Slowly inactivating potassium conductance (I(D)): a potential target for stroke therapy.
OBJECTIVE
Excessive accumulation of extracellular glutamate results in the death of most, but not all, neurons in the central nervous system. Understanding the unique properties of cells that can withstand this excitotoxic challenge may identify specific targets for novel stroke therapies.


METHODS
A combination of in vivo methods for analysis of excitotoxic cell death after activation of N-methyl-D-aspartate (NMDA) receptors and in vitro patch-clamp analysis of specific conductances in hypothalamic slices and dissociated cells has been used to assess the roles of specific potassium conductances in delayed cell death after NMDA receptor activation.


RESULTS
We report that a specific D-type potassium conductance (I(D)), necessary for the rapid repolarization of the membrane after a strong depolarization, serves such a protective purpose in magnocellular neurons of the paraventricular nucleus. Manipulations that inhibit this current (4-aminopyridine or angiotensin II) increase neuronal excitability and augment cell death after NMDA receptor activation. In addition, this protection is not observed in magnocellular neurons of spontaneously hypertensive rats, and intriguingly it can be reestablished by blocking angiotensin II receptors in these animals.


CONCLUSIONS
These observations provide a persuasive experimental explanation for the unexpected finding that therapeutic treatments for hypertension that block central as well as peripheral angiotensin type 1 receptors reduce the severity and occurrence of stroke.
Bains
J S
JS
Department of Physiology, Queen's University, Kingston, Ontario, Canada.
Follwell
M J
MJ
Latchford
K J
KJ
Anderson
J W
JW
Ferguson
A V
AV
D015761:4-Aminopyridine / Q000494:pharmacology; D000804:Angiotensin II / Q000494:pharmacology; D057911:Angiotensin Receptor Antagonists; D000818:Animals; D016923:Cell Death; D002478:Cells, Cultured; D004553:Electric Conductivity; D019706:Excitatory Postsynaptic Potentials; D006801:Humans; D007031:Hypothalamus / Q000166:cytology / Q000502:physiology*; D007700:Kinetics; D008297:Male; D016202:N-Methylaspartate / Q000633:toxicity; D009474:Neurons / Q000166:cytology / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology; D010286:Paraventricular Hypothalamic Nucleus / Q000166:cytology / Q000502:physiology; D018408:Patch-Clamp Techniques; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D015221:Potassium Channels / Q000502:physiology*; D051381:Rats; D011918:Rats, Inbred SHR; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy
D057911:Angiotensin Receptor Antagonists; D018696:Neuroprotective Agents; D026902:Potassium Channel Blockers; D015221:Potassium Channels; D000804:Angiotensin II; D016202:N-Methylaspartate; D015761:4-Aminopyridine