The purpose of this lecture is to introduce the results of researches concerning the pathophysiology of ischemic cerebrovascular disease (CVD) in my department and to consider its clinical application.
We found that gradual activation of voltage-sensitive Ca channel activity, a sensitive indicator of brain ischemia, occurs when CBF is reduced to 50%. This indicates the brain is more vulnerable to ischemia than had previously been believed.
Fig. 1 is a schema showing the release of glutamate, Ca influx, activation of NOS, etc. on ischemia. Administration of an N-type Ca channel blocker or K channel opener could decrease the concentration of glutamate and reduce the infarct volume produced by MCA occlusion in rats. We estimated NOS activity during brain ischemia by measuring nitrotyrosine, which is a footprint of peroxynitrite. nNOS was active in the early phase of ischemia and iNOS became predominant in the later phase of the acute stage of ischemia. Aminoguanidine, a relatively selective iNOS inhibitor, could reduce infarct volume if administered 12 hours after MCA ligation in rats. Cytoxic edema is an other important issue in ischemia. An NOS inhibitor, as well as L-type Ca channel blockers, could delay the shift of water from extra- to intracellular space. Increase in blood viscosity produced by increase in Ht, decrease in RBC deformability, accelerated RBC aggregation time and increase in plasma viscosity, as well as accelerated platelet aggregation, are important factors causing secondary circulatory disturbance after ischemia or inducing reattack.
The results are summarized in Fig. 11, and Fig. 10 shows various types of neuronal death after ischemia.
Because of the diversity in the pathophysiology, effective treatment may require a cocktail of drugs, but so far we have no idea what would be the best cocktail.
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