Dihydropyridine calcium channel blockers such as nicardipine are under evaluation for treating acute cerebral ischemia because they may increase cerebral blood flow by causing vasodilation and because they may be cytoprotective in part by limiting production of arachidonic acid metabolites. We demonstrated in a previous study that nicardipine improves postischemic neuronal function, as measured by somatosensory evoked potentials, without reducing the extent of light-microscopic CA-1 hippocampal histologk damage. To characterize further the effect of nicardipine on global ischemic injury, we administered the drug beginning 24 hours before 30 minutes of four-vessel ischemia in Wistar rats. We then measured hippocampal ATP, phosphocreatine, and glucose contents immediately and 2 hours after ischemia, and measured learning ability (working and reference errors) on an eight-arm radial maze beginning 30 days after ischemia. To gain insight into the possible mechanism of action, we measured production of arachidonic acid metabolites (eicosanoids: TXB 2 and 6-keto-PGF la ) and hemispheric and hippocampal cerebral blood flow by the [ 19 Nevertheless, the rationale behind their use and experimental results to date have been sufficiently encouraging that therapeutic trials in human stroke patients are underway. 20Our previous work has demonstrated that nicardipine (NC), a dihydropyridine calcium channel blocker, administered either before or immediately after ischemia improves outcome as measured by somatosensory evoked potentials (SEPs) but will not reduce the extent of histologic damage.1 Furthermore, we have demonstrated NC uptake into normal and ischemic brain, suggesting that biologically active quantities of the drug are available to neuronal dihydropyridine receptors. Presented in part at the Twelfth International Joint Conference on Stroke and Cerebral Circulation, Tampa, Florida, February 26-28, 1987, and the Thirteenth International Symposium on Cerebral Blood Flow and Metabolism, Montreal, Canada, June 24, 1987. Supported by grants from the Cullen Trust for health care and the Texas Affiliate of the American Heart Association.Address for correspondence: James C. Grotta, MD, The University of Texas Health Science Center at Houston, Department of Neurology -7.044, PO Box 20708, Houston, TX 77030. Received March 20, 1987; accepted December 10, 1987. There are two proposed mechanisms by which calcium channel blockers might ameliorate the effect of cerebral ischemia: relaxation of vascular smooth muscle, resulting in vasodilation and improved cerebral perfusion; and prevention of calcium flux into neurons, thereby limiting activation of phospholipases, proteases, and consequent membrane and protein degradation and production of damaging metabolic by-products such as free radicals. " 31Although data are conflicting, there is a consensus that dihydropyridines increase cerebral blood flow (CBF) after ischemia in animals and humans. 1 -9 " 12 Our previous studies indirectly suggest that NC is also effective b...

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The selective vulnerability of pyramidal neurons in the CA1 hippocampal region in ischemic rat brain may be preceded by regional alterations of energy metabolism during early reperfusion. We measured ATP, phosphocreatine (PCr), and glucose in paramedian and lateral CA1 and in an area showing little postischemic cell loss, CA2. ATP levels in paramedian CA1 were depressed immediately after 30 min of ischemia (P less than or equal to 0.02) and remained abnormal after 2 hr of reperfusion (P less than or equal to 0.05). PCr was reduced substantially in both subdivisions of CA1 immediately after ischemia (P less than or equal to 0.04) but returned to normal levels after 2 hr. Glucose levels were depressed in paramedian CA1 and CA2 after ischemia (P less than or equal to 0.02) but corrected with reperfusion. We determined approximately P, the sum of ATP and PCr, in separate experiments investigating regional differences in consumption of high-energy phosphate metabolites during complete ischemia. The approximately P levels of rats subjected to 30 min of reversible ischemia followed by 2 hr of reperfusion showed a different pattern of regional differences from those seen in sham-ischemic animals (P less than or equal to 0.01), indicating a persistent depression of metabolic rate in CA1 during reperfusion. We conclude that regional depletion of high-energy phosphates and alteration of metabolic rate may contribute to the selective vulnerability of the CA1 region during brain ischemia.