cyclic-gmp and Status-Epilepticus

Carbon monoxide (CO) and the excitatory amino acid glutamate both dilate cerebral arterioles in newborn pigs. The key enzyme in CO synthesis is heme oxygenase, which is highly expressed in neurons with glutamatergic receptor activity as well as cerebral microvessels. During seizures the extracellular level of glutamate is increased, which results in excessive depolarization of neurons. We hypothesized that CO is a mediator of excitatory amino acid-induced dilation of the cerebral microvasculature during seizures. Three groups of piglets were examined: 1) i.v. normal saline (sham control), 2) topical chromium mesoporphyrin (Cr-MP, 15 x 10(-6) M), and 3) i.v. tin-protoporphyrin (Sn-PP, 4 mg/kg). Synthetic metalloporphyrins (Cr-MP and Sn-PP) are heme oxygenase inhibitors, thereby reducing CO synthesis. Implanted closed cranial windows were used to monitor changes in pial arteriolar diameters. Seizures were induced by administration of i.v. bicuculline. Changes in pial arteriolar diameters were monitored during 30 min of status epilepticus. The percent increase in pial arteriolar dilation in the saline group during seizures was 68 +/- 3%. In the metalloporphyrin groups, the pial arteriolar dilation was markedly reduced (35 +/- 3% and 13 +/- 1%, for Cr-MP and Sn-PP, respectively; p < 0.05, compared with the saline group). We conclude that metalloporphyrins by inhibition of heme oxygenase and prevention of CO synthesis attenuate pial arteriolar dilation during seizures. Therefore, CO appears to be involved in cerebral vasodilation caused by glutamatergic seizures.

Topics: Animals; Animals, Newborn; Arterioles; Bicuculline; Carbon Monoxide; Cerebral Arteries; Cerebrovascular Circulation; Convulsants; Cyclic AMP; Cyclic GMP; Enzyme Inhibitors; GABA Antagonists; Glutamates; Heme; Heme Oxygenase (Decyclizing); Membrane Potentials; Mesoporphyrins; Metalloporphyrins; Nerve Tissue Proteins; Neurons; Pia Mater; Protoporphyrins; Seizures; Status Epilepticus; Swine; Vasodilation

Status epilepticus was produced in rats by administering pilocarpine (30 mg/kg, s.c.) 16 h after treatment with LiCl (3 meq/kg, i.p.). After 35 min of status epilepticus, several parameters of cholinergic activity were measured. Seizures had no effect on the in vivo concentration of acetylcholine or choline in cerebellum, cortex, hippocampus, or striatum. Synaptosomal high-affinity choline transport was also not changed by seizures in hippocampus, cortex, or striatum. Cortical slices from seizing rats had elevated concentrations of acetylcholine and released acetylcholine at a greater rate than did controls, but these effects seemed to be due to a reduction in the postmortem hydrolysis of acetylcholine. Synaptosomal 45calcium uptake during 2 to 60 s of incubation was no different from control rates in tissue prepared from seizing rats. These results indicate that presynaptic cholinergic activity is not markedly altered by 35 min of continuous seizure activity induced by lithium and pilocarpine. In contrast, the in vivo concentration of cyclic guanosine 5'-monophosphate was elevated above control values in seizing rats by 57 to 170% in cerebellum, cortex, hippocampus, and striatum.

Topics: Acetylcholine; Animals; Brain; Choline; Cyclic GMP; Decerebrate State; Drug Combinations; Lithium; Male; Nervous System; Osmolar Concentration; Pilocarpine; Rats; Rats, Inbred Strains; Status Epilepticus; Tissue Distribution