Nicardipine and MK-801 attenuate platelet-activating factor increases following cerebral ischemia-reperfusion in...

The effects of pretreatment with nicardipine (dihydropyridine Ca2+ channel antagonist), Bay K8644 (dihydropyridine Ca2+ channel agonist), and MK-801 (N-methyl-D-aspartate-receptor antagonist) on changes of platelet-activating factor (PAF) concentrations in transient ischemic brain are reported. The tissue concentration of PAF increases significantly in hippocampus, cortex and thalamus by 210%, 169% and 168% of controls without ischemia-reperfusion, respectively after 1 h of reperfusion. Nicardipine (5 mg/kg) reduces the accumulation of PAF, the remaining increases in hippocampus, cortex and thalamus being 151%, 138% and 145% of the controls, respectively. In contrast, Bay K8644 (2.5 mg/kg) enhances the accumulation of PAF, its concentrations in hippocampus, cortex and thalamus being 376%, 233% and 204% of the controls, respectively. The Bay K8644 enhancement in hippocampus is completely inhibited by pretreatment of nicardipine (5 mg/kg). MK-801 (10 mg/kg) reduces the accumulation of PAF, the remaining increases in hippocampus, cortex and thalamus being 152%, 147% and 144% of the controls, respectively. Moreover, brain tissue from animals subjected to the combined pretreatment with nicardipine (5 mg/kg) and MK-301 (10 mg/kg) indicates there is greater inhibition of ischemia-induced PAF increases than with either drug alone. These results indicate that PAF production in the ischemic brain may be regulated by Ca2+ influx through voltage-sensitive Ca2+ channels which are antagonized and agonized by nicardipine and Bay K8644, respectively and receptor-operated Ca2+ channels which are antagonized by MK-801. Because it is known that increases of intracellular Ca2+ in the brain accompany ischemia and early periods of reperfusion and that PAF exhibits neurotoxicity, the present findings support the role of PAF as a mediator in ischemia-induced brain damage at early stages of reperfusion.