cell membrane. Other workers, using a variety of compounds and preparations, have confirmed Fleckenstein's proposal. protect the myocardium from the effects of ischaemia," -15 although the mechanisms of this protection are unclear. Nimodipine has been shown 16 to be one of the most potent calcium antagonists with a selective action on the intracranial vessels. Kazda et al. 16 have shown that nimodipine improves the post-ischaemically impaired flow in cats following 7 minutes total ischaemia, and the same group 17 have shown increased survival rates and functional protection in the same preparation.The present study was designed to test the effects of nimodipine on cerebrovascular physiological responses and on the pathophysiological effects of acute middle cerebral artery occlu...
The effect of indomethacin (3mg/kg IA) preloading on the pathophysiology of a model of acute cerebral ischaemia has been tested. Primates anaesthetised with alpha-chloralose were used. Indomethacin reduced basal blood flow by 39% and reduced CO2 reactivity by 71%. Water content changes of the cerebral cortex and relationships between blood flow and extracellular potassium (Ke), and calcium (Cae) activities have been measured. Indomethacin infusion did not effect the water content of the left side but there was more water in all regions of the right hemisphere which were rendered ischaemic. There water increases were significant for blood flows greater than 5ml/100g/min in exposed areas. There was a significant increase in the flow thresholds for change in Ke and Cae. Possible mechanisms for these changes have been discussed.
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