Efficacy and mechanism of action of a calcium channel blocker after global cerebral ischemia in rats.

Abstract

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...

Protection Against Ischemia and Improvement of Cerebral Blood Flow in Genetically Hypertensive Rats by Chronic Pretreatment With an Angiotensin II AT 1 Antagonist

“…While inhibition of Ang II synthesis with captopril for 28 days protected equally against brain ischemia, pretreatment with nicardipine for 28 days did not, in agreement with reports that calcium channel blockers did not prevent cellular damage during ischemia. 23 This indicates that protection against ischemia is dependent on Ang II system inhibition 6,7,12 and not the consequence of differences in the progression of the antihypertensive effects because all compounds decreased blood pressure very early in the treatment. All prolonged antihypertensive treatments used here, including calcium channel blockade, protected from brain swelling, indicating that the mechanisms underlying brain swelling are not identical to those responsible for neuronal death and infarct size.…”

Immunohistochemical Determination of Calcium—Calmodulin Binding Predicts Neuronal Damage after Global Ischemia

“…Ischemia was produced for 30 min by a modification of the four-vessel occlusion method (Grotta et al, 1988). Animals were killed immediately after isch emia and after 2 and 24 h of reperfusion.…”

Effect of thromboxane synthase inhibition on eicosanoid levels and blood flow in ischemic rat brain.

“…14 - 16 Each rat in Subgroups Bl and B2 was anesthetized, paralyzed, and ventilated after reversal of ischemia as in Subgroups Al and A2. After 60 minutes of reperfusion, a bolus of 2.5 fid [ l4 C]butanol (specific activity 0.88 mCi/mmol; New England Nuclear, Boston, Massachusetts) was injected intravenously as arterial blood was withdrawn through PE-50 tubing into a 250-)ul Hamilton syringe using a syringe pump (Model 351, Sage Instruments, Boston, Massachusetts) set at 250 /xl/min.…”