Blockade of central histaminergic H2 receptors aggravates ischemic neuronal damage in gerbil hippocampus.
OBJECTIVE
Histaminergic H2 antagonists have been reported to provoke central nervous system dysfunction in humans. They also aggravate ischemic neuronal damage in experimental animals. Because energy failure and glutamate release are crucial factors in ischemic neuronal damage, the effects of ranitidine on energy state and the extracellular concentration of glutamate were investigated in gerbil brain.


METHODS
Prospective, randomized, controlled animal study.


METHODS
University animal laboratory.


METHODS
Male Mongolian gerbils.


METHODS
The changes in the direct-current potential shift in the hippocampal CA1 area produced by transient forebrain ischemia for 2.5 mins were compared in gerbils pretreated with saline or ranitidine (10 nmol) intracerebroventricularly. The histologic outcome was evaluated 7 days after ischemia by observing the delayed neuronal death in these animals. In a second study, brain concentrations of adenosine 5'-triphosphate after various durations of decapitation ischemia were determined, and the effect of ranitidine was evaluated. In a third experiment, changes in the extracellular concentrations of excitatory amino acids during forebrain ischemia were examined by a microdialysis procedure.


RESULTS
The forebrain ischemia produced a sudden shift in the membrane potential 62 +/- 5 secs (mean +/- sd, n = 6) after the start of ischemia. The preischemic administration of ranitidine facilitated onset of depolarization (38 +/- 8 secs; p <.01). The histologic outcome was aggravated by ranitidine (p <.01). Decapitation ischemia reduced brain adenosine 5'-triphosphate concentration rapidly. Ranitidine facilitated the ischemic reduction in adenosine 5'-triphosphate, and the value after 1 min was 55% of that in the corresponding saline group (p <.01). Ranitidine enhanced the ischemic increase in the glutamate concentration, and the peak value in the ranitidine group was 316% of that in the saline group (p <.05).


CONCLUSIONS
The deleterious effect of ranitidine on ischemic neuronal damage may involve the increase in the extracellular concentration of glutamate and facilitation of energy depletion in an anaerobic state.
Adachi
N
N
Department of Anesthesiology and Resuscitology, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-0295, Japan.
Seyfried
F J
FJ
Arai
T
T
D000227:Adenine Nucleotides / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000704:Analysis of Variance; D000818:Animals; D002545:Brain Ischemia / Q000473:pathology* / Q000503:physiopathology; D002118:Calcium / Q000502:physiology; D016923:Cell Death / Q000187:drug effects; D019706:Excitatory Postsynaptic Potentials / Q000502:physiology; D005849:Gerbillinae; D006624:Hippocampus / Q000473:pathology* / Q000503:physiopathology; D006635:Histamine H2 Antagonists / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D011446:Prospective Studies; D011899:Ranitidine / Q000494:pharmacology*; D018709:Statistics, Nonparametric
D000227:Adenine Nucleotides; D000596:Amino Acids; D006635:Histamine H2 Antagonists; D011899:Ranitidine; D002118:Calcium